# Trends in the relation between hyperglycemia correction and active Charcot neuroarthropathy: results from the EPICCHAR study

Dured Dardari, Sophie Schuldiner, Carole-Anne Julien, Georges Ha Van, Jocelyne M'bemba, Muriel Bourgeon, Ariane Sultan, Marc Lepeut, Sylvie Grandperret-Vauthier, Florence Baudoux, et al.

<figure><img src="image_1.png" /></figure>

## To cite this version:

Dured Dardari, Sophie Schuldiner, Carole-Anne Julien, Georges Ha Van, Jocelyne M'bemba, et al. "Trends in the relation between hyperglycemia correction and active Charcot neuroarthropathy: results from the EPICCHAR study." BMJ Open Diabetes Research & Care, 2022, 10 (5), pp.e002380. 10.1136/bmjdrc-2021-002380. [hal-03831582](https://hal.science/hal-03831582)

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# Trends in the relation between hyperglycemia correction and active Charcot neuroarthropathy: results from the EPICHER study

Dured Dardari,¹,² Sophie Schuldiner,³ Carole-Anne Julien,⁴ Georges Ha Van,⁵

Jocelyne M'Bemba,⁶ Muriel Bourgeon,⁷ Ariane Sultan,⁸,⁹ Marc Lepeut,¹⁰

Sylvie Grandperret-Vauthier,¹¹ Florence Baudoux,¹² Maud François,¹³

Sylvaine Clavel,¹⁴ Jacques Martini,¹⁵ Julien Vouillarmet,¹⁶ Paul Michon,¹⁶

Myriam Moret,¹⁷ Arnaud Monnier,¹⁸ Vaneva Chingan-Martino,¹⁹

Vincent Rigalleau,²⁰,²¹ Isabelle Dumont,²² Laurence Kessler,²³,²⁴ Ionela Stifii,²³

Benjamin Bouillet,²⁵,²⁶ Pierre Bonnin,²⁷ Amal Lemoine,²⁸

Enrique Da Costa Correia,²⁹ Marie Martine Bonello Faraill,³⁰ Marie Muller,³¹

Marie Cazaubiel,³² Mohammed Zakarya Zemmache,³³ Agnes Hartemann³⁴,³⁵

## ABSTRACT

**Introduction** The pathophysiology of Charcot neuroarthropathy (CN) remains unclear. There are a number of hypotheses but these are not exclusive. In its clinical presentation, this complication intersects with the semiology of diabetic-induced neuropathy, such as peripheral hypervascularization and the appearance of arteriovenous shunt. The EPICHER study is as yet an unpublished cohort of people living with diabetes complicated by CN (in active or chronic phase). Based on the findings of the EPICHER study, this study aimed to investigate whether a reduction in the rate of hyperglycemia accompanies the onset of an active phase of CN.

**Research design and methods** Hemoglobin A1c (HbA1c) levels were assessed 3 months (M3) and 6 months (M6) before the diagnosis of active CN (M0).

**Results** 103 patients living with diabetes and presenting active CN were included between January and December 2019 from the 31 centers participating in this study (30 in France and 1 in Belgium). The mean age of the participants was 60.2±12.2 years; the vast majority were men (71.8%) living with type 2 diabetes (75.5%). Mean HbA1c levels significantly declined between M6 (median 7.70; Q1, Q3: 7.00, 8.55) and M3 (median 7.65; Q1, Q3: 6.90, 8.50) (p=0.012), as well as between M6 and M0 (median 7.40; Q1, Q3: 6.50, 8.50) (p=0.014). No significant difference was found between M3 and M0 (p=0.072).

**Conclusions** A significant reduction in HbA1c levels seems to accompany the onset of the active phase of CN.

**Trial registration number** NCM03744039.

## INTRODUCTION

Neuroarthropathy or Charcot neuroarthropathy (CN) consists of acute osteoarticular destruction in the context of neuropathy, most commonly in the foot but also in the

## WHAT IS ALREADY KNOWN ON THIS TOPIC

⇒ Rapid correction of hyperglycaemia has previously been described in the form of treatment-induced neuropathy. However, little is known about the impact of this correction on the development of neuroarthropathy.

## WHAT THIS STUDY ADDS

⇒ The significant correction of hyperglycaemia based on the onset of neuroarthropathy seems to be the factor inducing inflammation, which is described as a central element in the mosaic of neuroarthropathy pathophysiology.

## HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

⇒ This link may help us to understand this complication and reduce its prevalence.

knee in some cases.¹ The physiopathology of this disorder is poorly understood and the knowledge of its causality remains at the theoretical stage. The most common explanation is inflammatory arthropathy, according to which CN occurs as an increased inflammatory response to a lesion inducing increased bone lysis, with the involvement of bone remodelling factors,² especially the receptor activator of nuclear factor B ligand (RANKL) and its natural antagonist osteoprotegerin (OPG). Many studies have confirmed abnormalities in the balance of the RANK/OPG system during the development of CN.³ A recent study examined in a retrospective
<table><caption>**Table 1** Demographic data and diabetes-related complications of participants with active CN</caption><thead><tr><th></th><th>Acute CN</th></tr></thead><tbody><tr><td>Age, mean years±IC (S1) (A2)</td><td>60.2±12.2</td></tr><tr><td>Men, n (%)</td><td>74 (71.8)</td></tr><tr><td>Body mass index (kg/m²), median (IQR)</td><td>30.11 (25.74–33.14)</td></tr><tr><td>Missing data, n</td><td>4</td></tr><tr><td>Type of diabetes, n (%)</td><td></td></tr><tr><td>Type 1</td><td>22 (21.6)</td></tr><tr><td>Type 2</td><td>77 (75.5)</td></tr><tr><td>Other</td><td>3 (2.9)</td></tr><tr><td>Missing data, n</td><td>1</td></tr><tr><td>Diabetes duration, years, n (%)</td><td></td></tr><tr><td>&gt;20</td><td>41 (40.2)</td></tr><tr><td>10–20</td><td>43 (42.2)</td></tr><tr><td>5–10</td><td>10 (9.8)</td></tr><tr><td>&lt;5</td><td>8 (7.8)</td></tr><tr><td>Missing data, n</td><td>1</td></tr><tr><td>Insulin use, n (%)</td><td>69 (67.6)</td></tr><tr><td>Missing data, n</td><td>1</td></tr><tr><td>Microangiopathy, n (%)</td><td>96 (94.1)</td></tr><tr><td>Missing data, n</td><td>1</td></tr><tr><td>Dialysis, n (%)</td><td>4 (10.3)</td></tr><tr><td>Missing data, n</td><td>64</td></tr><tr><td>GFR (mL/min/1.73 m²), median (IQR)</td><td>64 (46.5–90)</td></tr><tr><td>Missing data, n</td><td>71</td></tr><tr><td>Macroangiopathy, n (%)</td><td>30 (31.3)</td></tr><tr><td>Missing data, n</td><td>7</td></tr><tr><td>DFU history (grade 3 IWGDF), n (%)</td><td>63 (61.8)</td></tr><tr><td>Missing data, n</td><td>1</td></tr><tr><td>CN, Charcot neuroarthropathy.</td><td></td></tr></tbody></table>

manner the evolution of glycemic control in patients who have developed an active form of CN and demonstrated a significant drop in hemoglobin A1c (HbA1c) level in the near period of presentation of CN.⁴ We therefore wanted to know if the same reduction in the rate of HbA1c appears in cases of active CN presented through the descriptive multicentric study 'EPICCHAR' handled at diabetic foot centers in France and Belgium, the main objective of which is to map patients living with Charcot's foot (ie, identification of patients with acute and chronic Charcot and the diagnostics and therapeutic methods used).

## Study objectives

The primary objective of our study is to investigate if rapid correction of HbA1c levels is accompanied by onset of the active phase of CN. The primary assessment

criterion is the comparison of HbA1c levels 6 months (M6) before the diagnosis of the active phase of CN (M0). The secondary objective is to determine whether HbA1c levels rapidly fell between M6 and M3 (3 months) before the diagnosis of the active phase of CN, as well as between M3 and M0. The secondary assessment criterion is the dosage of HbA1c levels between M6 and M3 and between M3 and M0.

## METHODS

EPICCHAR is a prospective, multicenter, observational study conducted from January 1 to December 31, 2019. Thirty-one diabetic foot centers (30 in France and 1 in Belgium) took part in the study. The study population consisted of all people aged ≥18 years living with diabetes who were admitted to hospital or consulted for acute or chronic CN, with or without foot ulcers. Unless the patient was participating in another interventional study or refused to participate, no exclusion criteria were used. No follow-up was required in the protocol. For the active phase, the diagnosis of CN was retained if the clinical examination showed a joint with an inflamed appearance and a temperature that was 3°C higher than the contralateral joint. This was validated by MRI.

In this ancillary evaluation, we analyzed the HbA1c levels (measured by high-performance liquid chromatography) of participants with diabetes and acute CN who had been referred to one of the participating diabetic foot centers during the study period. For each patient living with diabetes who was admitted to one of the participating centers and presenting with active CN (diagnosis performed by MRI and clinical examination), HbA1c levels were assessed (M0). The HbA1c values 3 and 6 months before the discovery of CN (respectively, M3 and M6) were then cross-checked via the patient's medical file or by contacting his or her family physician.

Data are presented as median and IQR. To compare numerical values, statistical analysis was performed with non-parametric Wilcoxon signed-rank tests. Pairwise comparisons between time points were performed using the Bonferroni-Holm method for p value adjustment. The Benjamini and Hochberg false discovery rate method was used to adjust for multiple comparisons. Categorical variables were compared using the Fisher's exact test. Linear mixed-effect regression models were applied to investigate the evolution of repeated glycated hemoglobin measures and their association with diabetes type. The fixed-effect variable was diabetes type and the random-effect was the individual subject. Influence and residual diagnostics were performed to ascertain whether all the assumptions of the mixed-effects regression models were met in the analyses. An unstructured covariance was chosen. All statistical analyses were performed using the Statistical Analysis System. This study applied the MIXED procedure with fixed and random effects in SAS V.9.3 to implement the linear mixed-effects regression models.
<table><caption>**Table 2** HbA1c levels and the results for active Charcot neuroarthropathy cases in the EPICCHAR study</caption><thead><tr><th>Variable</th><th>Type 2 diabetes</th><th>Type 1</th><th>Type 2</th><th>Total</th><th>P value</th></tr></thead><tbody><tr><td rowspan="4">Age</td><td>n</td><td>22</td><td>77</td><td>99</td><td rowspan="4">0.0014</td></tr><tr><td>Median</td><td>54.00</td><td>63.00</td><td>61.00</td></tr><tr><td>Q1, Q3</td><td>44.00, 60.00</td><td>55.00, 71.00</td><td>54.00, 68.00</td></tr><tr><td>Min, max</td><td>30.00, 68.00</td><td>40.00, 90.00</td><td>30.00, 90.00</td></tr><tr><td rowspan="4">HbA1c_t0</td><td>n</td><td>15</td><td>60</td><td>75</td><td rowspan="4">0.4342</td></tr><tr><td>Median</td><td>7.50</td><td>7.30</td><td>7.40</td></tr><tr><td>Q1, Q3</td><td>6.60, 8.70</td><td>6.40, 8.35</td><td>6.50, 8.50</td></tr><tr><td>Min, max</td><td>6.20, 9.70</td><td>5.00, 12.10</td><td>5.00, 12.10</td></tr><tr><td rowspan="4">HbA1c_m_3</td><td>n</td><td>9</td><td>41</td><td>50</td><td rowspan="4">0.2943</td></tr><tr><td>Median</td><td>7.80</td><td>7.50</td><td>7.65</td></tr><tr><td>Q1, Q3</td><td>7.60, 8.40</td><td>6.90, 8.70</td><td>6.90, 8.50</td></tr><tr><td>Min, max</td><td>7.30, 9.10</td><td>5.20, 11.90</td><td>5.20, 11.90</td></tr><tr><td rowspan="4">HbA1c_m_6</td><td>n</td><td>14</td><td>30</td><td>44</td><td rowspan="4">0.2461</td></tr><tr><td>Median</td><td>8.05</td><td>7.60</td><td>7.70</td></tr><tr><td>Q1, Q3</td><td>7.20, 9.40</td><td>6.80, 8.40</td><td>7.00, 8.55</td></tr><tr><td>Min, max</td><td>6.40, 13.00</td><td>6.00, 12.00</td><td>6.00, 13.00</td></tr></tbody></table>

HbA1c, hemoglobin A1c; max, maximum; min, minimum.

This is an ancillary evaluation of the EPICCHAR cohort (unpublished results).

## RESULTS

There were 467 people recruited in the EPICCHAR study. In brief, 26.55% of the participants were women. The mean age of the population was 61.97 (SD 11.45). Of the patients, 17.13% had type 1 diabetes, 79.66% had type 2 diabetes, and 3% had other types of diabetes. Of the patients, 21.62% had bilateral Charcot foot. Only 103 participants presented an active phase of CN. All individuals with missing HbA1c levels at the three time points were excluded. The demographic characteristics of the participants and their body mass index, diabetes type and duration, and any diabetes-related complications are presented in table 1. The HbA1c levels and values of the

patients at M0, M3, and M6, expressed in percentages (DCCT/NGSP), are summarized in table 2.

In the total study sample, the paired Wilcoxon test showed a significant difference between M6 (median 7.70; Q1, Q3: 7.00, 8.55) and M3 (median 7.65; Q1, Q3: 6.90, 8.50) (p=0.012), with mean HbA1c levels significantly falling from 62 mmol/mol (7.8%±1.62) at M6 to 58 mmol/mol (7.45%±1.42) at M0. The paired Wilcoxon test likewise showed a significant difference between M6 and M0 (median 7.40; Q1, Q3: 6.50, 8.50) (p=0.014), with mean HbA1c levels decreasing from 62 mmol/mol (7.8%±1.62) at M6 to 60 mmol/mol (7.67%±1.48) at M3. However, the reduction in HbA1c levels was not significant between M3 and M0 as they decreased only slightly from 60 mmol/mol (7.67%±1.48) at M3 to 58 mmol/mol (7.45%±1.42) (p=0.072) at M0 (table 3 and figure 1).

<table><caption>**Table 3** Pairwise comparison of HbA1c levels for all diabetes types and for each group</caption><thead><tr><th>Diabetes type</th><th>Time 1</th><th>Time 2</th><th>Mean difference</th><th>SE</th><th>P value</th><th>Adjusted p value</th></tr></thead><tbody><tr><td>All</td><td>HbA1c_t0</td><td>HbA1c_m_3</td><td>-0.228</td><td>0.134</td><td>0.072</td><td>0.072</td></tr><tr><td>All</td><td>HbA1c_m_3</td><td>HbA1c_m_6</td><td>-0.627</td><td>0.234</td><td>0.012</td><td>0.021</td></tr><tr><td>All</td><td>HbA1c_t0</td><td>HbA1c_m_6</td><td>-0.608</td><td>0.232</td><td>0.014</td><td>0.021</td></tr><tr><td>Type 1</td><td>HbA1c_t0</td><td>HbA1c_m_3</td><td>-0.325</td><td>0.384</td><td>0.844</td><td>-</td></tr><tr><td>Type 1</td><td>HbA1c_m_3</td><td>HbA1c_m_6</td><td>-0.786</td><td>0.552</td><td>0.297</td><td>-</td></tr><tr><td>Type 1</td><td>HbA1c_t0</td><td>HbA1c_m_6</td><td>-0.667</td><td>0.485</td><td>0.210</td><td>-</td></tr><tr><td>Type 2</td><td>HbA1c_t0</td><td>HbA1c_m_3</td><td>-0.206</td><td>0.143</td><td>0.065</td><td>0.065</td></tr><tr><td>Type 2</td><td>HbA1c_m_3</td><td>HbA1c_m_6</td><td>-0.578</td><td>0.262</td><td>0.029</td><td>0.060</td></tr><tr><td>Type 2</td><td>HbA1c_t0</td><td>HbA1c_m_6</td><td>-0.579</td><td>0.258</td><td>0.04</td><td>0.060</td></tr></tbody></table>

HbA1c, hemoglobin A1c.
<figure><img src="image_3.png" /><figcaption>**Figure 1** Mean hemoglobin A1c (HbA1c) levels (mmol/mol) and their evolution at month 6 (M6), month 3 (M3), and month 0 (M0).</figcaption></figure>

We studied the evolution of HbA1c levels according to diabetes type (mixed model). A similar trend in the evolution of HbA1c was found (figure 2). There was a significant main effect of time between M6 and M0 and between M6 and M3. However, there were no significant main effects for diabetes type. It is important to note that the results of HbA1c adjusted and confounded for age, sex, body mass index, and duration of diabetes did not impact the significance of the reduction in HbA1c (table 4).

## DISCUSSION

CN generally evolves in two phases: (1) acute and (2) chronic.⁵⁶ The typical clinical picture of active CN is a red swollen joint with a temperature difference greater than 2°C compared with the unaffected joint. These symptoms may go unnoticed because the pain may be

<figure><img src="image_4.png" /><figcaption>**Figure 2** Mean hemoglobin A1c (HbA1c) levels (mmol/mol) and their evolution at month 6 (M6), month 3 (M3), and month 0 (M0) according to diabetes type.</figcaption></figure>

absent or disproportionate depending on the presence or absence of lesions on the foot.⁷ The pathogenic mechanisms of CN have been subject to a long-running debate with several diverging theories. The inflammatory arthropathy theory described by Jeffcoate² is the most common theory to explain the development of active CN. A new series of experiments were recently carried out to assess the evolution of bone modelling factors in the appearance of CN by associating RANKL and OPG.³ However, this explanation does not address the link between the appearance of the active phase of CN and the rapid correction of HbA1c levels. The latter element is increasingly present in the pathophysiology of CN, with several cases showing the onset of active CN after the rapid correction of HbA1c levels, as in the context of a double pancreatic kidney transplant⁸ or significant weight loss after bariatric surgery.⁹

<table><caption>**Table 4** HbA1c values adjusted for selected confounders</caption><thead><tr><th></th><th></th><th>Estimate</th><th>SE</th><th>Inferior</th><th>Superior</th><th>P value</th></tr></thead><tbody><tr><td>Intercept</td><td></td><td>11.2374</td><td>1.3134</td><td>8.6223</td><td>13.8525</td><td>&lt;0.0001</td></tr><tr><td rowspan="3">HbA1c (temporality)</td><td>M3</td><td>0.1876</td><td>0.1683</td><td>-0.1469</td><td>0.5222</td><td>0.268</td></tr><tr><td>M6</td><td>0.6137</td><td>0.1789</td><td>0.2581</td><td>0.9692</td><td>0.0009</td></tr><tr><td>M0</td><td>(ref)</td><td>(ref)</td><td>(ref)</td><td>(ref)</td><td>(ref)</td></tr><tr><td rowspan="2">Diabetes type</td><td>1</td><td>-0.3871</td><td>0.4516</td><td>-1.2878</td><td>0.5136</td><td>0.3942</td></tr><tr><td>2</td><td>(ref)</td><td>(ref)</td><td>(ref)</td><td>(ref)</td><td>(ref)</td></tr><tr><td>Age</td><td></td><td>-0.05798</td><td>0.01355</td><td>-0.08496</td><td>-0.031</td><td>&lt;0.0001</td></tr><tr><td rowspan="2">Sex</td><td>Female</td><td>-0.09947</td><td>0.3303</td><td>-0.7583</td><td>0.5594</td><td>0.7642</td></tr><tr><td>Male</td><td>(ref)</td><td>(ref)</td><td>(ref)</td><td>(ref)</td><td>(ref)</td></tr><tr><td>BMI</td><td></td><td>-0.01083</td><td>0.02981</td><td>-0.07028</td><td>0.04862</td><td>0.7174</td></tr><tr><td rowspan="3">Age of diabetes</td><td>≥20</td><td>0.5098</td><td>0.4354</td><td>-0.3579</td><td>1.3776</td><td>0.2454</td></tr><tr><td>10-20</td><td>0.4165</td><td>0.4161</td><td>-0.4129</td><td>1.246</td><td>0.3202</td></tr><tr><td>&lt;10</td><td>(ref)</td><td>(ref)</td><td>(ref)</td><td>(ref)</td><td>(ref)</td></tr></tbody></table>

BMI, body mass index; HbA1c, hemoglobin A1c; M3, month 3; M6, month 6; ref, reference.
Our study included 103 people with acute CN. This
represents a large sample size for a rare disorder, as
its frequency varies between 0.1% and 0.4% of people
with diabetes.¹⁰ Nevertheless, aggressive antidia-
betic therapy and rapid glycemic control may result
in diabetic neuropathy, also known as treatment-
induced neuropathy of diabetes (TIND).¹¹ It is note-
worthy that in the clinical presentation of active CN
and TIND, a common symptom is hypervasculariza-
tion in the extremities.

Taking the above elements into account, we may
legitimately consider that the rapid and significant
correction of HbA1c levels may accompany the onset
of the active phase of CN. An interesting evaluation¹²
demonstrated that the RANKL antagonist OPG is inhib-
ited by hyperglycemia correction, which may explain
the elevated levels of RANKL observed during the
active phase of CN.³ Indeed, high RANKL levels will
be linked to the inhibition of its antagonist following
decrease in HbA1c levels. It is important to mention
that osteoblast,² the cell described as the main actor
in the pathophysiology of CN, has insulin receptors
on its membranes. We may therefore suppose that the
sensitivity of these cells to insulin changes in the event
of a significant reduction in HbA1c levels. Therefore,
the rapid correction of hyperglycemia seems to be the
inflammation-inducing factor, which is described by
Jeffcoate² as a core component in the mosaic of the CN
pathophysiology.

In conclusion, the link between the onset of active
CN and a significant reduction in HbA1c levels
is once again brought to light in this paper. This
description can help to understand the physiopa-
thology of CN and potentially to implement moni-
toring measures, screening, and support for patients
living with neuropathy-complicated diabetes who
intend to rapidly correct their HbA1c levels.

Author affiliations

¹Diabetology, Centre Hospitalier Sud Francilien, Corbeil Essonne, France

²LBEPS, Université d'Evry, Evry, France

³Department of Endocrinology, Diabetology and Nutrition, University Hospital Nîmes, Nîmes, France

⁴Montpellier Medical School, Montpellier, France

⁵Diabetology, Hôpital Universitaire Pitie Salpetriere, Paris, France

⁶Diabetology, University Hospital Cochin, Paris, France

⁷Department of Endocrinology-Diabetology University Hospital Kremlin-Bicêtre
France + Department of Medecine University Hospital Antoine Béclère Clamart
France, Kremlin-Bicêtre, France

⁸Phymedexp, Université de Montpellier, Inserm, CNRS, CHRU de Montpellier,
Montpellier, France

¹Endocrinology Diabetes Department, CHU Montpellier, Montpellier, France

¹⁰Department of Endocrinology and Diabetology, Roubaix Hospital, Roubaix, France

¹¹Department of Endocrinology and Diabetology, University Hospital Jean Minjoz,
Besançon, France

¹²Department of Endocrinology and Diabetology, Claude Huriez Regional University Hospital, Lille, France

¹³Department of Endocrinology and Diabetology, Nutrition Robert Debré Hospital, Reims, France

¹⁴Department of Endocrinology and Diabetology, Hôtel Dieu Hospital, Le Creusot, France

¹⁵Department of Endocrinology and Diabetology, University Hospital Rangueil, Toulouse, France

¹⁶Department of Endocrinology and Diabetology, Lyon South Hospital, Lyon, France

¹⁷Department of Endocrinology and Diabetology, Cardiology Hospital Louis Pradel, Bron, France

¹⁸Le Coudray Hospital, Paris, France

¹⁹Department of Endocrinology and Diabetology, University Hospital, Pointe-à-Pitre, France

²⁰Department of Endocrinology and Diabetology, Haut-Lévêque University Hospital, Pessac, France

²¹Bordeaux Medical School, Bordeaux, France

²²Centre du pied, Ransart, Belgium

²³Internal Medicine Rheumatology Nutrition Endocrinology Diabetes Pole, Strasbourg University Hospitals, Strasbourg, France

²⁴Medicine School Strasbourg, Strasbourg, France

²⁵Department of Endocrinology, Diabetology and Nutrition, Dijon University Hospital, Dijon, France

²⁶INSERM Unit, LNC-UMR 1231, University of Burgundy, DIJON, France

²⁷Department of Infectiology, Annecy Genevois Hospital, Metz-Tessy, France

²⁸Vienne Hospital Centre Indoor Use Pharmacy, Vienne, France

²⁹Department of Endocrinology and Diabetology, Vichy Hospital, Vichy, France

³⁰University Hospital Centre Nice, Nice, France

³¹Department of Endocrinology and Diabetology, CHU MICHALON, Grenoble, France

³²Anesthesia Department, Tourcoing Hospital Center, Tourcoing, France

³³BESPIM Nîmes University Hospital, Nîmes, France

³⁴Department of Diabetes, Pitié Salpêtrière Hospital, Paris, France

³⁵Sorbonne University Médicine, PARIS, FRANCE

**Acknowledgements** The authors acknowledge the Diabetic Foot Group of the French Society of Diabetology for their support.

**Contributors** DD, SS, C-AJ, GHV, JM'B, MB, AS, ML, SG-V, FB, MF, SC, and JM conceived of the presented idea. DD, JV, PM, MMO, AM, VC-M, VR, ID, LK, IS, BB, PB, AL, EDCC, MMBF, MMu, MC, MZZ, and AH developed the theoretical formalism, performed the analytic calculations, and performed the numerical simulations.

**Funding** The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

**Competing interests** None declared.

**Patient consent for publication** Not required.

**Ethics approval** This study involves human participants. According to French law (Decree No 2016-1872 of December 26, 2016), a file was submitted to INDS (Institut National des Données de Santé) and CEREES (Comité d'Expertise pour les Recherches, les Etudes et les Evaluations dans le domaine de la Santé) for approval. The EPICHAR study received agreement from the ethical committee for the protection of patients (Barboin hospital authorization number: 18.09.01). Participants gave informed consent to participate in the study before taking part.

**Provenance and peer review** Not commissioned; externally peer reviewed.

**Data availability statement** All data relevant to the study are included in the article or uploaded as supplementary information.

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