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Diabetes Ther
Diabetes Ther
Diabetes Therapy
1869-6953
1869-6961
Springer Healthcare Cheshire

39153153
1640
10.1007/s13300-024-01640-4
Original Research
The Association of HbA1c Variability with 12 Week and 12 Month Outcomes on Diabetes Related Foot Ulcer Healing
Thomason Georgia 1
Gooday Catherine 2
Nunney Ian 1
http://orcid.org/0000-0003-3619-9579
Dhatariya Ketan Ketan.dhatariya@nnuh.nhs.uk

12
1 https://ror.org/026k5mg93 grid.8273.e 0000 0001 1092 7967 Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ UK
2 https://ror.org/01wspv808 grid.240367.4 0000 0004 0445 7876 Diabetic Foot Clinic, Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, NR4 7UY UK
17 8 2024
17 8 2024
10 2024
15 10 22232232
15 7 2024
7 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Introduction

This study aimed to determine the relationship between HbA1c variability and foot ulcer healing at 12 weeks and 12 months.

Methods

Using National Diabetic Foot Care Audit (NDFA) and hospital records, demographics, baseline ulcer characteristics and healing outcomes for subjects presenting with a foot ulcer between 2017–2022 were collected at 12 weeks and 12 months. Subjects had diabetes duration > 3 years and ≥ 3 HbA1c recordings in the 5 years prior to presentation.

Results

At 12 weeks, factors associated with an active ulcer were presence on hind foot (adjusted odds ratios) (2.1 [95% CI 1.3–3.7]), ischaemia (2.1 [95% CI:1.4–3.2]), area > 1 cm2 (2.7 [95% CI:1.7–4.2]) and diabetes duration > 24 years vs 3–10 (AOR 2.0 [95% CI 1.2–3.5]). After adjustment, HbA1c variability 6–10 mmol/mol and > 14.5 mmol/mol had AOR of 1.76 (95% CI 1.1–2.8; p = 0.0192) and 1.5 (95% CI 0.9–2.6; p = 0.1148) of an active ulcer at 12 weeks vs variability < 6 mmol/mol. At 12 months, ischaemia (AOR 2.4 [95% CI 1.5–3.8]) and diabetes duration > 24 years vs 3–10 years (AOR 3.3 [95% CI 1.7–6.4] were significant factors. HbA1c variability was not significant at 12 months.

Conclusion

In keeping with the national NDFA data, in our cohort ulcer characteristics, but not HbA1c variability, were the key factors associated with ulcer healing at 12 weeks and 12 months.

Plain Language Summary

Diabetes complications occur more frequently when glucose control is not as good as it could be. For a long time, HbA1c, or glycated haemoglobin, has been used as a measure of how well someone’s diabetes has been controlled. However, another way of looking at diabetes control is to look at the changes of HbA1c over time—this is called glycaemic variability. Diabetes-related foot disease is one of the most feared complications of the condition, and our group has previously shown in a small study that glycaemic variability was associated with ulcer healing at 12 weeks—with lower variability leading to better healing. However, it did not consider other variables known to be associated with not being alive and ulcer free at 12 months. In the UK, data are collected as part of the National Diabetes Footcare Audit (NDFA). This dataset collects a lot of information on new foot ulcers and their outcomes 12 weeks later. We have used our centre’s data to look at factors not included in the NDFA dataset—in particular glycaemic variability—to determine whether this influences ulcer outcomes at 12 weeks, but also at 12 months. We found that low glycaemic variability is associated with greater chances of healing but that the greatest association is the presence of poor blood flow and diabetes duration.

Keywords

HbA1c variability
Glycaemic variability
Ulcer healing
Diabetes-related foot ulcers
issue-copyright-statement© Springer Healthcare Ltd., part of Springer Nature 2024
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pmcKey Summary Points

Why carry out this study?	
Glycaemic variability as measured by visit-to-visit changes in glycated haemoglobin (HbA1c) is becoming an increasingly important risk factor in the development of microvascular and macrovascular complications of diabetes	
We have used a large single-centre database of people with diabetes with a foot ulcer to retrospectively assess whether glycaemic variability influences ulcer healing at 12 weeks and 12 months	
What was learned from the study?	
We show that at 12 weeks those who had the lowest variability had the greatest chance of healing, but at 12 months, only the presence of ischaemia and diabetes duration remained significant in predicting healing	
The retrospective nature of our data analysis means that only associations, not causation, can be inferred	

Introduction

Foot ulceration is an important and challenging complication of diabetes, with a lifetime risk reported of between 19–34% in people with diabetes [1, 2]. Following ulceration there is increased morbidity and mortality, with a high percentage of recurrence. Data from the most recent National Diabetes Foot Audit in the UK report a 15% mortality rate by 1 year in people presenting with severe ulcers [3]. Amputations remain a significant consequence, with approximately 84% being preceded by an ulcer and 3% of severe ulcers resulting in a major amputation by 1 year [1, 3–5]. In addition, not only do these ulcers impose a significant impact on quality of life, but management of these ulcers is very costly, accounting for up to 1% of the total NHS budget in England [3, 6]. It has recently been estimated that diabetes-related foot disease contributes to 2% of the global disease burden [7].

HbA1c variability is a measure of long-term glycaemic control, which assesses the variation in HbA1c values between visits over time. This has been shown to be associated with, and an independent risk factor for, the development of microvascular and macrovascular complications in type 1 and type 2 diabetes [8–15]. Lower extremity amputations also have a relationship to variability in HbA1c concentration, potentially as an independent marker of future major and minor amputations [16]. With one study suggesting a relationship with minor amputations in people with type 2 diabetes-related foot ulcers [16, 17].

A previous small study has suggested a significant relationship between HbA1c variability and healing of DFU [18]. However, as the first study of this kind, it had limitations, with no defined end point and a small sample size. Furthermore, it did not consider other variables known to be associated with not being alive and ulcer free at 12 months. It is already known that poor ulcer healing is influenced by a number of factors, in particular, the presence of ischaemia or infection, size and depth of ulceration, time to presentation at clinic and having multiple ulcerations [3]. The SINBAD (Site, Ischaemia, Neuropathy, Bacterial infection, Area and Depth) classification uses these variables associated with poor ulcer healing to create a score that can be used for comparison of ulcers at baseline presentation [19]. Nationally, 12-week outcomes are used, in the National Diabetes Foot Care Audit and act as a consistent end point to measure the association of variables on foot ulcer healing, specifically whether a person is alive and ulcer free [3]. Twelve-month outcomes can also be used to assess the association with long-term healing.

This study aimed to determine whether HbA1c variability influences 12-week and 12-month outcomes for DFU healing.

Methods

Study Design, Setting and Patients

This was a retrospective study conducted using data collected routinely from the multidisciplinary diabetic foot clinic at the Norfolk and Norwich University Hospitals NHS Foundation Trust. People with diabetes who presented to the diabetic foot clinic between January 2017–December 2022 and whose data were included in the National Diabetes Foot Care Audit (NFDA) were selected for this study. Those with a diabetes duration > 3 years and who had at least three HbA1c recordings in the 5 years prior to presentation were included in the analysis. Only the first ulcer presentation between 2017–2022 was included.

Data Collection

Data were collected using electronic hospital records, clinic letters and the NFDA reports. Data collected included sex, age at presentation, type and duration of diabetes. From the NFDA reports, the time interval to be first seen in clinic, the date of first presentation and 12-week follow-up dates were collected. Baseline retinopathy data were collected from the eye screening service. We used the highest stage between both eyes within 12 months of presentation.

Study Outcomes

Ulcer characteristics were recorded using the NDFA data and SINBAD classification. Using the NFDA definitions, a SINBAD score ≥ 3 was considered a severe ulcer. HbA1c recordings were collected from presentation to 5 years prior. Healing was defined as alive and ulcer free. Active ulcers, any resultant amputations or deaths by 12 weeks and 12 months were recorded. Amputations were classified into major (above the ankle) or minor.

The project was registered with the audit department at our institution who deemed that ethical approval was not required because of the anonymised, retrospective nature of the data collection. Trust approval for the project was granted by the service director for diabetes and endocrinology.

Statistical Analysis

Summary statistics of the demographic and clinical characteristics were presented for all eligible subjects. Descriptive statistics were reported using means and standard deviations (SD) for continuous variables and frequencies and percentages were reported for categorical variables.

Univariate and multiple variable logistic regressions were performed and their odds ratios and respective 95% confidence intervals presented. For the multiple logistic regression only factors seen to be significant at the 10% level from the univariate analysis were included in the model. To compare ulcer healing across the different levels of adjusted HbA1c variability (SD), the factors controlled for in the model were sex, age, ischaemia, ulcer area and depth, site of hind foot, SINBAD score ≥ 3 and diabetes duration.

As the number of individual visits (n) could influence the HbA1c variability (SD) (with fewer visits likely to artificially inflate the SD), values for HbA1c SD were divided by sqrt(n/n − 1) to adjust for this possibility.

Results

Using the NDFA database, 1100 subjects with diabetes were identified with presentation to the diabetic foot clinic between 2017–2022. Of these, 546 were included in the final analysis. Figure 1 shows the details on why people were excluded. No data were excluded because of deaths as only 21 subjects had died at 12 months.Fig. 1 Consort diagram to show patient selection

The baseline characteristics of those included in the 12-week analysis are shown in Table 1. Of those included, 17 people (5.4%) who had an active ulcer at 12 weeks had a major or minor amputation compared with 3 people (1%) in those who did not have an ulcer. Figure 2 shows the factors that were and were not significant for having an active ulcer at 12 weeks. These were the presence of the ulcer on the hind foot (adjusted odds ratio 2.1 [95% CI 1.3–3.7]), ischaemia (AOR 2.1 [95% CI 1.4–3.2]) and area > 1 cm2 (AOR 2.7 [95% CI 1.7–4.2]).Table 1 Baseline patient characteristics for those with 12-week data

	Active ulcer at 12 weeks
(N = 315)	No active ulcer at 12 weeks
(N = 291)	
Male n [%]	235 [74.6%]	197 [67.7%]	
Female n [%]	80 [25.4%]	94 [32.3%]	
Age (years) mean [SD]	70.5 [13.0]	69.3 [13.8]	
Interval to presentation 0–13 days n [%]	164 [52.4%]	168 [57.7%]	
Interval to presentation ≥ 14 days n [%]	142 [45.1%]	114 [39.2%]	
Self-presenting n [%]	8 [2.5%]	9 [3.1%]	
Type 1 diabetes n [%]	65 [20.7%]	55 [18.9%]	
Type 2 diabetes n [%]	246 [78.3%]	235 [80.8%]	
Other/unknown diabetes n [%]	3 [0.9%]	1 [0.3%]	
Duration of diabetes (years) mean [SD]	20.6 [13.4]	17.7 [11.6]	
SINBAD < 3 n [%]	153 [48.6%]	219 [75.3%]	
SINBAD ≥ 3 n [%]	162 [51.4%]	72 [24.7%]	
Mean HbA1c (mmol/mol) [SD]	71.4 [18.6]	69.7 [17.5]	
Mean HbA1c variability [SD]	10.2 [6.6]	9.7 [6.7]	
	(N = 275)	(N = 266)	
 Retinopathy n [%]	186 [67.6%]	176 [66.1%]	
	(N = 272)	(N = 267)	
 Maculopathy n [%]	50 [18.4%]	48 [18.0%]	
n number, SD standard deviation, SINBAD site, ischaemia, neuropathy, bacterial infection, area and depth

Fig. 2 Adjusted odds ratios for factors associated with having an active ulcer at 12 weeks

Duration of diabetes and HbA1c variability, after adjusting for other factors, were not statistically significant (p = 0.0754 and p = 0.0642 respectively). Diabetes duration suggested a potential trend, with ulcer healing less likely to occur as diabetes duration increased. Those that had diabetes for > 24 years were more likely to have an active ulcer at 12 weeks compared with those for 3–10 years (AOR 2.0 [95% CI 1.2–3.5]). HbA1c variability does not have the same monotonic trend as seen for diabetes duration. However, the subjects with lowest variability (< 6 mmol/mol) were at least risk of having an active ulcer at week 12. Those having HbA1c variability between 6 to 10 mmol/mol and HbA1c variability > 14.5 mmol/mol had higher risk than those with HbA1c variability between 10 to 14.5 mmol/mol. Those having HbA1c variability between 6 to 10 mmol/mol and HbA1c variability > 14.5 mmol/l had AOR 1.76 [95% CI 1.1–2.8] (p = 0.0192) and AOR 1.5 [95% CI 0.9–2.6] (p = 0.1148), respectively, of having an ulcer at week 12 compared to subjects with HbA1c variability < 6 mmol/mol.

Table 2 shows the characteristics of the subjects included in the 12-month analysis. Of those included, nine people (6.5%) who had an active ulcer at 12 months had a major or minor amputation compared with nine people (2.2%) in those who did not have an ulcer. Figure 3 shows the factors which were significantly and not significantly associated with ulcer healing at 12 months. After adjustment, type of diabetes, site of ulcer, area of ulcer, SINBAD score and HbA1c variability no longer showed a statistically significant association.Table 2 Baseline patient characteristics for those with 12-month data

	Active ulcer at 12 months
(N = 138)	No active ulcer at 12 months
(N = 408)	
Male n [%]	105 [76.1%]	287 [70.3%]	
Female n [%]	33 [23.9%]	121 [ 29.7%]	
Age (years) mean [SD]	69.2 [13.2]	69.4 [13.3]	
Interval to presentation 0–13 days n [%]	76 [55.1%]	227 [55.6%]	
Interval to presentation ≥ 14 days n [%]	58 [42%]	172 [42.1%]	
Self-presenting n [%]	4 [2.9%]	9 [2.2%]	
Type 1 diabetes n [%]	39 [28.3%]	72 [17.6%]	
Type 2 diabetes n [%]	97 [70.3%]	333 [81.6%]	
Other/unknown diabetes n [%]	2 [1.4%]	3 [0.7%]	
Duration of diabetes (years) mean [SD]	21.8 [13.5]	18.4 [12.3]	
SINBAD < 3 n [%]	70 [50.7%]	276 [67.6%]	
SINBAD ≥ 3 n [%]	68 [49.3%]	132 [32.4%]	
Mean HbA1c (mmol/mol) [SD]	72.5 [18.3]	70.4 [18.1]	
Mean HbA1c variability [SD]	9.9 [6.2]	10.0 [6.7]	
	N = 123	N = 372	
 Retinopathy n [%]	82 [66.7%]	248 [66.7%]	
	N = 122	N = 373	
 Maculopathy n [%]	17 [13.9%]	75 [20.1%]	
n number, SD standard deviation, SINBAD site, ischaemia, neuropathy, bacterial infection, area, and depth

Fig. 3 Adjusted odds ratios for factors associated with having an active ulcer at 12 months

Significant factors associated with amputation at 12 months before adjustment were mean HbA1c, HbA1c variability, ulcer depth and SINBAD score. However, after adjustment, the only significant factors were age at presentation, ischaemia (AOR 6.4 [95% CI 2.8–14.4]) and ulcer area > 1 cm2 (AOR 2.3 [95% CI 1.0–5.4]). For every year increase in age, the odds of amputation were 0.97 (95% CI 0.94–0.99).

Sex and ischaemia were the factors associated with being alive at 12 months. The adjusted odds of being alive at 12 months were 2.7 (95% CI 1.1–6.7) for male patients compared to female patients and 4.3 (95% CI 1.7–11.2) for those without ischaemia.

Discussion

Our data showed that HbA1c variability does not significantly influence the likelihood of DFU healing at 12 weeks or 12 months. After adjustment, ulcer site on the hind foot, ischaemia and area > 1 cm2 were the factors which had the greatest association with ulcer healing at 12 weeks. Although glycaemic control was not a significant factor, our data did suggest that those with the lowest HbA1c variability had the lowest risk of having an active ulcer at 12 weeks. At 12 months, ischaemia and diabetes duration were the only remaining significant variables related to ulcer healing in our cohort.

Unlike ulcer healing, visit-to-visit HbA1c variability has already been reported as a predictor and a marker of lower extremity amputations in adults with type 2 diabetes, particularly in those with a diabetes duration > 3 years [16, 17]. A meta-analysis looking at people with type 2 diabetes suggested that HbA1c variability is associated with micro- and macrovascular complications [11]. The authors reported that the risk of neuropathy in relation to glycaemic variability was not significant and diabetes-related ulceration was not assessed [11]. This link between HbA1c variability and the increased risk of developing diabetes-related complications has previously been suggested to be explained by the hypothesis that glycaemic fluctuations correlate with oxidative stress along with interference of lipid peroxidation and cell membrane behaviour [20]. That our data did not reflect this may be due to a relatively small sample size. As mentioned, a meta-analysis of 23 studies with > 370,000 subjects suggested an association between HbA1c variability and microvascular disease, but single-centre studies of just a few thousand such as the current study or others may not be able to replicate that [21].

Regarding DFU, a previous study suggested that glycaemic variability had a significant association with healing time. Those with low HbA1c (< 58 mmol/mol) and low variability healed faster than those with high HbA1c and high variability (73.5 days [59.5—90.8] vs 111.0 days [92.0—134.0], p = 0.007) [18]. However, the link between glycaemic variability and likelihood of ulcer healing was not significant and, without a defined endpoint, it is difficult to compare the variables associated with ulcer healing. A recent retrospective study described the clinical characteristics of people with DFU according to glucose variability including the relationship between variability and DFU outcomes [22]. The study concluded that indices of glycaemic variability as coefficient of variation and standard deviation of glucose measurements were independent predictors of failure to heal DFU [22]. A significantly higher proportion of the low glucose variability group healed within 6 months compared with those having high glucose variability (65% vs 38%, p < 0.001) [22]. Compared to the present study, these studies have suggested a significant relationship between glycaemic variability and ulcer healing. However, neither have assessed these variables at 12 weeks. In addition, our study looked at variability in HbA1c, not glucose.

Our data are consistent with those from the NDFA regarding variables associated with being alive and ulcer free at 12 weeks. Our study has showed that ulcer characteristics are the key factors which influence healing of ulcerations, in particular ischaemia, area and site on the hind foot. However, depth was not a significant factor in our dataset compared to the NDFA results [3]. Whilst the NDFA do not collect data beyond 12 weeks, a potentially surprising finding from our 12-month results was that the ulcer characteristics, with the exception of ischaemia, were no longer significant factors. There are many potential reasons for this finding. One suggestion for this may be that although these specific ulcer characteristics increase the healing time for DFU at 12 weeks, by 12 months many ulcerations have healed regardless of the initial characteristics of the ulcer or that the individuals may have died. More work needs to be done to try and explain these findings.

Although our study included many subjects, with the population being characteristic of people with DFU generally, we do recognise some limitations. We only included people from a single centre with a largely white population, which may impact the generalisability of the results. The COVID-19 pandemic also had an impact on our results, with some people taking longer to present to clinic and a reduction in follow-up leading to missing outcomes in our dataset and exclusion of subjects from analysis. Data previously published by NHS England showed a reduction in amputation rates during the pandemic [23]. Due to the retrospective nature of the study, there were missing outcomes for some people, including those who died during follow-up, leading to exclusions in the patient selection process.

Conclusions

In summary, our data have shown that ulcer characteristics are the key variables associated with DFU healing at 12 weeks and 12 months, with diabetes duration also playing a role in the longer term outcomes. HbA1c variability < 6 mmol/mol was associated with the least risk of an active ulcer at 12 weeks however was not a significant variable affecting the likelihood of ulcer healing at 12 months. Ischaemia was the only ulcer variable shown in our dataset to be associated with both 12 weeks and 12 month ulcer healing.

Author Contributions

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Georgia Thomason collected the data, did the initial data analysis and wrote the initial draft of the manuscript. Ian Nunney analysed the data. Ketan Dhatariya and Catherine Gooday conceived the study and wrote the final draft of the manuscript. All authors saw and approved the final draft. The authors accept that there was no patient and public involvement representation in the writing of this manuscript.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Ketan Dhatariya is an Editorial Board member of Diabetes Therapy and was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Georgia Thomason, Catherine Gooday, and Ian Nunney have nothing to disclose.

Ethical Approval

The project was registered with the audit department at our institution who deemed that ethical approval was not required due to the anonymised, retrospective nature of the data collection.
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References

1. Edmonds M Manu C Vas P The current burden of diabetic foot disease J Clin Orthop Trauma 2021 17 88 93 10.1016/j.jcot.2021.01.017 33680841
Edmonds M, Manu C, Vas P. The current burden of diabetic foot disease. J Clin Orthop Trauma. 2021;17:88–93.33680841
2. Armstrong DG Boulton AJ Bus SA Diabetic foot ulcers and their recurrence N Engl J Med 2017 376 2367 2375 10.1056/NEJMra1615439 28614678
Armstrong DG, Boulton AJ, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376:2367–75.28614678
3. NHS Digital. National Diabetes Foot Care Audit 2018 to 2023. 2024.
4. McDermott K Fang M Boulton AJ Selvin E Hicks CW Etiology, epidemiology, and disparities in the burden of diabetic foot ulcers Diabetes Care 2022 46 209 221 10.2337/dci22-0043
McDermott K, Fang M, Boulton AJ, Selvin E, Hicks CW. Etiology, epidemiology, and disparities in the burden of diabetic foot ulcers. Diabetes Care. 2022;46:209–21.
5. Pecoraro RE Reiber GE Burgess EM Pathways to diabetic limb amputation. Basis for prevention Diabetes Care 1990 13 513 521 10.2337/diacare.13.5.513 2351029
Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation. Basis for prevention. Diabetes Care. 1990;13:513–21.2351029
6. Kerr M Barron E Chadwick P Evans T Kong WM Rayman G The cost of diabetic foot ulcers and amputations to the National Health Service in England Diabet Med 2019 36 995 1002 10.1111/dme.13973 31004370
Kerr M, Barron E, Chadwick P, Evans T, Kong WM, Rayman G, et al. The cost of diabetic foot ulcers and amputations to the National Health Service in England. Diabet Med. 2019;36:995–1002.31004370
7. Lazzarini PA Raspovic KM Meloni M van Netten JJ A new declaration for feet's sake: halving the global diabetic foot disease burden from 2% to 1% with next generation care Diabetes Metab Res Rev 2024 40 e3747 10.1002/dmrr.3747 37997627
Lazzarini PA, Raspovic KM, Meloni M, van Netten JJ. A new declaration for feet’s sake: halving the global diabetic foot disease burden from 2% to 1% with next generation care. Diabetes Metab Res Rev. 2024;40: e3747.37997627
8. Bonke FC Donnachie E Schneider A Mehring M Association of the average rate of change in HbA1c with severe adverse events: a longitudinal evaluation of audit data from the Bavarian Disease Management Program for patients with type 2 diabetes mellitus Diabetologia 2016 59 286 293 10.1007/s00125-015-3797-z 26518684
Bonke FC, Donnachie E, Schneider A, Mehring M. Association of the average rate of change in HbA1c with severe adverse events: a longitudinal evaluation of audit data from the Bavarian Disease Management Program for patients with type 2 diabetes mellitus. Diabetologia. 2016;59:286–93.26518684
9. Waden J Forsblom C Thorn LM Gordin D Saraheimo M Groop PH A1C variability predicts incident cardiovascular events, microalbuminuria, and overt diabetic nephropathy in patients with type 1 diabetes Diabetes 2009 58 2649 2655 10.2337/db09-0693 19651819
Waden J, Forsblom C, Thorn LM, Gordin D, Saraheimo M, Groop PH. A1C variability predicts incident cardiovascular events, microalbuminuria, and overt diabetic nephropathy in patients with type 1 diabetes. Diabetes. 2009;58:2649–55.19651819
10. Gorst C Kwok CS Aslam S Buchan I Kontopantelis E Myint PK Long-term glycemic variability and risk of adverse outcomes: a systematic review and meta-analysis Diabetes Care 2015 38 2354 2369 10.2337/dc15-1188 26604281
Gorst C, Kwok CS, Aslam S, Buchan I, Kontopantelis E, Myint PK, et al. Long-term glycemic variability and risk of adverse outcomes: a systematic review and meta-analysis. Diabetes Care. 2015;38:2354–69.26604281
11. Sartore G Ragazzi E Caprino R Lapolla A Long-term HbA1c variability and macro-/micro-vascular complications in type 2 diabetes mellitus: a meta-analysis update Acta Diabetol 2023 60 721 738 10.1007/s00592-023-02037-8 36715767
Sartore G, Ragazzi E, Caprino R, Lapolla A. Long-term HbA1c variability and macro-/micro-vascular complications in type 2 diabetes mellitus: a meta-analysis update. Acta Diabetol. 2023;60:721–38.36715767
12. Kilpatrick ES Rigby AS Atkin SL A1C variability and the risk of microvascular complications in type 1 diabetes Diabetes Care 2008 31 2198 2202 10.2337/dc08-0864 18650371
Kilpatrick ES, Rigby AS, Atkin SL. A1C variability and the risk of microvascular complications in type 1 diabetes. Diabetes Care. 2008;31:2198–202.18650371
13. Sugawara A Kawai K Motohashi S Saito K Kodama S Yachi Y HbA(1c) variability and the development of microalbuminuria in type 2 diabetes: Tsukuba Kawai Diabetes Registry 2 Diabetologia 2012 55 2128 2131 10.1007/s00125-012-2572-7 22580991
Sugawara A, Kawai K, Motohashi S, Saito K, Kodama S, Yachi Y, et al. HbA(1c) variability and the development of microalbuminuria in type 2 diabetes: Tsukuba Kawai Diabetes Registry 2. Diabetologia. 2012;55:2128–31.22580991
14. Hsu CC Chang HY Huang MC Hwang SJ Yang YC Lee YS HbA1c variability is associated with microalbuminuria development in type 2 diabetes: a 7-year prospective cohort study Diabetologia 2012 55 3163 3172 10.1007/s00125-012-2700-4 22923064
Hsu CC, Chang HY, Huang MC, Hwang SJ, Yang YC, Lee YS, et al. HbA1c variability is associated with microalbuminuria development in type 2 diabetes: a 7-year prospective cohort study. Diabetologia. 2012;55:3163–72.22923064
15. Xu Y Dong S Fu EL Sjölander A Grams ME Selvin E Long-term visit-to-visit variability in hemoglobin A(1c) and kidney-related outcomes in persons with diabetes Am J Kidney Dis 2023 82 267 278 10.1053/j.ajkd.2023.03.007 37182597
Xu Y, Dong S, Fu EL, Sjölander A, Grams ME, Selvin E, et al. Long-term visit-to-visit variability in hemoglobin A(1c) and kidney-related outcomes in persons with diabetes. Am J Kidney Dis. 2023;82:267–78.37182597
16. Jagannathan R Schechter MC Alvarez JA Blanco G Rajani R Santamaria G 124-OR: HbA1c variability is independently associated with lower-extremity amputation and death among patients with diabetic foot ulcers Diabetes 2022 10.2337/db22-124-OR
Jagannathan R, Schechter MC, Alvarez JA, Blanco G, Rajani R, Santamaria G, et al. 124-OR: HbA1c variability is independently associated with lower-extremity amputation and death among patients with diabetic foot ulcers. Diabetes. 2022. 10.2337/db22-124-OR.
17. Li CI Cheng HM Liu CS Lin CH Lin WY Wang MC Association between glucose variation and lower extremity amputation incidence in individuals with type 2 diabetes: a nationwide retrospective cohort study Diabetologia 2020 63 194 205 10.1007/s00125-019-05012-7 31686118
Li CI, Cheng HM, Liu CS, Lin CH, Lin WY, Wang MC, et al. Association between glucose variation and lower extremity amputation incidence in individuals with type 2 diabetes: a nationwide retrospective cohort study. Diabetologia. 2020;63:194–205.31686118
18. Dhatariya KK Li Ping Wah-Pun Sin E Cheng JO Li FY Yue AW Gooday C The impact of glycaemic variability on wound healing in the diabetic foot—a retrospective study of new ulcers presenting to a specialist multidisciplinary foot clinic Diabetes Res Clin Pract 2018 135 23 29 10.1016/j.diabres.2017.10.022 29097286
Dhatariya KK, Li Ping Wah-Pun Sin E, Cheng JO, Li FY, Yue AW, Gooday C, et al. The impact of glycaemic variability on wound healing in the diabetic foot—a retrospective study of new ulcers presenting to a specialist multidisciplinary foot clinic. Diabetes Res Clin Pract. 2018;135:23–9.29097286
19. Ince P Abbas ZG Lutale JK Basit A Ali SM Chohan F Use of the SINBAD classification system and score in comparing outcome of foot ulcer management on three continents Diabetes Care 2008 31 964 967 10.2337/dc07-2367 18299441
Ince P, Abbas ZG, Lutale JK, Basit A, Ali SM, Chohan F, et al. Use of the SINBAD classification system and score in comparing outcome of foot ulcer management on three continents. Diabetes Care. 2008;31:964–7.18299441
20. Rodrigues R de Medeiros LA Cunha LM Garrote-Filho MS Bernardino Neto M Jorge PT Correlations of the glycemic variability with oxidative stress and erythrocytes membrane stability in patients with type 1 diabetes under intensive treatment Diabetes Res Clin Pract 2018 144 153 160 10.1016/j.diabres.2018.01.031 29427698
Rodrigues R, de Medeiros LA, Cunha LM, Garrote-Filho MS, Bernardino Neto M, Jorge PT, et al. Correlations of the glycemic variability with oxidative stress and erythrocytes membrane stability in patients with type 1 diabetes under intensive treatment. Diabetes Res Clin Pract. 2018;144:153–60.29427698
21. Dhatariya K Humberstone A Hasnat A Wright R Lujan M Nunney I The association between mean glycated haemoglobin or glycaemic variability and the development of retinopathy in people with diabetes: a retrospective observational cohort study Diabetes Therapy 2021 12 2755 2766 10.1007/s13300-021-01146-3 34491530
Dhatariya K, Humberstone A, Hasnat A, Wright R, Lujan M, Nunney I. The association between mean glycated haemoglobin or glycaemic variability and the development of retinopathy in people with diabetes: a retrospective observational cohort study. Diabetes Therapy. 2021;12:2755–66.34491530
22. Caruso P Scappaticcio L Gicchino M Castaldo F Barrasso M Carbone C Short-term glucose variability as a determinant of the healing rate of diabetic foot ulcer: a retrospective study Diabetes Metab Syndr Clin Res Rev 2024 18 102990 10.1016/j.dsx.2024.102990
Caruso P, Scappaticcio L, Gicchino M, Castaldo F, Barrasso M, Carbone C, et al. Short-term glucose variability as a determinant of the healing rate of diabetic foot ulcer: a retrospective study. Diabetes Metab Syndr Clin Res Rev. 2024;18:102990.
23. Valabhji J Barron E Vamos EP Dhatariya K Game F Kar P Temporal trends in lower-limb major and minor amputation and revascularization procedures in people with diabetes in England during the COVID-19 pandemic Diabetes Care 2021 44 e133 135 10.2337/dc20-2852 34016616
Valabhji J, Barron E, Vamos EP, Dhatariya K, Game F, Kar P, et al. Temporal trends in lower-limb major and minor amputation and revascularization procedures in people with diabetes in England during the COVID-19 pandemic. Diabetes Care. 2021;44:e133-135.34016616
