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Glycaemic control during the lockdown for COVID-19 in adults with type 1 diabetes: A meta-analysis of observational studies

  • Monia Garofolo
    Affiliations
    Section of Diabetes and Metabolic Disease, Department of Clinical and Experimental Medicine, University of Pisa and Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
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  • Michele Aragona
    Affiliations
    Section of Diabetes and Metabolic Disease, Department of Clinical and Experimental Medicine, University of Pisa and Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
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  • Cosimo Rodia
    Affiliations
    Section of Endocrinology, ASL Brindisi, DSS-1, Brindisi, Italy
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  • Pierpaolo Falcetta
    Affiliations
    Section of Diabetes and Metabolic Disease, Department of Clinical and Experimental Medicine, University of Pisa and Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
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  • Alessandra Bertolotto
    Affiliations
    Section of Diabetes and Metabolic Disease, Department of Clinical and Experimental Medicine, University of Pisa and Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
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  • Fabrizio Campi
    Affiliations
    Section of Diabetes and Metabolic Disease, Department of Clinical and Experimental Medicine, University of Pisa and Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
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  • Stefano Del Prato
    Correspondence
    Corresponding author at: Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, Via Paradisa, 2, 56124 Pisa, Italy.
    Affiliations
    Section of Diabetes and Metabolic Disease, Department of Clinical and Experimental Medicine, University of Pisa and Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
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  • Giuseppe Penno
    Affiliations
    Section of Diabetes and Metabolic Disease, Department of Clinical and Experimental Medicine, University of Pisa and Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
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Published:September 22, 2021DOI:https://doi.org/10.1016/j.diabres.2021.109066

      Abstract

      Aims

      To assess the effects of lockdown due to COVID-19 pandemic on glucose metrics, measured by glucose monitoring systems, in adult individuals with type 1 diabetes.

      Methods

      We conducted a systematic literature search for English language articles from MEDLINE, Scopus and Web of Science up to February 28, 2021, using “diabetes”, “lockdown”, and “glucose” as key search terms. Time in range (TIR) was the main outcome; other metrics were time above range (TAR), time below range (TBR), mean blood glucose (MBG) and its variability (%CV), estimated HbA1c (eA1c) or glucose management indicator (GMI).

      Results

      Seventeen studies for a total of 3,441 individuals with type 1 diabetes were included in the analysis. In the lockdown period, TIR 70–180 mg/dl increased by 3.05% (95% CI 1.67–4.43%; p < 0.0001) while TAR (>180 mg/dL and > 250 mg/dL) declined by 3.39% (−5.14 to −1.63%) and 1.96% (−2.51 to −1.42%), respectively (p < 0.0001 for both). Both TBR < 70 and <54 mg/dL remained unchanged. MBG slightly decreased by 5.40 mg/dL (−7.29 to −3.51 mg/dL; p < 0.0001) along with a reduction in %CV. Pooled eA1c and GMI decreased by 0.18% (−0.24 to −0.11%; p < 0.0001) and a similar reduction was observed when GMI alone was considered (0.15%, −0.23 to −0.07%; p < 0.0001). Sensor use was only slightly but not significantly reduced during lockdown.

      Conclusions

      This meta-analysis shows that well-controlled people with type 1 diabetes on both MDI and CSII with continuous or flash glucose monitoring did not experience a deterioration in glucose control throughout the COVID-19 lockdown, showing a modest, though statistically significant improvement in many glucose control parameters.

      Keywords

      1. Introduction

      The World Health Organization (WHO) declared the outbreak of Coronavirus Disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) a public health emergency of international concern on January 30th, 2020, and a pandemic on March 11th, 2020 [

      Statement on the second meeting of the International Health Regulations (2005) Emergency Committee regarding the outbreak of novel coronavirus (2019-nCoV)“, World Health Organization (WHO), 30 January 2020. Archived from the original on 31 January 2020. Accessed on 30 November 2020.

      ,

      “WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020”, World Health Organization, 11 March 2020. Accessed on 30 November 2020.

      ]. Right after that, many countries implemented mobility restrictions to limit the spreading of the pandemic, and in March many European countries entered a lockdown with severe limitations of people’s movement, including outdoor physical activity and access to hospitals and health services for routine care. This has resulted in drastic changes in everyone’s daily habits, family, social, and work relationships.
      Diabetes ranks among the most prevalent comorbidities in subjects with COVID-19, after cardiovascular diseases [
      • Riddle M.C.
      Diabetes and COVID-19: Moving from News to Knowledge and a Glucose Hypothesis.
      ]. People with diabetes are up to three times more likely than non-diabetic subjects to develop a more severe COVID-19 with increased need for admission to ICU, mechanical ventilation as well as higher mortality [
      • Riddle M.C.
      Diabetes and COVID-19: Moving from News to Knowledge and a Glucose Hypothesis.
      ,
      • McGurnaghan S.J.
      • Weir A.
      • Bishop J.
      • Kennedy S.
      • Blackbourn L.A.K.
      • McAllister D.A.
      • et al.
      Public Health Scotland COVID-19 Health Protection Study Group; Scottish Diabetes Research Network Epidemiology Group. Risks of and risk factors for COVID-19 disease in people with diabetes: a cohort study of the total population of Scotland.
      ]. The perception of belonging to a highly vulnerable population entails a severe emotional impact in people with diabetes. Moreover, because of the lockdown, one could expect an increased sedentary behaviour, poorer diet adherence, more physiological stress that could affect daily management of chronic diseases like diabetes [
      • Koliaki C.
      • Tentolouris A.
      • Eleftheriadou I.
      • Melidonis A.
      • Dimitriadis G.
      • Tentolouris N.
      Clinical Management of Diabetes Mellitus in the Era of COVID-19: Practical Issues, Peculiarities and Concerns.
      ,
      • Wicaksana A.L.
      • Hertanti N.S.
      • Ferdiana A.
      • Pramono R.B.
      Diabetes management and specific considerations for patients with diabetes during coronavirus diseases pandemic: A scoping review.
      ] and undermine glycaemic control, especially in subjects on complex insulin therapy, such as those with type 1 diabetes. In these individuals, achievement of glycaemic control is a complex task requiring multiple daily activities, including glucose monitoring and adequate insulin dose titration. This process has become easier and more effective by continuous glucose monitoring (CGM) or flash continuous monitoring (FGM) systems and data uploading on online platforms. These large repositories of glucose control data have offered a unique opportunity to explore the impact of the lockdown on glycaemic control in patients with type 1 diabetes. At variance of what was expected, rather than a worsening a trend toward improved glycaemic control has been reported. However, most of these studies included a limited number of participants so that the true impact of the lockdown in people with type 1 diabetes remains inconclusive.
      Therefore, we have performed an updated systematic review and meta-analysis of studies assessing the effects of lockdown during COVID-19 pandemic on glucose metrics in adult subjects with type 1 diabetes using CGM or FGM.

      2. Methods

      2.1 Information sources and study selection

      We conducted a systematic literature search on Medline, Scopus and Web of Science for articles published in English up to 28 February 2021 using the key search terms “diabetes”, “lockdown”, and “glucose”. We reviewed all abstracts obtained from the search, examined reference lists to check for additional potentially relevant publications and obtained full text of all articles. A systematic review and meta-analysis were then conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [
      • Moher D.
      • Liberati A.
      • Tetzlaf J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ]. Protocol of this meta-analysis has been submitted for registration to PROSPERO #CRD42021266936 (https://www.crd.york.ac.uk/PROSPERO/).
      Prespecified inclusion criteria were 1) cohort observational studies of adult patients with type 1 diabetes exploring the impact of lockdown on glucose control; and 2) studies based on data obtained by CGM or FGM. Studies were excluded if they 1) included children, adolescents, or pregnant women, 2) included only subjects with type 2 diabetes, 3) glycaemic control was assessed by self-monitoring blood glucose (SMBG) or self-reported. Eligible studies had to provide at least the following information: age, type of diabetes, pre- and during-lockdown periods of observation, type of glucose monitoring (CGM and/or FGM), percentage of time in range (TIR; 70–180 mg/dL) and/or other relevant glucose metrics [
      • Battelino T.
      • Danne T.
      • Bergenstal R.M.
      • Amiel S.A.
      • Beck R.
      • Biester T.
      • et al.
      Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range.
      ,
      • Danne T.
      • Nimri R.
      • Battelino T.
      • Bergenstal R.M.
      • Close K.L.
      • DeVries J.H.
      • et al.
      International Consensus on Use of Continuous Glucose Monitoring.
      ,
      • Bruttomesso D.
      • Laviola L.
      • Avogaro A.
      • Bonora E.
      • Del Prato S.
      • Frontoni S.
      • et al.
      of the Italian Diabetes Society (SID). The use of real time continuous glucose monitoring or flash glucose monitoring in the management of diabetes: A consensus view of Italian diabetes experts using the Delphi method.
      ].
      The systemic search for literature was conducted by two independent investigators (MG and GP) and retrieved articles were independently examined for eligibility by the same investigators. Conflicts were resolved by consensus with a third investigator (SDP). Data were extracted by using pre-determined forms and mainly included: first author, year of publication, country where the study was performed, periods of observation, type of diabetes, sample size, type of glucose monitoring (CGM or FGM), type of therapy (CSII or MDI), pre- and during-lockdown TIR and/or other glucose metrics including time above range (TAR; >180 mg/dL and >250 mg/dL), time below range (TBR; <70 mg/dL and <54 mg/dL), glucose variability estimated as coefficient of variation (%CV), average glucose (mg/dL), glucose management indicator (GMI) or estimated HbA1c (eA1c) [
      • Leelarathna L.
      • Thabit H.
      • Hovorka R.
      • Evans M.
      Estimated HbA1c and glucose management indicator (GMI): are they the same?.
      ], and percentage of sensor use (%).
      The risk of bias for each study (Supplementary Table 1), was evaluated by the Newcastle-Ottawa Scale [

      G.A. Wells, B. Shea, D. O'Connell, et al., The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed on 30 November 2020).

      ]. To be considered a high-quality study, ≥3 stars (score) in the selection domain and ≥ 1 star in the comparability domain, and ≥2 stars in the outcome domain were required.

      2.2 Statistical analysis

      We tabulated the characteristics of all included studies. The Comprehensive Meta-Analysis software V3 (Biostat, Englewood, NJ, USA) was employed to perform the meta-analyses using mean, standard deviation (SD; pre- and post-data) and sample size. Statistical heterogeneity of studies was assessed using I2 index (<50%, 50–75%, and >75% represent low, moderate, and high heterogeneity, respectively). We analysed the results pooling differences in means and lower and upper limits (95% confidence interval, CI) by the random effect model to minimize the heterogeneity or between-study variance because the included studies differed to some extent both clinically and methodologically. Where appropriate, we performed a sensitivity analysis after exclusion of studies with adjunctive specific inclusion criteria. Potential publication bias was analysed using Egger’s test and by inspection of the funnel plots. Funnel plots and Egger’s test results are provided in the supplementary appendix. Institutional ethical approval was not required because this was a meta-analysis of primary published studies only.

      3. Results

      A total of 221 articles were obtained. After screening titles and abstracts, and after applying all inclusion/exclusion criteria, 18 studies were selected. A further study was excluded because subjects with type 1 diabetes were on a hybrid closed-loop system [
      • Longo M.
      • Caruso P.
      • Petrizzo M.
      • Castaldo F.
      • Sarnataro A.
      • Gicchino M.
      • et al.
      Glycemic control in people with type 1 diabetes using a hybrid closed loop system and followed by telemedicine during the COVID-19 pandemic in Italy.
      ]; thus, a final number of 17 studies was included in this analysis (Fig. 1). Table 1 summarizes the main characteristics of these studies. All of them had retrospective observational design; seven studies have been carried out in Italy [
      • Bonora B.M.
      • Boscari F.
      • Avogaro A.
      • Bruttomesso D.
      • Fadini G.P.
      Glycaemic Control Among People with Type 1 Diabetes During Lockdown for the SARS-CoV-2 Outbreak in Italy.
      ,
      • Maddaloni E.
      • Coraggio L.
      • Pieralice S.
      • Carlone A.
      • Pozzilli P.
      • Buzzetti R.
      Effects of COVID-19 Lockdown on Glucose Control: Continuous Glucose Monitoring Data From People With Diabetes on Intensive Insulin Therapy.
      ,
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      ,
      • Caruso I.
      • Di Molfetta S.
      • Guarini F.
      • Giordano F.
      • Cignarelli A.
      • Natalicchio A.
      • et al.
      Reduction of hypoglycaemia, lifestyle modifications and psychological distress during lockdown following SARS-CoV-2 outbreak in type 1 diabetes.
      ,
      • Aragona M.
      • Rodia C.
      • Bertolotto A.
      • Campi F.
      • Coppelli A.
      • Giannarelli R.
      • et al.
      Type 1 diabetes and COVID-19: The “lockdown effect”.
      ,
      • Barchetta I.
      • Cimini F.A.
      • Bertoccini L.
      • Ceccarelli V.
      • Spaccarotella M.
      • Baroni M.G.
      • et al.
      Effects of work status changes and perceived stress on glycaemic control in individuals with type 1 diabetes during COVID-19 lockdown in Italy.
      ,
      • Di Dalmazi G.
      • Maltoni G.
      • Bongiorno C.
      • Tucci L.
      • Di Natale V.
      • Moscatiello S.
      • et al.
      Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.
      ], six in Spain [
      • Fernández E.
      • Cortazar A.
      • Bellido V.
      Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.
      ,
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ,
      • Cotovad-Bellas L.
      • Tejera-Pérez C.
      • Prieto-Tenreiro A.
      • Sánchez-Bao A.
      • Bellido-Guerrero D.
      The challenge of diabetes home control in COVID-19 times: Proof is in the pudding.
      ,
      • Viñals C.
      • Mesa A.
      • Roca D.
      • Vidal M.
      • Pueyo I.
      • Conget I.
      • et al.
      Management of glucose profile throughout strict COVID-19 lockdown by patients with type 1 diabetes prone to hypoglycaemia using sensor-augmented pump.
      ,
      • Pla B.
      • Arranz A.
      • Knott C.
      • Sampedro M.
      • Jiménez S.
      • Hernando I.
      • et al.
      Impact of COVID-19 Lockdown on Glycemic Control in Adults with Type 1 Diabetes Mellitus.
      ,
      • Moreno-Domínguez Ó.
      • González-Pérez de Villar N.
      • Barquiel B.
      • Hillman-Gadea N.
      • Gaspar-Lafuente R.
      • Arévalo-Gómez M.
      • et al.
      Factors Related to Improvement of Glycemic Control Among Adults with Type 1 Diabetes During Lockdown Due to COVID-19.
      ], two in UK [
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      ,
      • Prabhu Navis J.
      • Leelarathna L.
      • Mubita W.
      • Urwin A.
      • Rutter M.K.
      • Schofield J.
      • et al.
      Impact of COVID-19 lockdown on flash and real-time glucose sensor users with type 1 diabetes in England.
      ], and one in Greece [
      • Barmpagianni A.
      • Lambadiari V.
      • Papazafiropoulou A.
      • Kountouri A.
      • Stergiou A.
      • Melidonis A.
      • et al.
      Glycemic Control of Patients with Type 1 Diabetes Using an Insulin Pump Before and During the COVID-19–Associated Quarantine.
      ] and one in France [
      • Potier L.
      • Hansel B.
      • Larger E.
      • Gautier J.-F.
      • Carreira D.
      • Assemien R.
      • et al.
      Stay-at-Home Orders During the COVID-19 Pandemic, an Opportunity to Improve Glucose Control Through Behavioral Changes in Type 1 Diabetes.
      ]. The sample size ranged from a minimum of 33 and a maximum of 1,378 subjects per study, with a total of 3,441 individuals. One study included few participants with other types of diabetes [
      • Maddaloni E.
      • Coraggio L.
      • Pieralice S.
      • Carlone A.
      • Pozzilli P.
      • Buzzetti R.
      Effects of COVID-19 Lockdown on Glucose Control: Continuous Glucose Monitoring Data From People With Diabetes on Intensive Insulin Therapy.
      ], one study compared subjects who continued vs. those who did not continue working during lockdown [
      • Bonora B.M.
      • Boscari F.
      • Avogaro A.
      • Bruttomesso D.
      • Fadini G.P.
      Glycaemic Control Among People with Type 1 Diabetes During Lockdown for the SARS-CoV-2 Outbreak in Italy.
      ]. For this study [
      • Bonora B.M.
      • Boscari F.
      • Avogaro A.
      • Bruttomesso D.
      • Fadini G.P.
      Glycaemic Control Among People with Type 1 Diabetes During Lockdown for the SARS-CoV-2 Outbreak in Italy.
      ], subjects who stopped working and those who continued working were included separately in the analysis. Two studies explicitly included subjects prone to hypoglycaemia [
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ,
      • Viñals C.
      • Mesa A.
      • Roca D.
      • Vidal M.
      • Pueyo I.
      • Conget I.
      • et al.
      Management of glucose profile throughout strict COVID-19 lockdown by patients with type 1 diabetes prone to hypoglycaemia using sensor-augmented pump.
      ]. Finally, there was no homogeneity between studies across the selected pre- and during lockdown periods (Table 1). Egger’s tests and funnel plots inspection did not show significant publication bias (Supplementary Fig. 1 and Supplementary Table 2).
      Table 1Baseline characteristics of subjects enrolled in the 17 studies included in the meta-analysis.
      StudyCountryn.Type of DMObservation periods compared in the meta-analysisAge (years)DD (years)HbA1c (%)% of CGM/FGM% of MDI/CSII
      Bonora BM et al, 2020
      • Bonora B.M.
      • Boscari F.
      • Avogaro A.
      • Bruttomesso D.
      • Fadini G.P.
      Glycaemic Control Among People with Type 1 Diabetes During Lockdown for the SARS-CoV-2 Outbreak in Italy.
      Italy20

      13
      20 subjects stopped working; 13 subjects continued working; ‡ subjects prone to hypoglycaemia; § sensor data comparison between pre-lockdown and lockdown periods available for 223 individuals; ¶ this study included also 30 children (≤12 years) and 24 teenagers (13–17 years).
      100%

      T1DM
      1 week before the SARS-CoV-2 outbreak vs the first week after lockdown36.9 ± 13.4

      45.0 ± 12.0
      15.0 ± 11.1

      24.6 ± 12.3
      7.6 ± 1.2

      7.3 ± 0.6
      100% FGM76% MDI

      24% CSII
      Maddaloni E et al, 2020
      • Maddaloni E.
      • Coraggio L.
      • Pieralice S.
      • Carlone A.
      • Pozzilli P.
      • Buzzetti R.
      Effects of COVID-19 Lockdown on Glucose Control: Continuous Glucose Monitoring Data From People With Diabetes on Intensive Insulin Therapy.
      Italy5591% T1DM

      5% T2DM

      4% post-pancreatectomy
      14 days preceding lockdown (24 February to 8 March) and 14 days following lockdown (10–25 March)41

      [IQR 28–49]
      11

      [IQR 5–23]
      100% CGM, not specified51% MDI

      49% CSII
      Capaldo B et al, 2020
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      Italy207100% T1DM2 weeks before lockdown (January to February) and 2 weeks during lockdown (March to April)38.4 ± 12.763% FGM

      37% CGM
      50% MDI

      50% CSII
      Fernandez E et al, 2020
      • Fernández E.
      • Cortazar A.
      • Bellido V.
      Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.
      Spain307100% T1DM14 days before start of lockdown (1–14 March) to the last 14 days of 8 weeks of lockdown (25 April to 9 May)45.8 ± 12.621.1 ± 12.3100% FGM93% MDI

      7% CSII
      Mesa A et al, 2020
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      Spain92100% T1DMBefore lockdown (23 February to 7 March) to during lockdown (1–14 April)42.8 ± 13.923.1 ± 12.682% FGM

      18% CGM
      100% MDI
      Dover AR et al, 2020
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      UK572100% T1DMBefore lockdown (within 7 days of 11 March) to during lockdown (within 7 days of 14 May)39

      [IQR 31–50)
      18

      [IQR 9–27)
      7.6

      [IQR 7.0–8.3)
      100% FGM74% MDI

      26% CSII
      Cotovad-Bellas L et al, 2020
      • Cotovad-Bellas L.
      • Tejera-Pérez C.
      • Prieto-Tenreiro A.
      • Sánchez-Bao A.
      • Bellido-Guerrero D.
      The challenge of diabetes home control in COVID-19 times: Proof is in the pudding.
      Spain44100% T1DM2 weeks before lockdown (1–14 March) to 2 weeks during lockdown (6–19 April)37 ± 18100% FGM100% MDI
      Caruso I et al, 2020
      • Caruso I.
      • Di Molfetta S.
      • Guarini F.
      • Giordano F.
      • Cignarelli A.
      • Natalicchio A.
      • et al.
      Reduction of hypoglycaemia, lifestyle modifications and psychological distress during lockdown following SARS-CoV-2 outbreak in type 1 diabetes.
      Italy48100% T1DMBefore lockdown (first 2 weeks of February) to the last 2 weeks before a remote scheduled visit on April42.4 ± 15.97.4 ± 1.0100% FGM81% MDI

      19% CSII
      Aragona M et al, 2020
      • Aragona M.
      • Rodia C.
      • Bertolotto A.
      • Campi F.
      • Coppelli A.
      • Giannarelli R.
      • et al.
      Type 1 diabetes and COVID-19: The “lockdown effect”.
      Italy63100% T1DM14 days before start of lockdown (21 February − 6 March) to mid-lockdown (11–25 April)44 ± 1222 [IQR 12–327.2 ± 0.982% FGM

      18% CGM
      56% MDI

      44% CSII
      Prabhu Navis J et al, 2020
      • Prabhu Navis J.
      • Leelarathna L.
      • Mubita W.
      • Urwin A.
      • Rutter M.K.
      • Schofield J.
      • et al.
      Impact of COVID-19 lockdown on flash and real-time glucose sensor users with type 1 diabetes in England.
      UK269§100% T1DMPre-lockdown period (1–14 February) and mid-lockdown period (1–14 May)41.4 ± 12.923.6 ± 12.97.3 ± 1.371% FGM

      29% CGM
      30% MDI

      70% CSII
      Barchetta I et al, 2020
      • Barchetta I.
      • Cimini F.A.
      • Bertoccini L.
      • Ceccarelli V.
      • Spaccarotella M.
      • Baroni M.G.
      • et al.
      Effects of work status changes and perceived stress on glycaemic control in individuals with type 1 diabetes during COVID-19 lockdown in Italy.
      Italy50100% T1DMPre-lockdown period (20 January − 3 February) and mid-lockdown period

      (28 March − 11 April)
      40.7 ± 13.517.7 ± 9.77.3 [IQR 6.6–7.8]44% CGM

      56% FGM
      56% MDI

      44& CSII
      Di Dalmazi G et al. 2020
      • Di Dalmazi G.
      • Maltoni G.
      • Bongiorno C.
      • Tucci L.
      • Di Natale V.
      • Moscatiello S.
      • et al.
      Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.
      Italy76100% T1DM20 days before the lockdown (20 February − 10 March) and 20 days starting from 11 to 30 March (during lockdown)45.0 [IQR 29.0–58.1]22.0 [IQR 14.3–30.8]7.3 [IQR 6.6–8.0]46% CGM

      54% FGM
      83% MDI

      17% CSII
      Vinals C. et al, 2020
      • Viñals C.
      • Mesa A.
      • Roca D.
      • Vidal M.
      • Pueyo I.
      • Conget I.
      • et al.
      Management of glucose profile throughout strict COVID-19 lockdown by patients with type 1 diabetes prone to hypoglycaemia using sensor-augmented pump.
      Spain59100% T1DM using SAP14 consecutive days before lockdown (23 February − 7 March) to 14 consecutive days during lockdown (1–14 April)46.2 ± 13.0100% CGM100% CSII
      Pla B. et al, 2020
      • Pla B.
      • Arranz A.
      • Knott C.
      • Sampedro M.
      • Jiménez S.
      • Hernando I.
      • et al.
      Impact of COVID-19 Lockdown on Glycemic Control in Adults with Type 1 Diabetes Mellitus.
      Spain50100% T1DM14 days before start of lockdown (1–14 March) to 14 days during lockdown (from 11 april onwards)43.4 ± 15.622.2 ± 12.27.3 ± 0.8100% FGM90% MDI

      10% CSII
      Barmpagianni A et al, 2021
      • Barmpagianni A.
      • Lambadiari V.
      • Papazafiropoulou A.
      • Kountouri A.
      • Stergiou A.
      • Melidonis A.
      • et al.
      Glycemic Control of Patients with Type 1 Diabetes Using an Insulin Pump Before and During the COVID-19–Associated Quarantine.
      Greece46100% T1DM15 days immediately before lockdown and lockdown days 16–3038.2 ± 12.919.5 [IQR 12–28]100% FGM100% CSII
      Moreno-Dominguez O et al, 2020
      • Moreno-Domínguez Ó.
      • González-Pérez de Villar N.
      • Barquiel B.
      • Hillman-Gadea N.
      • Gaspar-Lafuente R.
      • Arévalo-Gómez M.
      • et al.
      Factors Related to Improvement of Glycemic Control Among Adults with Type 1 Diabetes During Lockdown Due to COVID-19.
      Spain138100% T1DM2 weeks before lockdown (21 February – 5 March) and 2 weeks of lockdown (16–29 March)42.5 ± 15.321.7 ± 13.87.1 ± 0.9100% FGM81% MDI

      19% CSII
      Potier L et al, 2020
      • Potier L.
      • Hansel B.
      • Larger E.
      • Gautier J.-F.
      • Carreira D.
      • Assemien R.
      • et al.
      Stay-at-Home Orders During the COVID-19 Pandemic, an Opportunity to Improve Glucose Control Through Behavioral Changes in Type 1 Diabetes.
      France1,378100% T1DM1 month after lockdown (17 March) and two months before lockdown45.6 ± 13.67.4 ± 1.0100% FGM84% MDI

      16% CSII
      DM: diabetes mellitus; T1DM: type 1 diabetes mellitus; T2DM: type 2 diabetes mellitus; DD: diabetes duration; CGM: continuous glucose monitoring; FGM: flash glucose monitoring; MDI: multiple daily insulin; CSII: continuous subcutaneous insulin infusion; SAP sensor-augmented pump.
      20 subjects stopped working; 13 subjects continued working; subjects prone to hypoglycaemia; § sensor data comparison between pre-lockdown and lockdown periods available for 223 individuals; this study included also 30 children (≤12 years) and 24 teenagers (13–17 years).

      3.1 Time in range (TIR)

      TIR was the only outcome available in all studies [
      • Bonora B.M.
      • Boscari F.
      • Avogaro A.
      • Bruttomesso D.
      • Fadini G.P.
      Glycaemic Control Among People with Type 1 Diabetes During Lockdown for the SARS-CoV-2 Outbreak in Italy.
      ,
      • Maddaloni E.
      • Coraggio L.
      • Pieralice S.
      • Carlone A.
      • Pozzilli P.
      • Buzzetti R.
      Effects of COVID-19 Lockdown on Glucose Control: Continuous Glucose Monitoring Data From People With Diabetes on Intensive Insulin Therapy.
      ,
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      ,
      • Caruso I.
      • Di Molfetta S.
      • Guarini F.
      • Giordano F.
      • Cignarelli A.
      • Natalicchio A.
      • et al.
      Reduction of hypoglycaemia, lifestyle modifications and psychological distress during lockdown following SARS-CoV-2 outbreak in type 1 diabetes.
      ,
      • Aragona M.
      • Rodia C.
      • Bertolotto A.
      • Campi F.
      • Coppelli A.
      • Giannarelli R.
      • et al.
      Type 1 diabetes and COVID-19: The “lockdown effect”.
      ,
      • Barchetta I.
      • Cimini F.A.
      • Bertoccini L.
      • Ceccarelli V.
      • Spaccarotella M.
      • Baroni M.G.
      • et al.
      Effects of work status changes and perceived stress on glycaemic control in individuals with type 1 diabetes during COVID-19 lockdown in Italy.
      ,
      • Di Dalmazi G.
      • Maltoni G.
      • Bongiorno C.
      • Tucci L.
      • Di Natale V.
      • Moscatiello S.
      • et al.
      Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.
      ,
      • Fernández E.
      • Cortazar A.
      • Bellido V.
      Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.
      ,
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ,
      • Cotovad-Bellas L.
      • Tejera-Pérez C.
      • Prieto-Tenreiro A.
      • Sánchez-Bao A.
      • Bellido-Guerrero D.
      The challenge of diabetes home control in COVID-19 times: Proof is in the pudding.
      ,
      • Viñals C.
      • Mesa A.
      • Roca D.
      • Vidal M.
      • Pueyo I.
      • Conget I.
      • et al.
      Management of glucose profile throughout strict COVID-19 lockdown by patients with type 1 diabetes prone to hypoglycaemia using sensor-augmented pump.
      ,
      • Pla B.
      • Arranz A.
      • Knott C.
      • Sampedro M.
      • Jiménez S.
      • Hernando I.
      • et al.
      Impact of COVID-19 Lockdown on Glycemic Control in Adults with Type 1 Diabetes Mellitus.
      ,
      • Moreno-Domínguez Ó.
      • González-Pérez de Villar N.
      • Barquiel B.
      • Hillman-Gadea N.
      • Gaspar-Lafuente R.
      • Arévalo-Gómez M.
      • et al.
      Factors Related to Improvement of Glycemic Control Among Adults with Type 1 Diabetes During Lockdown Due to COVID-19.
      ,
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      ,
      • Prabhu Navis J.
      • Leelarathna L.
      • Mubita W.
      • Urwin A.
      • Rutter M.K.
      • Schofield J.
      • et al.
      Impact of COVID-19 lockdown on flash and real-time glucose sensor users with type 1 diabetes in England.
      ,
      • Barmpagianni A.
      • Lambadiari V.
      • Papazafiropoulou A.
      • Kountouri A.
      • Stergiou A.
      • Melidonis A.
      • et al.
      Glycemic Control of Patients with Type 1 Diabetes Using an Insulin Pump Before and During the COVID-19–Associated Quarantine.
      ,
      • Potier L.
      • Hansel B.
      • Larger E.
      • Gautier J.-F.
      • Carreira D.
      • Assemien R.
      • et al.
      Stay-at-Home Orders During the COVID-19 Pandemic, an Opportunity to Improve Glucose Control Through Behavioral Changes in Type 1 Diabetes.
      ]. TIR increased in all but one study [
      • Barchetta I.
      • Cimini F.A.
      • Bertoccini L.
      • Ceccarelli V.
      • Spaccarotella M.
      • Baroni M.G.
      • et al.
      Effects of work status changes and perceived stress on glycaemic control in individuals with type 1 diabetes during COVID-19 lockdown in Italy.
      ]. Overall, TIR (difference in means) increased by 3.05% (95% CI 1.67 to 4.43%; p < 0.0001) during lockdown, with high heterogeneity (I2 = 92%; Fig. 2A). The statistics did not change after removal of individual studies and even after the removal of the study by Potier et al. (3.03%; 95% CI 1.42 to 4.64%; p < 0.0001), in which TIR was not set according to international recommendations [
      • Battelino T.
      • Danne T.
      • Bergenstal R.M.
      • Amiel S.A.
      • Beck R.
      • Biester T.
      • et al.
      Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range.
      ,
      • Danne T.
      • Nimri R.
      • Battelino T.
      • Bergenstal R.M.
      • Close K.L.
      • DeVries J.H.
      • et al.
      International Consensus on Use of Continuous Glucose Monitoring.
      ,
      • Bruttomesso D.
      • Laviola L.
      • Avogaro A.
      • Bonora E.
      • Del Prato S.
      • Frontoni S.
      • et al.
      of the Italian Diabetes Society (SID). The use of real time continuous glucose monitoring or flash glucose monitoring in the management of diabetes: A consensus view of Italian diabetes experts using the Delphi method.
      ] but was estimated from the mean TIR during the last 90-day period (including the very last 30 days of lockdown) as compared to these 30 lockdown days [
      • Potier L.
      • Hansel B.
      • Larger E.
      • Gautier J.-F.
      • Carreira D.
      • Assemien R.
      • et al.
      Stay-at-Home Orders During the COVID-19 Pandemic, an Opportunity to Improve Glucose Control Through Behavioral Changes in Type 1 Diabetes.
      ].
      Figure thumbnail gr2a
      Fig. 2Effect of lockdown on blood glucose metrics during lockdown compared to the pre-lockdown period. (A) time-in-range, TIR (70–180 mg/dL); (B) time-above-range, TAR (>180 mg/dL); (C) time-below-range, TBR (<70 mg/dL).
      Figure thumbnail gr2b
      Fig. 2Effect of lockdown on blood glucose metrics during lockdown compared to the pre-lockdown period. (A) time-in-range, TIR (70–180 mg/dL); (B) time-above-range, TAR (>180 mg/dL); (C) time-below-range, TBR (<70 mg/dL).

      3.2 Time above range (TAR)

      TAR, defined as time spent at glucose levels > 180 mg/dL, was available in 12 out of 17 studies [
      • Bonora B.M.
      • Boscari F.
      • Avogaro A.
      • Bruttomesso D.
      • Fadini G.P.
      Glycaemic Control Among People with Type 1 Diabetes During Lockdown for the SARS-CoV-2 Outbreak in Italy.
      ,
      • Caruso I.
      • Di Molfetta S.
      • Guarini F.
      • Giordano F.
      • Cignarelli A.
      • Natalicchio A.
      • et al.
      Reduction of hypoglycaemia, lifestyle modifications and psychological distress during lockdown following SARS-CoV-2 outbreak in type 1 diabetes.
      ,
      • Aragona M.
      • Rodia C.
      • Bertolotto A.
      • Campi F.
      • Coppelli A.
      • Giannarelli R.
      • et al.
      Type 1 diabetes and COVID-19: The “lockdown effect”.
      ,
      • Barchetta I.
      • Cimini F.A.
      • Bertoccini L.
      • Ceccarelli V.
      • Spaccarotella M.
      • Baroni M.G.
      • et al.
      Effects of work status changes and perceived stress on glycaemic control in individuals with type 1 diabetes during COVID-19 lockdown in Italy.
      ,
      • Di Dalmazi G.
      • Maltoni G.
      • Bongiorno C.
      • Tucci L.
      • Di Natale V.
      • Moscatiello S.
      • et al.
      Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.
      ,
      • Fernández E.
      • Cortazar A.
      • Bellido V.
      Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.
      ,
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ,
      • Viñals C.
      • Mesa A.
      • Roca D.
      • Vidal M.
      • Pueyo I.
      • Conget I.
      • et al.
      Management of glucose profile throughout strict COVID-19 lockdown by patients with type 1 diabetes prone to hypoglycaemia using sensor-augmented pump.
      ,
      • Moreno-Domínguez Ó.
      • González-Pérez de Villar N.
      • Barquiel B.
      • Hillman-Gadea N.
      • Gaspar-Lafuente R.
      • Arévalo-Gómez M.
      • et al.
      Factors Related to Improvement of Glycemic Control Among Adults with Type 1 Diabetes During Lockdown Due to COVID-19.
      ,
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      ,
      • Prabhu Navis J.
      • Leelarathna L.
      • Mubita W.
      • Urwin A.
      • Rutter M.K.
      • Schofield J.
      • et al.
      Impact of COVID-19 lockdown on flash and real-time glucose sensor users with type 1 diabetes in England.
      ,
      • Barmpagianni A.
      • Lambadiari V.
      • Papazafiropoulou A.
      • Kountouri A.
      • Stergiou A.
      • Melidonis A.
      • et al.
      Glycemic Control of Patients with Type 1 Diabetes Using an Insulin Pump Before and During the COVID-19–Associated Quarantine.
      ] including 1,707 individuals (range: 33 [
      • Bonora B.M.
      • Boscari F.
      • Avogaro A.
      • Bruttomesso D.
      • Fadini G.P.
      Glycaemic Control Among People with Type 1 Diabetes During Lockdown for the SARS-CoV-2 Outbreak in Italy.
      ] to 572 [
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      ]). TAR decreased in all but two studies [
      • Caruso I.
      • Di Molfetta S.
      • Guarini F.
      • Giordano F.
      • Cignarelli A.
      • Natalicchio A.
      • et al.
      Reduction of hypoglycaemia, lifestyle modifications and psychological distress during lockdown following SARS-CoV-2 outbreak in type 1 diabetes.
      ,
      • Barchetta I.
      • Cimini F.A.
      • Bertoccini L.
      • Ceccarelli V.
      • Spaccarotella M.
      • Baroni M.G.
      • et al.
      Effects of work status changes and perceived stress on glycaemic control in individuals with type 1 diabetes during COVID-19 lockdown in Italy.
      ]. Overall, TAR decreased by 3.39% (95% CI −5.14 to −1.63%; p < 0.0001), with high heterogeneity (I2 = 88%; Fig. 2B). TAR, defined as time spent at very high glucose (>250 mg/dL), was available in 7 studies [
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      ,
      • Di Dalmazi G.
      • Maltoni G.
      • Bongiorno C.
      • Tucci L.
      • Di Natale V.
      • Moscatiello S.
      • et al.
      Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.
      ,
      • Fernández E.
      • Cortazar A.
      • Bellido V.
      Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.
      ,
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ,
      • Cotovad-Bellas L.
      • Tejera-Pérez C.
      • Prieto-Tenreiro A.
      • Sánchez-Bao A.
      • Bellido-Guerrero D.
      The challenge of diabetes home control in COVID-19 times: Proof is in the pudding.
      ,
      • Viñals C.
      • Mesa A.
      • Roca D.
      • Vidal M.
      • Pueyo I.
      • Conget I.
      • et al.
      Management of glucose profile throughout strict COVID-19 lockdown by patients with type 1 diabetes prone to hypoglycaemia using sensor-augmented pump.
      ,
      • Barmpagianni A.
      • Lambadiari V.
      • Papazafiropoulou A.
      • Kountouri A.
      • Stergiou A.
      • Melidonis A.
      • et al.
      Glycemic Control of Patients with Type 1 Diabetes Using an Insulin Pump Before and During the COVID-19–Associated Quarantine.
      ], corresponding to 831 subjects (from 44 [
      • Cotovad-Bellas L.
      • Tejera-Pérez C.
      • Prieto-Tenreiro A.
      • Sánchez-Bao A.
      • Bellido-Guerrero D.
      The challenge of diabetes home control in COVID-19 times: Proof is in the pudding.
      ] to 307 [
      • Fernández E.
      • Cortazar A.
      • Bellido V.
      Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.
      ]) and it decreased by 1.96% (95% CI −2.51 to −1.42; p < 0.0001), with low heterogeneity (I2 = 0%; Supplementary Fig. 2A). For both outcomes, statistics did not change after the removal of each individual study.

      3.3 Time below range (TBR)

      TBR, defined as time spent at glucose levels < 70 mg/dL, was available in 12 studies [
      • Bonora B.M.
      • Boscari F.
      • Avogaro A.
      • Bruttomesso D.
      • Fadini G.P.
      Glycaemic Control Among People with Type 1 Diabetes During Lockdown for the SARS-CoV-2 Outbreak in Italy.
      ,
      • Caruso I.
      • Di Molfetta S.
      • Guarini F.
      • Giordano F.
      • Cignarelli A.
      • Natalicchio A.
      • et al.
      Reduction of hypoglycaemia, lifestyle modifications and psychological distress during lockdown following SARS-CoV-2 outbreak in type 1 diabetes.
      ,
      • Aragona M.
      • Rodia C.
      • Bertolotto A.
      • Campi F.
      • Coppelli A.
      • Giannarelli R.
      • et al.
      Type 1 diabetes and COVID-19: The “lockdown effect”.
      ,
      • Barchetta I.
      • Cimini F.A.
      • Bertoccini L.
      • Ceccarelli V.
      • Spaccarotella M.
      • Baroni M.G.
      • et al.
      Effects of work status changes and perceived stress on glycaemic control in individuals with type 1 diabetes during COVID-19 lockdown in Italy.
      ,
      • Di Dalmazi G.
      • Maltoni G.
      • Bongiorno C.
      • Tucci L.
      • Di Natale V.
      • Moscatiello S.
      • et al.
      Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.
      ,
      • Fernández E.
      • Cortazar A.
      • Bellido V.
      Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.
      ,
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ,
      • Viñals C.
      • Mesa A.
      • Roca D.
      • Vidal M.
      • Pueyo I.
      • Conget I.
      • et al.
      Management of glucose profile throughout strict COVID-19 lockdown by patients with type 1 diabetes prone to hypoglycaemia using sensor-augmented pump.
      ,
      • Pla B.
      • Arranz A.
      • Knott C.
      • Sampedro M.
      • Jiménez S.
      • Hernando I.
      • et al.
      Impact of COVID-19 Lockdown on Glycemic Control in Adults with Type 1 Diabetes Mellitus.
      ,
      • Moreno-Domínguez Ó.
      • González-Pérez de Villar N.
      • Barquiel B.
      • Hillman-Gadea N.
      • Gaspar-Lafuente R.
      • Arévalo-Gómez M.
      • et al.
      Factors Related to Improvement of Glycemic Control Among Adults with Type 1 Diabetes During Lockdown Due to COVID-19.
      ,
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      ,
      • Barmpagianni A.
      • Lambadiari V.
      • Papazafiropoulou A.
      • Kountouri A.
      • Stergiou A.
      • Melidonis A.
      • et al.
      Glycemic Control of Patients with Type 1 Diabetes Using an Insulin Pump Before and During the COVID-19–Associated Quarantine.
      ] including 1,534 individuals (from 33 [
      • Bonora B.M.
      • Boscari F.
      • Avogaro A.
      • Bruttomesso D.
      • Fadini G.P.
      Glycaemic Control Among People with Type 1 Diabetes During Lockdown for the SARS-CoV-2 Outbreak in Italy.
      ] to 572 [
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      ]). TBR increased in 8 studies [
      • Barchetta I.
      • Cimini F.A.
      • Bertoccini L.
      • Ceccarelli V.
      • Spaccarotella M.
      • Baroni M.G.
      • et al.
      Effects of work status changes and perceived stress on glycaemic control in individuals with type 1 diabetes during COVID-19 lockdown in Italy.
      ,
      • Di Dalmazi G.
      • Maltoni G.
      • Bongiorno C.
      • Tucci L.
      • Di Natale V.
      • Moscatiello S.
      • et al.
      Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.
      ,
      • Fernández E.
      • Cortazar A.
      • Bellido V.
      Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.
      ,
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ,
      • Viñals C.
      • Mesa A.
      • Roca D.
      • Vidal M.
      • Pueyo I.
      • Conget I.
      • et al.
      Management of glucose profile throughout strict COVID-19 lockdown by patients with type 1 diabetes prone to hypoglycaemia using sensor-augmented pump.
      ,
      • Moreno-Domínguez Ó.
      • González-Pérez de Villar N.
      • Barquiel B.
      • Hillman-Gadea N.
      • Gaspar-Lafuente R.
      • Arévalo-Gómez M.
      • et al.
      Factors Related to Improvement of Glycemic Control Among Adults with Type 1 Diabetes During Lockdown Due to COVID-19.
      ,
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      ,
      • Barmpagianni A.
      • Lambadiari V.
      • Papazafiropoulou A.
      • Kountouri A.
      • Stergiou A.
      • Melidonis A.
      • et al.
      Glycemic Control of Patients with Type 1 Diabetes Using an Insulin Pump Before and During the COVID-19–Associated Quarantine.
      ], decreased in 3 [
      • Bonora B.M.
      • Boscari F.
      • Avogaro A.
      • Bruttomesso D.
      • Fadini G.P.
      Glycaemic Control Among People with Type 1 Diabetes During Lockdown for the SARS-CoV-2 Outbreak in Italy.
      ,
      • Caruso I.
      • Di Molfetta S.
      • Guarini F.
      • Giordano F.
      • Cignarelli A.
      • Natalicchio A.
      • et al.
      Reduction of hypoglycaemia, lifestyle modifications and psychological distress during lockdown following SARS-CoV-2 outbreak in type 1 diabetes.
      ,
      • Pla B.
      • Arranz A.
      • Knott C.
      • Sampedro M.
      • Jiménez S.
      • Hernando I.
      • et al.
      Impact of COVID-19 Lockdown on Glycemic Control in Adults with Type 1 Diabetes Mellitus.
      ] and did not change in one [
      • Aragona M.
      • Rodia C.
      • Bertolotto A.
      • Campi F.
      • Coppelli A.
      • Giannarelli R.
      • et al.
      Type 1 diabetes and COVID-19: The “lockdown effect”.
      ]. In the study by Bonora et al. [
      • Bonora B.M.
      • Boscari F.
      • Avogaro A.
      • Bruttomesso D.
      • Fadini G.P.
      Glycaemic Control Among People with Type 1 Diabetes During Lockdown for the SARS-CoV-2 Outbreak in Italy.
      ], TBR was reduced in subjects who stopped working and increased in those who continued. Overall, TBR did not change significantly (0.27%, 95% CI −0.04 to 0.58%; p = 0.086), with a moderate between-study heterogeneity (I2 = 55%; Fig. 2C). Six studies (785 subjects; range 44 [
      • Cotovad-Bellas L.
      • Tejera-Pérez C.
      • Prieto-Tenreiro A.
      • Sánchez-Bao A.
      • Bellido-Guerrero D.
      The challenge of diabetes home control in COVID-19 times: Proof is in the pudding.
      ] to 307 [
      • Fernández E.
      • Cortazar A.
      • Bellido V.
      Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.
      ]) reported TBR as time spent at very low glucose levels (<54 mg/dL) [
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      ,
      • Di Dalmazi G.
      • Maltoni G.
      • Bongiorno C.
      • Tucci L.
      • Di Natale V.
      • Moscatiello S.
      • et al.
      Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.
      ,
      • Fernández E.
      • Cortazar A.
      • Bellido V.
      Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.
      ,
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ,
      • Cotovad-Bellas L.
      • Tejera-Pérez C.
      • Prieto-Tenreiro A.
      • Sánchez-Bao A.
      • Bellido-Guerrero D.
      The challenge of diabetes home control in COVID-19 times: Proof is in the pudding.
      ,
      • Viñals C.
      • Mesa A.
      • Roca D.
      • Vidal M.
      • Pueyo I.
      • Conget I.
      • et al.
      Management of glucose profile throughout strict COVID-19 lockdown by patients with type 1 diabetes prone to hypoglycaemia using sensor-augmented pump.
      ]. TBR < 54 mg/dL decreased in 3 studies [
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      ,
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ,
      • Cotovad-Bellas L.
      • Tejera-Pérez C.
      • Prieto-Tenreiro A.
      • Sánchez-Bao A.
      • Bellido-Guerrero D.
      The challenge of diabetes home control in COVID-19 times: Proof is in the pudding.
      ] and point estimate TBR < 54 mg/dL did not change significantly (−0.14%, 95% CI −0.53 to 0.26; p = 0.497, I2 = 86%; Supplementary Fig. 2B). For TBR < 70 mg/dL, removal of any one of the 3 studies in whom TBR decreased, resulted in a significant effect of lockdown (p < 0.05).

      3.4 Mean blood glucose and glycaemic variability

      Mean blood glucose (MBG) and glycaemic variability (%CV) were available for 15 and 14 studies including 3,163 and 1,958 individuals, respectively [
      • Bonora B.M.
      • Boscari F.
      • Avogaro A.
      • Bruttomesso D.
      • Fadini G.P.
      Glycaemic Control Among People with Type 1 Diabetes During Lockdown for the SARS-CoV-2 Outbreak in Italy.
      ,
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      ,
      • Caruso I.
      • Di Molfetta S.
      • Guarini F.
      • Giordano F.
      • Cignarelli A.
      • Natalicchio A.
      • et al.
      Reduction of hypoglycaemia, lifestyle modifications and psychological distress during lockdown following SARS-CoV-2 outbreak in type 1 diabetes.
      ,
      • Aragona M.
      • Rodia C.
      • Bertolotto A.
      • Campi F.
      • Coppelli A.
      • Giannarelli R.
      • et al.
      Type 1 diabetes and COVID-19: The “lockdown effect”.
      ,
      • Barchetta I.
      • Cimini F.A.
      • Bertoccini L.
      • Ceccarelli V.
      • Spaccarotella M.
      • Baroni M.G.
      • et al.
      Effects of work status changes and perceived stress on glycaemic control in individuals with type 1 diabetes during COVID-19 lockdown in Italy.
      ,
      • Di Dalmazi G.
      • Maltoni G.
      • Bongiorno C.
      • Tucci L.
      • Di Natale V.
      • Moscatiello S.
      • et al.
      Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.
      ,
      • Fernández E.
      • Cortazar A.
      • Bellido V.
      Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.
      ,
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ,
      • Cotovad-Bellas L.
      • Tejera-Pérez C.
      • Prieto-Tenreiro A.
      • Sánchez-Bao A.
      • Bellido-Guerrero D.
      The challenge of diabetes home control in COVID-19 times: Proof is in the pudding.
      ,
      • Viñals C.
      • Mesa A.
      • Roca D.
      • Vidal M.
      • Pueyo I.
      • Conget I.
      • et al.
      Management of glucose profile throughout strict COVID-19 lockdown by patients with type 1 diabetes prone to hypoglycaemia using sensor-augmented pump.
      ,
      • Pla B.
      • Arranz A.
      • Knott C.
      • Sampedro M.
      • Jiménez S.
      • Hernando I.
      • et al.
      Impact of COVID-19 Lockdown on Glycemic Control in Adults with Type 1 Diabetes Mellitus.
      ,
      • Moreno-Domínguez Ó.
      • González-Pérez de Villar N.
      • Barquiel B.
      • Hillman-Gadea N.
      • Gaspar-Lafuente R.
      • Arévalo-Gómez M.
      • et al.
      Factors Related to Improvement of Glycemic Control Among Adults with Type 1 Diabetes During Lockdown Due to COVID-19.
      ,
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      ,
      • Barmpagianni A.
      • Lambadiari V.
      • Papazafiropoulou A.
      • Kountouri A.
      • Stergiou A.
      • Melidonis A.
      • et al.
      Glycemic Control of Patients with Type 1 Diabetes Using an Insulin Pump Before and During the COVID-19–Associated Quarantine.
      ,
      • Potier L.
      • Hansel B.
      • Larger E.
      • Gautier J.-F.
      • Carreira D.
      • Assemien R.
      • et al.
      Stay-at-Home Orders During the COVID-19 Pandemic, an Opportunity to Improve Glucose Control Through Behavioral Changes in Type 1 Diabetes.
      ]; %CV was not reported by Potier et al. [
      • Potier L.
      • Hansel B.
      • Larger E.
      • Gautier J.-F.
      • Carreira D.
      • Assemien R.
      • et al.
      Stay-at-Home Orders During the COVID-19 Pandemic, an Opportunity to Improve Glucose Control Through Behavioral Changes in Type 1 Diabetes.
      ] MBG and %CV decreased in all but 2 [
      • Caruso I.
      • Di Molfetta S.
      • Guarini F.
      • Giordano F.
      • Cignarelli A.
      • Natalicchio A.
      • et al.
      Reduction of hypoglycaemia, lifestyle modifications and psychological distress during lockdown following SARS-CoV-2 outbreak in type 1 diabetes.
      ,
      • Barchetta I.
      • Cimini F.A.
      • Bertoccini L.
      • Ceccarelli V.
      • Spaccarotella M.
      • Baroni M.G.
      • et al.
      Effects of work status changes and perceived stress on glycaemic control in individuals with type 1 diabetes during COVID-19 lockdown in Italy.
      ] and 4 studies [14(only subjects who continue to work), [
      • Aragona M.
      • Rodia C.
      • Bertolotto A.
      • Campi F.
      • Coppelli A.
      • Giannarelli R.
      • et al.
      Type 1 diabetes and COVID-19: The “lockdown effect”.
      ,
      • Di Dalmazi G.
      • Maltoni G.
      • Bongiorno C.
      • Tucci L.
      • Di Natale V.
      • Moscatiello S.
      • et al.
      Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.
      ,
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ], respectively. Overall, MBG decreased by 5.40 mg/dL (95% CI −7.29 to −3.51 mg/dL; p < 0.0001), with high heterogeneity (I2 = 77%; Fig. 3A). Coefficient of variation was marginally but statistically modified (−0.66%, 95% CI −1.24 to −0.07%; p = 0.029), with high heterogeneity (I2 = 84%; Fig. 3B). For MBG, statistics was unaffected by the removal of individual studies nor it was after removal of the study by Potier et al. (−5.13 mg/dL; 95% CI −7.30 to −2.96 mg/dL; p < 0.0001), in which pre-lockdown MBG was estimated from the MBG of the last 90 days from FGM minus MBG of the last 30 days, assuming the latter to be representative of glycaemic control during lockdown [
      • Potier L.
      • Hansel B.
      • Larger E.
      • Gautier J.-F.
      • Carreira D.
      • Assemien R.
      • et al.
      Stay-at-Home Orders During the COVID-19 Pandemic, an Opportunity to Improve Glucose Control Through Behavioral Changes in Type 1 Diabetes.
      ].
      Figure thumbnail gr3
      Fig. 3Effect of lockdown on (A) average blood glucose and (B) coefficient of variation.

      3.5 Estimated HbA1c (eA1c) and glucose management indicator (GMI)

      Although different calculating methods are used to derive eA1c and GMI [
      • Leelarathna L.
      • Thabit H.
      • Hovorka R.
      • Evans M.
      Estimated HbA1c and glucose management indicator (GMI): are they the same?.
      ], in a first analysis we pooled the two variables. Then, a sensitivity analysis was performed including GMI only. Estimated A1c or GMI were reported in all [
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      ,
      • Caruso I.
      • Di Molfetta S.
      • Guarini F.
      • Giordano F.
      • Cignarelli A.
      • Natalicchio A.
      • et al.
      Reduction of hypoglycaemia, lifestyle modifications and psychological distress during lockdown following SARS-CoV-2 outbreak in type 1 diabetes.
      ,
      • Aragona M.
      • Rodia C.
      • Bertolotto A.
      • Campi F.
      • Coppelli A.
      • Giannarelli R.
      • et al.
      Type 1 diabetes and COVID-19: The “lockdown effect”.
      ,
      • Barchetta I.
      • Cimini F.A.
      • Bertoccini L.
      • Ceccarelli V.
      • Spaccarotella M.
      • Baroni M.G.
      • et al.
      Effects of work status changes and perceived stress on glycaemic control in individuals with type 1 diabetes during COVID-19 lockdown in Italy.
      ,
      • Di Dalmazi G.
      • Maltoni G.
      • Bongiorno C.
      • Tucci L.
      • Di Natale V.
      • Moscatiello S.
      • et al.
      Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.
      ,
      • Fernández E.
      • Cortazar A.
      • Bellido V.
      Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.
      ,
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ,
      • Cotovad-Bellas L.
      • Tejera-Pérez C.
      • Prieto-Tenreiro A.
      • Sánchez-Bao A.
      • Bellido-Guerrero D.
      The challenge of diabetes home control in COVID-19 times: Proof is in the pudding.
      ,
      • Viñals C.
      • Mesa A.
      • Roca D.
      • Vidal M.
      • Pueyo I.
      • Conget I.
      • et al.
      Management of glucose profile throughout strict COVID-19 lockdown by patients with type 1 diabetes prone to hypoglycaemia using sensor-augmented pump.
      ,
      • Pla B.
      • Arranz A.
      • Knott C.
      • Sampedro M.
      • Jiménez S.
      • Hernando I.
      • et al.
      Impact of COVID-19 Lockdown on Glycemic Control in Adults with Type 1 Diabetes Mellitus.
      ,
      • Moreno-Domínguez Ó.
      • González-Pérez de Villar N.
      • Barquiel B.
      • Hillman-Gadea N.
      • Gaspar-Lafuente R.
      • Arévalo-Gómez M.
      • et al.
      Factors Related to Improvement of Glycemic Control Among Adults with Type 1 Diabetes During Lockdown Due to COVID-19.
      ,
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      ,
      • Barmpagianni A.
      • Lambadiari V.
      • Papazafiropoulou A.
      • Kountouri A.
      • Stergiou A.
      • Melidonis A.
      • et al.
      Glycemic Control of Patients with Type 1 Diabetes Using an Insulin Pump Before and During the COVID-19–Associated Quarantine.
      ] but 4 studies accounting for a total of 1,752 subjects (from 44 [
      • Cotovad-Bellas L.
      • Tejera-Pérez C.
      • Prieto-Tenreiro A.
      • Sánchez-Bao A.
      • Bellido-Guerrero D.
      The challenge of diabetes home control in COVID-19 times: Proof is in the pudding.
      ] to 572 [
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      ]). The eA1c value decreased in all but 3 studies in which it did not change [
      • Caruso I.
      • Di Molfetta S.
      • Guarini F.
      • Giordano F.
      • Cignarelli A.
      • Natalicchio A.
      • et al.
      Reduction of hypoglycaemia, lifestyle modifications and psychological distress during lockdown following SARS-CoV-2 outbreak in type 1 diabetes.
      ,
      • Aragona M.
      • Rodia C.
      • Bertolotto A.
      • Campi F.
      • Coppelli A.
      • Giannarelli R.
      • et al.
      Type 1 diabetes and COVID-19: The “lockdown effect”.
      ,
      • Barchetta I.
      • Cimini F.A.
      • Bertoccini L.
      • Ceccarelli V.
      • Spaccarotella M.
      • Baroni M.G.
      • et al.
      Effects of work status changes and perceived stress on glycaemic control in individuals with type 1 diabetes during COVID-19 lockdown in Italy.
      ]. Overall, eA1c decreased by 0.18% (95% CI −0.24 to −0.11%; p < 0.0001), with moderate heterogeneity (I2 = 70%; Fig. 4A). GMI was available in 7 studies [
      • Caruso I.
      • Di Molfetta S.
      • Guarini F.
      • Giordano F.
      • Cignarelli A.
      • Natalicchio A.
      • et al.
      Reduction of hypoglycaemia, lifestyle modifications and psychological distress during lockdown following SARS-CoV-2 outbreak in type 1 diabetes.
      ,
      • Aragona M.
      • Rodia C.
      • Bertolotto A.
      • Campi F.
      • Coppelli A.
      • Giannarelli R.
      • et al.
      Type 1 diabetes and COVID-19: The “lockdown effect”.
      ,
      • Di Dalmazi G.
      • Maltoni G.
      • Bongiorno C.
      • Tucci L.
      • Di Natale V.
      • Moscatiello S.
      • et al.
      Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.
      ,
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ,
      • Pla B.
      • Arranz A.
      • Knott C.
      • Sampedro M.
      • Jiménez S.
      • Hernando I.
      • et al.
      Impact of COVID-19 Lockdown on Glycemic Control in Adults with Type 1 Diabetes Mellitus.
      ,
      • Moreno-Domínguez Ó.
      • González-Pérez de Villar N.
      • Barquiel B.
      • Hillman-Gadea N.
      • Gaspar-Lafuente R.
      • Arévalo-Gómez M.
      • et al.
      Factors Related to Improvement of Glycemic Control Among Adults with Type 1 Diabetes During Lockdown Due to COVID-19.
      ,
      • Barmpagianni A.
      • Lambadiari V.
      • Papazafiropoulou A.
      • Kountouri A.
      • Stergiou A.
      • Melidonis A.
      • et al.
      Glycemic Control of Patients with Type 1 Diabetes Using an Insulin Pump Before and During the COVID-19–Associated Quarantine.
      ], including 513 individuals (from 46 [
      • Barmpagianni A.
      • Lambadiari V.
      • Papazafiropoulou A.
      • Kountouri A.
      • Stergiou A.
      • Melidonis A.
      • et al.
      Glycemic Control of Patients with Type 1 Diabetes Using an Insulin Pump Before and During the COVID-19–Associated Quarantine.
      ] to 138 [
      • Moreno-Domínguez Ó.
      • González-Pérez de Villar N.
      • Barquiel B.
      • Hillman-Gadea N.
      • Gaspar-Lafuente R.
      • Arévalo-Gómez M.
      • et al.
      Factors Related to Improvement of Glycemic Control Among Adults with Type 1 Diabetes During Lockdown Due to COVID-19.
      ]) and decreased in 5 with no change in 2 [
      • Caruso I.
      • Di Molfetta S.
      • Guarini F.
      • Giordano F.
      • Cignarelli A.
      • Natalicchio A.
      • et al.
      Reduction of hypoglycaemia, lifestyle modifications and psychological distress during lockdown following SARS-CoV-2 outbreak in type 1 diabetes.
      ,
      • Aragona M.
      • Rodia C.
      • Bertolotto A.
      • Campi F.
      • Coppelli A.
      • Giannarelli R.
      • et al.
      Type 1 diabetes and COVID-19: The “lockdown effect”.
      ]. Overall, GMI decreased by 0.15% (95% CI −0.23 to −0.07%; p < 0.0001), with moderate heterogeneity (I2 = 67%; Fig. 4B). For both parameters, the lockdown effects did not substantially differ with the exclusion of any cohort.
      Figure thumbnail gr4
      Fig. 4Effect of lockdown on (A) estimated A1c (eA1c) plus glucose management indicator (GMI) pooled; (B) glucose management indicator alone (GMI).

      3.6 Sensor use

      The percent of sensor use was reported in 10 out of 17 studies accounting for a total of 1,608 subjects. It was found slightly reduced during lockdown as compared to the pre-lockdown period (−0.75%, 95% CI −1.29 to −0.21%; p = 0.007), with low heterogeneity (I2 = 40%). In particular, it was reduced in 7 cohorts [
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      ,
      • Aragona M.
      • Rodia C.
      • Bertolotto A.
      • Campi F.
      • Coppelli A.
      • Giannarelli R.
      • et al.
      Type 1 diabetes and COVID-19: The “lockdown effect”.
      ,
      • Di Dalmazi G.
      • Maltoni G.
      • Bongiorno C.
      • Tucci L.
      • Di Natale V.
      • Moscatiello S.
      • et al.
      Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.
      ,
      • Fernández E.
      • Cortazar A.
      • Bellido V.
      Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.
      ,
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ,
      • Moreno-Domínguez Ó.
      • González-Pérez de Villar N.
      • Barquiel B.
      • Hillman-Gadea N.
      • Gaspar-Lafuente R.
      • Arévalo-Gómez M.
      • et al.
      Factors Related to Improvement of Glycemic Control Among Adults with Type 1 Diabetes During Lockdown Due to COVID-19.
      ,
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      ], increased in 2 [
      • Viñals C.
      • Mesa A.
      • Roca D.
      • Vidal M.
      • Pueyo I.
      • Conget I.
      • et al.
      Management of glucose profile throughout strict COVID-19 lockdown by patients with type 1 diabetes prone to hypoglycaemia using sensor-augmented pump.
      ,
      • Pla B.
      • Arranz A.
      • Knott C.
      • Sampedro M.
      • Jiménez S.
      • Hernando I.
      • et al.
      Impact of COVID-19 Lockdown on Glycemic Control in Adults with Type 1 Diabetes Mellitus.
      ] and unchanged in the last one [
      • Cotovad-Bellas L.
      • Tejera-Pérez C.
      • Prieto-Tenreiro A.
      • Sánchez-Bao A.
      • Bellido-Guerrero D.
      The challenge of diabetes home control in COVID-19 times: Proof is in the pudding.
      ]. The effect of lockdown did not substantially differ with the exclusion of any cohort with the only exception of the study by Dover et al. [
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      ], the largest one, whose removal made the difference only marginally significant (p = 0.062).

      4. Discussion

      This meta-analysis including data from 17 observational studies and a total of 3,441 subjects provides evidence that glucose control modestly though significantly improved during the COVID-19 lockdown period in adults with type 1 diabetes on multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusion (CSII) using continuous (CGM) or flash glucose monitoring (FGM) systems. This finding may sound at odds with the potential impact of the disruption of regular daily activities, diet, and physical exercise along with a stressful condition the mobility limitation during the lockdown could have exerted. Of interest, only one study has reported a clear-cut worsening of glucose control parameters [
      • Barchetta I.
      • Cimini F.A.
      • Bertoccini L.
      • Ceccarelli V.
      • Spaccarotella M.
      • Baroni M.G.
      • et al.
      Effects of work status changes and perceived stress on glycaemic control in individuals with type 1 diabetes during COVID-19 lockdown in Italy.
      ]. Although, the reason for such a difference is not readily apparent, the main trend was for a slight improvement in glycaemic control. As such, our results support and expand those recently published by Silverii et al [
      • Silverii G.A.
      • Delli Poggi C.
      • Dicembrini I.
      • Monami M.
      Mannucci E Glucose control in diabetes during home confinement for the first pandemic wave of COVID-19: a meta-analysis of observational studies.
      ] as other features such as estimated HbA1c and use of the sensor have been included.
      The observed improvements in diabetes control were mainly accounted for by an increase in TIR and a concomitant reduction in TAR (both TAR > 180 mg/dL, as well TAR > 250 mg/dL), whereas TBR was only marginally affected, with a trend for an increase in TBR < 70 mg/dL but no changes in TBR < 54 mg/dL. To support this improvement in glycaemic control, a modest thought statistically significant reduction in mean BG as well as in glucose variability were detected. Consistently, also eA1c and GMI improved. These latter parameters are derived from average glucose levels to predict laboratory measured HbA1c [
      • Bergenstal R.M.
      • Beck R.W.
      • Close K.L.
      • Grunberger G.
      • Sacks D.B.
      • Kowalski A.
      • et al.
      Glucose Management Indicator (GMI): A New Term for Estimating A1C From Continuous Glucose Monitoring.
      ]. The GMI represents only a slight modification of the eA1c formula, and, therefore, we have pooled the two parameters in our analysis. However, a sensitivity analysis employing just GMI did not yield different results. Of note, all the documented changes in glycaemic control parameters were not due to greater use of the sensors, which was comparable before and during lockdown. Almost all studies included in our meta-analysis collected glucose measurements over at least two weeks immediately before and during lockdown. A 14-day FGM or CGM recording has been previously claimed to provide reliable estimate of glucose metrics [
      • Battelino T.
      • Danne T.
      • Bergenstal R.M.
      • Amiel S.A.
      • Beck R.
      • Biester T.
      • et al.
      Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range.
      ,
      • Bergenstal R.M.
      • Beck R.W.
      • Close K.L.
      • Grunberger G.
      • Sacks D.B.
      • Kowalski A.
      • et al.
      Glucose Management Indicator (GMI): A New Term for Estimating A1C From Continuous Glucose Monitoring.
      ].
      Many reasons could account for this result. Diabetes has been recognized as a major risk factor for severe COVID-19 [
      • McGurnaghan S.J.
      • Weir A.
      • Bishop J.
      • Kennedy S.
      • Blackbourn L.A.K.
      • McAllister D.A.
      • et al.
      Public Health Scotland COVID-19 Health Protection Study Group; Scottish Diabetes Research Network Epidemiology Group. Risks of and risk factors for COVID-19 disease in people with diabetes: a cohort study of the total population of Scotland.
      ,
      • Apicella M.
      • Campopiano M.C.
      • Mantuano M.
      • Mazoni L.
      • Coppelli A.
      • Del Prato S.
      COVID-19 in people with diabetes: understanding the reasons for worse outcomes.
      ], which may have increased alertness of people with diabetes and made them to pay more attention to management of their condition [
      • Lim S.
      • Bae J.H.
      • Kwon H.-S.
      • Nauck M.A.
      COVID-19 and diabetes mellitus: from pathophysiology to clinical management.
      ]. During lockdown, daily care routine has changed deeply, physical activity was found to be reduced [
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      ,
      • Assaloni R.
      • Pellino V.C.
      • Puci M.V.
      • Ferraro O.E.
      • Lovecchio N.
      • Girelli A.
      • et al.
      Coronavirus disease (Covid-19): How does the exercise practice in active people with type 1 diabetes change? A preliminary survey.
      ], but more regular patterns of nutrient intake and sleep have been reported [
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      ]. Reduction of physical activity was related to poorer glycaemic control by some [
      • Assaloni R.
      • Pellino V.C.
      • Puci M.V.
      • Ferraro O.E.
      • Lovecchio N.
      • Girelli A.
      • et al.
      Coronavirus disease (Covid-19): How does the exercise practice in active people with type 1 diabetes change? A preliminary survey.
      ] but not all investigators [
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      ]. Capaldo et al. [
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      ] showed that reduced physical activity was associated with less glucose variability along with no change in TIR. These discrepant results may not be of a surprise given the variable impact physical activity can have on glucose control in subjects with type 1 diabetes. Although regular exercise can exert a favourable effect it can also represent a challenge in balancing nutrient intake and insulin doses.
      Another possible reason for improved glycaemic control could rely in a more regular distribution of daily duties associated with the mobility limitation of the lockdown. In keeping with this hypothesis, Bonora et al. [
      • Bonora B.M.
      • Boscari F.
      • Avogaro A.
      • Bruttomesso D.
      • Fadini G.P.
      Glycaemic Control Among People with Type 1 Diabetes During Lockdown for the SARS-CoV-2 Outbreak in Italy.
      ] found that, during lockdown, glucose control improved in FGM users who work from home, but not in those who continued their usual working activities. Also, more regular meal patterns, more reproducible mealtimes and increased sleep duration were associated to an increase in TIR [
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      ]. To this regard, it is of interest that at least one study [
      • Aragona M.
      • Rodia C.
      • Bertolotto A.
      • Campi F.
      • Coppelli A.
      • Giannarelli R.
      • et al.
      Type 1 diabetes and COVID-19: The “lockdown effect”.
      ] observed a less pronounced “dawn phenomenon” during lockdown, a glycaemic pattern that is supported by the release of counterregulatory stress hormones.
      The lack of significant change in TBR deserves some consideration. This may be simply because the rate of hypoglycaemic events was already generally low in most studies. Nevertheless, a significant reduction in TBR was more common for glucose values in the severe hypoglycaemic range (<54 mg/dL) [
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      ,
      • Cotovad-Bellas L.
      • Tejera-Pérez C.
      • Prieto-Tenreiro A.
      • Sánchez-Bao A.
      • Bellido-Guerrero D.
      The challenge of diabetes home control in COVID-19 times: Proof is in the pudding.
      ], and in subgroups with higher TBR at baseline [
      • Bonora B.M.
      • Boscari F.
      • Avogaro A.
      • Bruttomesso D.
      • Fadini G.P.
      Glycaemic Control Among People with Type 1 Diabetes During Lockdown for the SARS-CoV-2 Outbreak in Italy.
      ,
      • Aragona M.
      • Rodia C.
      • Bertolotto A.
      • Campi F.
      • Coppelli A.
      • Giannarelli R.
      • et al.
      Type 1 diabetes and COVID-19: The “lockdown effect”.
      ], but not in those cohorts claimed at higher risk of severe hypoglycaemia [
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ,
      • Viñals C.
      • Mesa A.
      • Roca D.
      • Vidal M.
      • Pueyo I.
      • Conget I.
      • et al.
      Management of glucose profile throughout strict COVID-19 lockdown by patients with type 1 diabetes prone to hypoglycaemia using sensor-augmented pump.
      ].
      An issue that needs to be taken into consideration in interpreting these results is to which extent the observed changes in glucose control may not simply represent yearly fluctuations. However, by comparing changes occurred during lockdown with the same calendar period in 2019, Dover et al. [
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      ] ruled out that such changes may simply represent a seasonal variation.
      Our results, obtained in adult persons with type 1 diabetes, are supported by observational studies performed in children or adolescents with type 1 diabetes using CGM or FGM. In the pediatric age, glucose metrics during lockdown were stable as compared to the pre-lockdown period in some studies [
      • Di Dalmazi G.
      • Maltoni G.
      • Bongiorno C.
      • Tucci L.
      • Di Natale V.
      • Moscatiello S.
      • et al.
      Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.
      ,
      • Brener A.
      • Mazor-Aronovitch K.
      • Rachmiel M.
      • Levek N.
      • Barash G.
      • Pinhas-Hamiel O.
      • et al.
      Lessons learned from the continuous glucose monitoring metrics in pediatric patients with type 1 diabetes under COVID-19 lockdown.
      ,
      • Christoforidis A.
      • Kavoura E.
      • Nemtsa A.
      • Pappa K.
      • Dimitriadou M.
      Coronavirus lockdown effect on type 1 diabetes management οn children wearing insulin pump equipped with continuous glucose monitoring system.
      ] and significantly improved in others [
      • Di Dalmazi G.
      • Maltoni G.
      • Bongiorno C.
      • Tucci L.
      • Di Natale V.
      • Moscatiello S.
      • et al.
      Comparison of the effects of lockdown due to COVID-19 on glucose patterns among children, adolescents, and adults with type 1 diabetes: CGM study.
      ,
      • Predieri B.
      • Leo F.
      • Candia F.
      • Lucaccioni L.
      • Madeo S.F.
      • Pugliese M.
      • et al.
      Glycemic Control Improvement in Italian Children and Adolescents With Type 1 Diabetes Followed Through Telemedicine During Lockdown Due to the COVID-19 Pandemic.
      ]. These results also sustain the role of technology for management of diabetes that may provide even greater aid during challenging condition as it has been recently reviewed [
      • Danne T.
      • Limbert C.
      • Puig Domingo M.
      • Del Prato S.
      • Renard E.
      • Choudhary P.
      • et al.
      Telemonitoring, Telemedicine and Time in Range During the Pandemic: Paradigm Change for Diabetes Risk Management in the Post-COVID Future.
      ]. This is further supported by the results of Longo et al [
      • Longo M.
      • Caruso P.
      • Petrizzo M.
      • Castaldo F.
      • Sarnataro A.
      • Gicchino M.
      • et al.
      Glycemic control in people with type 1 diabetes using a hybrid closed loop system and followed by telemedicine during the COVID-19 pandemic in Italy.
      ] showing that subjects with type 1 diabetes on hybrid closed loop systems with telemedicine support had a significant improvement of metrics of glucose control during the pandemic lockdown.
      In summary, the hypothesized deleterious effects of lockdown were not sufficient to disrupt glycaemic control role in type 1 diabetes, or other consequences of the lockdown may have offset such negative effects. It is worth recalling that all these data have been obtained in subjects using CGM or FGM. As such we cannot extend these results to those on traditional SBGM. Telehealth strategies, telemedicine and remote access to sensor data have been proved as effective and efficient tools in the management of type 1 diabetes during COVID-19. These novel ways of delivering care have been explored successfully both in adults [
      • Boscari F.
      • Ferretto S.
      • Uliana A.
      • Avogaro A.
      • Bruttomesso D.
      Efficacy of telemedicine for persons with type 1 diabetes during Covid19 lockdown.
      ] as well in children and adolescents with type 1 diabetes [
      • Rachmiel M.
      • Lebenthal Y.
      • Mazor-Aronovitch K.
      • Brener A.
      • Levek N.
      • Levran N.
      • et al.
      Glycaemic control in the paediatric and young adult population with type 1 diabetes following a single telehealth visit - what have we learned from the COVID-19 lockdown?.
      ]. These opportunities might have contributed ensuring glucose control as seen in our meta-analysis, which included studies carried out in developed countries. Consistently, in a recent study, only individuals with type 1 diabetes who attended telemedicine compared to non-attenders had a significant improvement in glucose metrics [
      • Alharthi S.K.
      • Alyusuf E.Y.
      • Alguwaihes A.M.
      • Alfadda A.
      • Al-Sofiani M.E.
      The impact of a prolonged lockdown and use of telemedicine on glycemic control in people with type 1 diabetes during the COVID-19 outbreak in Saudi Arabia.
      ]. On the contrary, higher levels of socio-economic deprivation (poorer diet, greater stress), which may have also hampered the use of modern technology for glucose monitoring and online supervision, have been reported to be independent predictors for deterioration of glucose control during lockdown [
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      ].
      As already mentioned, our results cannot not be generalized to the wider type 1 diabetes population. Recruitments are skewed towards younger individuals recruited within advanced health systems as suggested by many individuals on CSII in many of the cohorts included in our meta-analysis. With respect to this, we could not compare results in subjects on MDI and CSII, even though some studies reported similar results both in adults [
      • Capaldo B.
      • Annuzzi G.
      • Creanza A.
      • Giglio C.
      • De Angelis R.
      • Lupoli R.
      • et al.
      Blood Glucose Control During Lockdown for COVID-19: CGM Metrics in Italian Adults With Type 1 Diabetes.
      ,
      • Fernández E.
      • Cortazar A.
      • Bellido V.
      Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.
      ] as well as in pediatric individuals [
      • Brener A.
      • Mazor-Aronovitch K.
      • Rachmiel M.
      • Levek N.
      • Barash G.
      • Pinhas-Hamiel O.
      • et al.
      Lessons learned from the continuous glucose monitoring metrics in pediatric patients with type 1 diabetes under COVID-19 lockdown.
      ]. Most of the studies included only people with effective data capture, which may represent a potential selection bias.
      On top of that, our meta-analysis has other potential limitations. First, we cannot separate data for CGM users and FGM users nor we could determine the percentage of subjects with a clinically relevant change in eA1c or GMI, for instance an improvement ≥ 0.4%. Similarly, we could not estimate how many people had a TIR > 70% or an at least improvement in TIR > 4%, a change reflecting an additional hour per day spent in-range [
      • Battelino T.
      • Danne T.
      • Bergenstal R.M.
      • Amiel S.A.
      • Beck R.
      • Biester T.
      • et al.
      Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range.
      ]. In the study by Fernández et al. [
      • Fernández E.
      • Cortazar A.
      • Bellido V.
      Impact of COVID-19 lockdown on glycemic control in patients with type 1 diabetes.
      ], a reduction in eA1c ≥ 0.4% and an increase in TIR ≥ 5% were observed in 46.6% and 48.2% of subjects, respectively, with 35.8% of subjects with type 1 diabetes achieving such changes. Similar trends, though with numerically different percentages, have been reported in other studies [
      • Mesa A.
      • Viñals C.
      • Pueyo I.
      • Roca D.
      • Vidal M.
      • Giménez M.
      • et al.
      The impact of strict COVID-19 lockdown in Spain on glycemic profiles in patients with type 1 Diabetes prone to hypoglycemia using standalone continuous glucose monitoring.
      ,
      • Viñals C.
      • Mesa A.
      • Roca D.
      • Vidal M.
      • Pueyo I.
      • Conget I.
      • et al.
      Management of glucose profile throughout strict COVID-19 lockdown by patients with type 1 diabetes prone to hypoglycaemia using sensor-augmented pump.
      ,
      • Moreno-Domínguez Ó.
      • González-Pérez de Villar N.
      • Barquiel B.
      • Hillman-Gadea N.
      • Gaspar-Lafuente R.
      • Arévalo-Gómez M.
      • et al.
      Factors Related to Improvement of Glycemic Control Among Adults with Type 1 Diabetes During Lockdown Due to COVID-19.
      ,
      • Prabhu Navis J.
      • Leelarathna L.
      • Mubita W.
      • Urwin A.
      • Rutter M.K.
      • Schofield J.
      • et al.
      Impact of COVID-19 lockdown on flash and real-time glucose sensor users with type 1 diabetes in England.
      ], while a deterioration was found to be more common in individuals with higher TIR and lower eA1c at baseline [
      • Dover A.R.
      • Ritchie S.A.
      • McKnight J.A.
      • Strachan M.W.J.
      • Zammitt N.N.
      • Wake D.J.
      • et al.
      Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.
      ]. Finally, most studies selected subjects using both glucose monitoring systems and platforms for remote data sharing, while no solid data documented the extent of life-style changes and the psychological burden. Sometimes, data on physical activity, dietary habits, sleeping patterns, or working routine were provided by online questionnaires and were mainly qualitative and self-reported [
      • Potier L.
      • Hansel B.
      • Larger E.
      • Gautier J.-F.
      • Carreira D.
      • Assemien R.
      • et al.
      Stay-at-Home Orders During the COVID-19 Pandemic, an Opportunity to Improve Glucose Control Through Behavioral Changes in Type 1 Diabetes.
      ].
      In conclusion, our meta-analysis of aggregate data shows that well-controlled people with type 1 diabetes on both MDI and CSII with continuous or flash glucose monitoring did not experience a deterioration in glucose control throughout the COVID-19 lockdown, showing a modest, though statistically significant improvement in many glucose control parameters.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      We are indebted to all Authors of the single studies we have included in our meta-analysis. In particular, we thank Dr. Dover AR and co-authors (27), Dr. Barchetta I and co-authors (19), and Dr. Di Dalmazi G and co-authors (20) for providing us original data to be included in the meta-analysis.

      Funding information

      This research has been supported by a research grant Punteggio Rating of the University of Pisa, Italy .

      Author contributions

      M.G., G.P., and S.D.P. performed literature search, data collection and data analysis. All Authors contributed to interpretation of the findings. M.G. and G.P. wrote the first draft of the paper and all authors provided critical input for intellectual content and approved the final version. All authors had full access to all data of the study, while the corresponding author, S.D.P., had final responsibility for the decision to submit for publication. S.D.P. and G.P. should be considered joint senior author.

      Data availability statement

      The data that support the findings of this study are available from the corresponding author upon reasonable request.

      Appendix A. Supplementary material

      The following are the Supplementary data to this article:

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