Correlation between time on target and glycated hemoglobin in people with diabetes mellitus: systematic review

Lima, Rafael Aparecido Dias; Fernandes, Daiane Rubinato; Garcia, Rute Aparecida Casas; Carvalho, Lucas Ariel da Rocha; Silveira, Renata Cristina de Campos Pereira; Teixeira, Carla Regina de Souza

doi:10.1590/1518-8345.6655.4089

Rafael Aparecido Dias Lima Corresponding author: Rafael Aparecido Dias Lima E-mail: rafael.aparecido.lima@usp.br https://orcid.org/0000-0002-5700-1333

Study concept and design

Obtaining data

Data analysis and interpretation

Statistical analysis

Obtaining financing

Drafting the manuscript

Critical review of the manuscript as to its relevant intellectual content

Universidade de São Paulo, Escola de Enfermagem de Ribeirão Preto, PAHO/WHO Collaborating Centre for Nursing Research Development, Ribeirão Preto, SP, Brazil.

https://orcid.org/0000-0002-5700-1333

Daiane Rubinato Fernandes

Study concept and design

Data analysis and interpretation

Statistical analysis

Obtaining financing

Drafting the manuscript

Critical review of the manuscript as to its relevant intellectual content

Universidade de São Paulo, Escola de Enfermagem de Ribeirão Preto, PAHO/WHO Collaborating Centre for Nursing Research Development, Ribeirão Preto, SP, Brazil.

Scholarship holder at the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil.

https://orcid.org/0000-0002-9363-0057

Rute Aparecida Casas Garcia

Study concept and design

Data analysis and interpretation

Drafting the manuscript

Critical review of the manuscript as to its relevant intellectual content

Universidade de São Paulo, Escola de Enfermagem de Ribeirão Preto, PAHO/WHO Collaborating Centre for Nursing Research Development, Ribeirão Preto, SP, Brazil.

https://orcid.org/0000-0002-1908-4262

Lucas Ariel da Rocha Carvalho

Study concept and design

Data analysis and interpretation

Drafting the manuscript

Critical review of the manuscript as to its relevant intellectual content

Universidade Federal de Minas Gerais, UniEscola de Engenharia, Belo Horizonte, MG, Brazil.

https://orcid.org/0000-0003-3086-3985

Renata Cristina de Campos Pereira Silveira

Study concept and design

Data analysis and interpretation

Drafting the manuscript

Critical review of the manuscript as to its relevant intellectual content

Universidade de São Paulo, Escola de Enfermagem de Ribeirão Preto, PAHO/WHO Collaborating Centre for Nursing Research Development, Ribeirão Preto, SP, Brazil.

https://orcid.org/0000-0002-2883-3640

Carla Regina de Souza Teixeira

Study concept and design

Data analysis and interpretation

Drafting the manuscript

Critical review of the manuscript as to its relevant intellectual content

Universidade de São Paulo, Escola de Enfermagem de Ribeirão Preto, PAHO/WHO Collaborating Centre for Nursing Research Development, Ribeirão Preto, SP, Brazil.

https://orcid.org/0000-0002-8887-5439

Corresponding author:
Rafael Aparecido Dias Lima E-mail: rafael.aparecido.lima@usp.br https://orcid.org/0000-0002-5700-1333

Conflict of interest: the authors have declared that there is no conflict of interest

Associate Editor:

Rosalina Aparecida Partezani Rodrigues

Database	Search strategy
PubMed	((((“Diabetes Mellitus”[MeSH Terms]) OR “Diabetes Mellitus” [All Fields] OR “Diabetes Mellitus, Type 1”[MeSH Terms] OR “Diabetes Mellitus, Type 1”[All Fields] OR “Diabetes Mellitus, Type 2”[MeSH Terms] OR “Diabetes Mellitus, Type 2”[All Fields] OR “Diabetes, Gestational”[MeSH Terms] OR “Diabetes, Gestacional”[All Fields]))) AND ((“Blood Glucose Self-Monitoring”[MeSH Terms] OR “Blood Glucose Self-Monitoring”[All Fields] OR “Home Blood Glucose Monitoring”[All Fields] OR “Continuous Glucose Monitoring”[All Fields])) AND ((“Time in range”[All Fields] OR “Time Above Range”[All Fields] OR “Time Below Range”[All Fields])) AND ((“Glycated Hemoglobin A”[MeSH Terms] OR “Glycated Hemoglobin A”[All Fields] OR “Hb A1c”[All Fields] OR “Glycated Hemoglobin”[All Fields]))
Scopus	(( ‘diabetes AND mellitus’ OR ‘diabetes AND mellitus, AND type AND 1’ OR ‘diabetes AND mellitus, AND type AND 2’ OR ‘diabetes, AND gestational’ ) AND ( ‘blood AND glucose AND self-monitoring’ OR ‘home AND blood AND glucose AND monitoring’ OR ‘continuous AND glucose AND monitoring’ ) AND ( ‘time AND in AND range’ OR ‘time AND above AND range’ OR ‘time AND below AND range’ ) AND ( ‘glycated AND hemoglobin AND a’ OR ‘hb AND a1c’ OR ‘glycated AND hemoglobin’ ))
Embase	(‘diabetes mellitus’ OR ‘diabetes mellitus, type 1’ OR ‘diabetes mellitus, type 2’ OR ‘diabetes, gestational’) AND (‘blood glucose self-monitoring’ OR ‘home blood glucose monitoring’ OR ‘continuous glucose monitoring’) AND (‘time in range’ OR ‘time above range’ OR ‘time below range’) AND (‘glycated hemoglobin a’ OR ‘hb a1c’ OR ‘glycated hemoglobin’)
CINAHL	“Diabetes Mellitus” OR “Diabetes Mellitus, Type 1” OR “Diabetes Mellitus, Type 2” OR “Diabetes, Gestational” AND “Blood Glucose Self-Monitoring” OR “Home Blood Glucose Monitoring” OR “Continuous Glucose Monitoring” AND “Time in range” OR “Time Above Range” OR “Time Below Range” AND “Glycated Hemoglobin A” OR “Hb A1c” OR “Glycated Hemoglobin”
Cochrane Library	0 Trials matching “Diabetes Mellitus” OR “Diabetes Mellitus, Type 1” OR “Diabetes Mellitus, Type 2” OR “Diabetes, Gestational” AND “Blood Glucose Self-Monitoring” OR “Home Blood Glucose Monitoring” OR “Continuous Glucose Monitoring” AND “Time in range” OR “Time Above Range” OR “Time Below Range” AND “Glycated Hemoglobin A” OR “Hb A1c” OR “Glycated Hemoglobin” in Title Abstract Keyword
LILACS	“Diabetes Mellitus” OR “Diabetes Mellitus, Type 1” OR “Diabetes Mellitus, Type 2” OR “Diabetes, Gestational” OR “Diabetes Mellitus, Tipo 1” OR “Diabetes Mellitus, Tipo 2” OR “Diabetes, Gestacional” AND “Blood Glucose Self-Monitoring” OR “Automonitorização da Glicemia Capilar” OR “Automonitorizacion de la Glucosa” OR “Continuous Glucose Monitoring” OR “Monitorização Continua da Glicose” OR “Monitorizacion Continua de Glucosa” AND “Time in range” OR “Tempo no intervalo” OR “Tiempo em Rango” AND “Glycated Hemoglobin A” OR “Hemoglobina A Glicada” OR “Hemoglobina A Glucada”
Google Scholar	(Diabetes Mellitus) OR (Diabetes Mellitus Type 1) OR (Diabetes Mellitus, Type 2) OR (Diabetes Gestational) AND (Blood Glucose Self-Monitoring) OR (Home Blood Glucose Monitoring) OR (Continuous Glucose Monitoring) AND (Time in range) OR (Time Above Range) OR (Time Below Range) AND (Glycated Hemoglobin A) OR (Hb A1c) OR (Glycated Hemoglobin)

Author, year, journal (impact factor), country, study design and sample	Objective	Intervention	Main results
Beck, et al. (2019) ⁽ ²²22. Beck RW, Bergenstal RM, Cheng P, Kollman C, Carlson AL, Johnson ML, et al. The Relationships Between Time in Range, Hyperglycemia Metrics, and HbA1c. J Diabetes Sci Technol. 2019;13(4):614-26. https://doi.org/10.1177/1932296818822496 https://doi.org/10.1177/1932296818822496... ⁾ Journal of Diabetes Science and Technology (1,306) USA Cross-sectional study 545 people ≥ 18 years old living with DM1*	To evaluate aspects of glycemia metrics by CBGM ^† and their relationship with HbA1c ^‡ aiming to facilitate the effective use of CBGM ^† optimizing DM management ^§.	Participants underwent 6 months of CBGM ^†. The main CBGM ^† metrics included in the analyzes were: time on target (70-180 mg/dl); optimal time on target (70-140 mg/dl); time above target (>180 mg/dl); time above target (>250 mg/dl), time below target (<70 mg/dl) and time below target (<54 mg/dl). Spearman partial correlation coefficient.	Moderate correlation between time on target (70-180 mg/dl) and HbA1c ^‡ (-0.73 at month 6). Time on target (70-180 mg/dl) of 50% on average was associated with an HbA1c ^‡ level of about 8%. Time on target (70-180 mg/dl) of 30% on average was associated with an HbA1c ^‡ of about 8.7%. Time on target (70-180 mg/dl) of 70% on average was associated with an HbA1c ^‡ of about 7%.
Hirsch, et al. (2019) ⁽ ²³23. Hirsch IB, Welsh JB, Calhoun P, Puhr S, Walker TC, Price DA. Associations between HbA1c and continuous glucose monitoring-derived glycaemic variables. Diabet Med. 2019;36(12):1637-42. https://doi.org/10.1111/dme.14065 https://doi.org/10.1111/dme.14065... ⁾ Diabetic Medicine (4,359) USA Cross-sectional study 530 people ≥ 18 years old (455 with DM1* and 75 with DM2 ^\|\| on insulin treatment)	To identify clinically useful associations between HbA1c ^‡ levels and CBGM ^†-derived metrics.	≥ 2 weeks of blood glucose data from CBGM ^† sensors were analyzed. The main metrics included in the analyzes were: time on target (70-180 mg/dl), time above target (>250 mg/dl) and time below target (<70 mg/dl), correlating these variables with HbA1c ^‡ (corresponding to the last 3 months of study participation). Multiple regression analysis.	Strong inverse correlation between HbA1c ^‡ and time on target (70-180 mg/dl) (-0.75), each 10% change in time on target was associated with a 0.7% change in HbA1c ^‡. Strong positive correlations between HbA1c ^‡ and time above target level 2 (>250 mg/dl) (0.72). Weak inverse correlation between HbA1c ^‡ and time below target (<70 mg/dl) (-0.39). Of 139 subjects with time on target ≥70%, 111 had HbA1c ^‡ ≤7%.
Peterson, et al. (2019) ⁽ ²⁴24. Petersson J, Åkesson K, Sundberg F, Särnblad S. Translating glycated hemoglobin A1c into time spent in glucose target range: A multicenter study. Pediatr Diabetes. 2019;20(3):339-44. https://doi.org/10.1111/pedi.12817 https://doi.org/10.1111/pedi.12817... ⁾ Pediatric Diabetes (4,866) Sweden Cross-sectional study 105 children and adolescents ≤18 years old with DM1*	To analyze the relationship between time on target and HbA1c ^‡.	Data on CBGM ^† blood glucose values from the last 30, 60 and 90 days were analyzed. The metrics included in the analyzes were : time on target (70-180 mg/dl); optimal time on target (70-140 mg/dl); time above target (>180 mg/dl) and time below target (<70 mg/dl). Regression analysis was used to estimate the association between optimal time on target, time on target, and HbA1c ^‡. Both linear and quadratic models were calculated and the explained variance (R2 ) between the two models was compared	Significant linear relationship between optimal time on target and HbA1c ^‡ ( R ² = 0.63, p < 0.0001). Significant linear (B = 0.51, R ² = 0.68, p < 0.0001) and non-linear ( R ² = 0.70, p < 0.001) relationship between time above target (>180 mg/dl) in the last 60 days and HbA1c ^‡. Weak linear relationship between time below target (<70 mg/dl) and HbA1c ^‡ in the last 30 days ( R ² = 0.08), 60 days ( R ² = 0.06), and 90 days ( R ² = 0,01). HbA1c ^‡ of 6.5% equals 50.0% optimal time on target (70-140 mg/dl)
Tsuchiya, et al. (2020) ⁽ ²⁵25. Tsuchiya T, Saisho Y, Murakami R, Watanabe Y, Inaishi J, Itoh H. Relationship between daily and visit-to-visit glycemic variability in patients with type 2 diabetes. Endocr J. 2020;67(8):877-81. https://doi.org/10.1507/endocrj.ej20-0012 https://doi.org/10.1507/endocrj.ej20-001... ⁾ Endocrine Journal (2,349) Japan Cross-sectional study 156 people ≥ 18 years old with DM2 ^\|\| being treated with insulin or oral hypoglycemic medication	To characterize the relationship between Daily Glycemic Variability assessed by CBGM ^† and Visit-to-Visit Glycemic Variability in Japanese patients with DM2 ^\|\|.	5-day CBGM ^† values. HbA1c ^‡ was obtained from patient records. Time on target (70-180 mg/dl), time above target (> 180 mg/dl) and time below target (<70 mg/dl) were evaluated. Spearman correlation coefficient and multiple regression analysis.	Time on target (70-180 mg/dl) was significantly correlated with HbA1c ^‡ (–0.310, p < 0.01). The association between time on target (70-180 mg/dl) and HbA1c ^‡ remained significant after adjusting for age, sex and BMI in multiple regression analysis (β = –0.300, p < 0.001).
Cutruzzola, et al. (2020) ⁽ ²⁶26. Cutruzzolà A, Irace C, Parise M, Fiorentino R, Tripodi PFP, Ungaro S, et al. Time spent in target range assessed by self-monitoring blood glucose associates with glycated hemoglobin in insulin treated patients with diabetes. Nutr Metab Cardiovasc Dis. 2020;30(10):1800-5. https://doi.org/10.1016/j.numecd.2020.06.009 https://doi.org/10.1016/j.numecd.2020.06... ⁾ Nutrition, Metabolism, and Cardiovascular Diseases (4,222) Italy Cross-sectional study 233 people ≥18 years old with DM ^§ treated with insulin (197 with DM1* and 36 with DM2 ^\|\| on insulin treatment)	To evaluate the association between HbA1c ^‡ and percentage of points spent in time on target calculated from SMCBG values in patients with DM1* and DM2 ^\|\| treated with insulin.	SMCBG data was downloaded and two distinct periods were selected to calculate new metrics: 2 months and 2 weeks before the last HbA1c ^‡ available. The metrics used were point on target (70-180 mg/dl), point above target (>180 mg/dl) and point below target (<70 mg/dl). Univariate linear regression analysis.	Significant and negative correlation (R= -0.72) between HbA1c ^‡ and percentage point on target measured over 2 weeks and 2 months in individuals with DM1* and DM2 ^\|\|). A significant and inverse correlation (R= -0.18) was found between HbA1c ^‡ and the point below the target, and a significant and positive correlation (R= 0.75) between HbA1c ^‡ and the point above the target. Point on target equal to 70% corresponded to an HbA1c ^‡ value of approximately 7%. Each change in target point by 10% corresponded to a change in HbA1c ^‡ of 0.4%.
Urakami, et al. (2020) ⁽ ²⁷27. Urakami T, Yoshida K, Kuwabara R, Mine Y, Aoki M, Suzuki J, et al. Individualization of recommendations from the international consensus on continuous glucose monitoring-derived metrics in Japanese children and adolescents with type 1 diabetes. Endocr J. 2020;67(10):1055-62. https://doi.org/10.1507/endocrj.ej20-0193 https://doi.org/10.1507/endocrj.ej20-019... ⁾ Endocrine Journal (2,860) Japan Cross-sectional study 85 children and adolescents ≤18 years old with DM1*	To assess the significance of international consensus recommendations on metrics derived from the CBGM ^† in Japanese children and adolescents with DM1*.	28-day CBGM ^† blood glucose data. The relationship between CBGM-derived metrics ^† was evaluated: time on target (70-180 mg/dl), time above target (>180 mg/dl) and time below target (<70 mg/dl) with the HbA1c ^‡. Statistical analysis: Pearson correlation coefficients.	HbA1c ^‡ levels showed a highly inverse correlation with time on target (70-180 mg/dl) (-0.869, p < 0.0001), highly positive correlation with time above target (>180 mg/dl) (0.934, p < 0.0001) and weakly inverse correlation with time below target (<70 mg/dl) (–0.351, p = 0.001). HbA1c ^‡ of 7.0% corresponded to a time on target of 55.1%.
Valenzano, et al. (2021) ⁽ ²⁸28. Valenzano M, Bertolotti IC, Valenzano A, Grassi G. Time in range-A1c hemoglobin relationship in continuous glucose monitoring of type 1 diabetes: a real-world study. BMJ Open Diabetes Res Care. 2021;9(1):e001045. https://doi.org/10.1136/bmjdrc-2019-001045 https://doi.org/10.1136/bmjdrc-2019-0010... ⁾ BMJ Open Diabetes (3,388) Italy Cross-sectional study 59 people between 20 and 60 years old with DM1*	To contribute, with data from around the world, to an understanding of the relationship between Time on target and HbA1c ^‡.	Participants used CBGM ^† devices for 1 year. Follow-up visits were performed after 90, 180, and 365 days from baseline and percentage time on target (70-180 mg/dl) assessed for the 90-day period prior to each visit. Pearson correlation coefficient and univariate linear regression.	Strong correlation (-0.73) between HbA1c ^‡ and time on target (70-180 mg/dl) based on 90-day CBGM ^† data under real-life conditions. There was a 0.5% decrease in HbA1c ^‡, from 7.5% to 7.0% in an improvement in percentage time on target (70-180 mg/dl) from 52.9% to 58.8%.
Kuroda, et al. (2021) ⁽ ²⁹29. Kuroda N, Kusunoki Y, Osugi K, Ohigashi M, Azuma D, Ikeda H, et al. Diabetes Hypoglycemia Cognition Complications (HDHCC) study group. Relationships between time in range, glycemic variability including hypoglycemia and types of diabetes therapy in Japanese patients with type 2 diabetes mellitus: Hyogo Diabetes Hypoglycemia Cognition Complications study. J Diabetes Investig. 2021;12(2):244-53. https://doi.org/10.1111/jdi.13336 https://doi.org/10.1111/jdi.13336... ⁾ Journal of Diabetes Investigation (4,232) Japan Cohort study 281 people between 40 and 75 years old with DM2 ^\|\| being treated with insulin or oral hypoglycemic drugs	To investigate the relationship between Time on target, glycemic variability and characteristics of patients with DM2 ^\|\|	Blood glucose sensor data was primarily collected over a 10-day period (≥70% of 14-day CBGM data). Time on target (70-180 mg/dl) and time below target (<70 mg/dl) were used as objective variable, and multiple regression analysis was performed using variables including age, sex, disease duration and HbA1c ^‡, as explanatory variables.	The results showed that HbA1c ^‡ (standard partial regression coefficient; β = -0.573, p < 0.001), disease duration ( β = -0.160, p = 0.003) were useful explanatory factors for time on target (70-180 mg/ dl). HbA1c ^‡ (β = −0.431, p < 0.001) and use of medications with a high risk of hypoglycemia (β = 0.147, p = 0.030) were useful explanatory factors for time below target.
Ling, et al. (2021) ⁽ ³⁰30. Ling P, Yang D, Gu N, Xiao X, Lu J, Liu F, et al. Achieving the HbA1c Target Requires Longer Time in Range in Pregnant Women With Type 1 Diabetes. J Clin Endocrinol Metab. 2021;106(11):e4309-e4317. https://doi.org/10.1210/clinem/dgab502 https://doi.org/10.1210/clinem/dgab502... ⁾ The Journal of Clinical Endocrinology and Metabolism (5,958) China Cross-sectional study 98 pregnant women > 18 years old with DM1*	To investigate the relationship between MCG ^† and laboratory HbA1c ^‡ metrics in pregnant women with DM1*.	CBGM ^† data during pregnancy and postpartum. Data was collected to calculate Time on Target (60-140 mg/dl), Time on Target (70-180 mg/dl), Time Above Target (>140 mg/dl), Time Above Target (>180 mg/dl), time below target (<60 mg/dl) and time below target (<54 mg/dl). Spearman coefficient analysis.	The analysis showed a negative correlation between time on target (70-180 mg/dl) and HbA1c ^‡ during pregnancy (-0.429) and in the postpartum period (-0.766). HbA1c ^‡ of 6.0%, 6.5% and 7.0% were equivalent to a time on target of 78%, 74% and 69%, respectively.
Den Braber, et al. (2021) ⁽ ³¹31. den Braber N, Vollenbroek-Hutten MMR, Westerik KM, Bakker SJL, Navis G, van Beijnum BF, et al. Glucose Regulation Beyond HbA1c in Type 2 Diabetes Treated With Insulin: Real-World Evidence From the DIALECT-2 Cohort. Diabetes Care. 2021;44(10):2238-44. https://doi.org/10.2337/dc20-2241 https://doi.org/10.2337/dc20-2241... ⁾ Diabetes Care (19,112) Netherlands Cohort study 79 people ≥18 years old with DM2 ^\|\| treated with insulin	To investigate blood glucose variations associated with HbA1c ^‡ in patients with DM2 ^\|\| treated with insulin.	CBGM ^†-derived parameters for 2 weeks. The following metrics were analyzed: time on target (70-180 mg/dl); time above target (>180 mg/dl); time above target (>250 mg/dl), time below target (<70 mg/dl) and time below target (<54 mg/dl). Best-fit regression analyzes with 95% prediction intervals.	Correlation between HbA1c ^‡ and time on target (70-180 mg/dl) R ² = 0.65. Time below target (<70 mg/dl) decreased progressively in increasing HbA1c categories ^‡ while time above target (>180 mg/dl) increased progressively.
Bosoni, et al. (2021) ⁽ ³²32. Bosoni P, Calcaterra V, Tibollo V, Malovini A, Zuccotti G, Mameli C, et al. Exploring the inter-subject variability in the relationship between glucose monitoring metrics and glycated hemoglobin for pediatric patients with type 1 diabetes. J Pediatr Endocrinol Metab. 2021;34(5):619-25. https://doi.org/10.1515/jpem-2020-0725 https://doi.org/10.1515/jpem-2020-0725... ⁾ Journal of Pediatric Endocrinology and Metabolism (1,520) Italy Cross-sectional study 23 children and adolescents ≤18 years old with DM1*	Investigate the relationship between CBGM ^†-derived glycemic metrics and HbA1c ^‡.	CBGM ^† blood glucose data for 30, 60 and 90 days. The following metrics from the CBGM ^† were considered: Time on target (70-180 mg/dl); optimal time on target (70-140 mg/dl); time above target (>180 mg/dl); time above target (>250 mg/dl), time below target (<70 mg/dl) and time below target (<54 mg/dl). Linear regression analysis.	Time on target (70-180 mg/dl) and optimal time on target (70-140 mg/dl) had a negative linear relationship with HbA1c ^‡ (R ²⁼ 0.88). Time above target (>180 mg/dl) and time above target (>250 mg/dl) showed a positive linear relationship with HbA1c ^‡ (R ²⁼ 0.75). For an HbA1c ^‡ ≤ 7%, a Time on Target (70-180 mg/dl) of 65% and an Optimal Time on Target (70-140 mg/dl) of 48% are required.
Babaya, et al. ( 2021) ⁽ ³³33. Babaya N, Noso S, Hiromine Y, Taketomo Y, Niwano F, Yoshida S, et al. Relationship of continuous glucose monitoring-related metrics with HbA1c and residual β-cell function in Japanese patients with type 1 diabetes. Sci Rep. 2021;11(1):4006. https://doi.org/10.1038/s41598-021-83599-x https://doi.org/10.1038/s41598-021-83599... ⁾ Scientific Reports (4,996) Japan Cross-sectional study 19 people ≥18 years old with DM1*	Clarify the relationship between various CBGM ^† metrics and HbA1c ^‡.	Data obtained by CBGM ^† during 4 months. CBGM ^† data from 120, 90, 60, 30 and 7 days were used to calculate time on target (70-180 mg/dl); optimal time on target (70-140 mg/dl); time above target (>180 mg/dl); time above target (>250 mg/dl), time below target (<70 mg/dl) and time below target (<54 mg/dl). Univariate regression analysis.	Time on target (70-180 mg/dl) was strongly correlated with HbA1c ^‡ values (R²= 0.888; p <0.0001). There was a strong positive correlation between time above target (>180 mg/dl) and HbA1c ^‡ (R²= 0.944; p<0.0001). HbA1c ^‡ of approximately 7% corresponded to a time on target (70-180 mg/dl) of 74%.
Ohigashi, et al. (2021) ⁽ ³⁴34. Ohigashi M, Osugi K, Kusunoki Y, Washio K, Matsutani S, Tsunoda T, et al. Association of time in range with hemoglobin A1c, glycated albumin and 1,5-anhydro-d-glucitol. J Diabetes Investig. 2021;12(6):940-9. https://doi.org/10.1111/jdi.13437 https://doi.org/10.1111/jdi.13437... ⁾ Journal of Diabetes Investigation (3,681) Japan Cohort study 167 people between 20 and 80 years old with DM ^§, 67 with DM1* and 100 with DM2 ^\|\| using oral hypoglycemic medication and/or insulin	Investigate relationships between CBGM ^† and HbA1c ^‡ metrics.	14-day CBGM ^† data. HbA1c ^‡ was collected in the laboratory on the day of CBGM ^† application. Time on target (70-180 mg/dl) was calculated; time above target (>180 mg/dl); time above target (>250 mg/dl), time below target (<70 mg/dl) and time below target (<54 mg/dl). Spearman correlation coefficient and multiple regression.	In patients with DM1* and DM2\|\|, HbA1c ^‡ was negatively (-0.62) correlated with time on target (70-180 mg/dl). Strong positive correlation between time above target (>180 mg/dl) and HbA1c ^‡ (0.66). In patients with DM1*, a time on target of 70% corresponded to an HbA1c ^‡ of 6.9%. In patients with DM2 ^\|\|, a time on target of 70% corresponded to an HbA1c ^‡ of 7.1%.
Díaz-Soto, et al. (2021) ⁽ ³⁵35. Díaz-Soto G, Bahíllo-Curieses MP, Jimenez R, Nieto MO, Gomez E, Torres B, et al. The relationship between glycosylated hemoglobin, time-in-range and glycemic variability in type 1 diabetes patients under flash glucose monitoring. Endocrinol Diabetes Nutr. 2021;68(7):465-71. https://doi.org/10.1016/j.endien.2021.11.006 https://doi.org/10.1016/j.endien.2021.11... ⁾ Endocrinology , Diabetes and Nutrition (1,833) Spain Cross-sectional study 195 people with DM1* (70 <20 years and 125 >20 years)	To evaluate the relationship between HbA1c ^‡, Time on Target and glycemic variability in a cohort of pediatric and adult patients with DM1* and CBGM ^†.	CBGM ^† 90-day blood glucose data. Time on target (70-180 mg/dl) was calculated; time above target (>180 mg/dl) and time below target (<70 mg/dl). The different times were correlated with HbA1c ^‡. Statistical analysis: Pearson’s linear correlation coefficient and multiple regression.	There was a strong negative linear correlation (−0.746; p<0.001) between time on target and HbA1c ^‡.
Kurozumi, et al. (2022) ⁽ ³⁶36. Kurozumi A, Okada Y, Mita T, Wakasugi S, Katakami N, Yoshii H, et al. Associations between continuous glucose monitoring-derived metrics and HbA1c in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2022;186:109836. https://doi.org/10.1016/j.diabres.2022.109836 https://doi.org/10.1016/j.diabres.2022.1... ⁾ Diabetes Research and Clinical Practice (8,180) Japan Cross-sectional study 999 people with DM2 ^\|\| aged ≥ 30 and < 80 years treated with insulin or oral hypoglycemic agent	Define the relationship between Time on Target and HbA1c levels ^‡ in patients with DM2 ^\|\|.	14-day CBGM ^† data. Correlation was performed between time on target (70-180 mg/dl); time above target (>180 mg/dl); time above target (>250 mg/dl), time below target (<70 mg/dl) and time below target (<54 mg/dl) with the last laboratory- collected HbA1c ^‡. Statistical analysis: Pearson correlation coefficient and linear regression.	HbA1c ^‡ significantly correlated with time on target (70-180 mg/dl) (-0.71). An HbA1c ^‡ of 7% was associated with a time on target (70-180 mg/dl) of 80.64%. HbA1c ^‡ decreased by 0.3% for every 10% increase in time on target.
Alarcon, et al. (2022) ⁽ ³⁷37. Alarcón PP, Felgueroso CA, Blanco JA, Sánchez PM, Goitia CL, Escobedo RR, et al. Correlation between glucose measurement parameters of continuous flash monitoring and HbA1c. Real life experience in Asturias. Endocrinol Diabetes Nutr. 2022;69(7):493-9. https://doi.org/10.1016/j.endien.2022.08.001 https://doi.org/10.1016/j.endien.2022.08... ⁾ Endocrinology, Diabetes and Nutrition (1,833) Spain Cross-sectional study 252 people with DM1* aged between 15-79 years	Evaluate the correlation between MCG ^† and HbA1c ^‡ parameters	14-day CBGM ^† blood glucose data Correlated with time on target (70-180 mg/dl); time above target (>180 mg/dl); and time below target (<70 mg/dl) with the last laboratory-collected HbA1c ^‡. Statistical analysis: Correlation with the Pearson test and linear regression.	Statistically significant correlation between time on target (70-180 mg/dl) and HbA1c ^‡ (-0.623; p < 0.01).

Studies	Q1*	Q2 ^†	Q3 ^‡	Q4 ^§	Q5 ^\|\|	Q6 ^¶	Q7**	Q8 ^††
^{Beck, et al. (2019)}22. Beck RW, Bergenstal RM, Cheng P, Kollman C, Carlson AL, Johnson ML, et al. The Relationships Between Time in Range, Hyperglycemia Metrics, and HbA1c. J Diabetes Sci Technol. 2019;13(4):614-26. https://doi.org/10.1177/1932296818822496 https://doi.org/10.1177/1932296818822496...	S	S	S	S	UN	UN	S	S
^{Hirsch, et al. (2019)}23. Hirsch IB, Welsh JB, Calhoun P, Puhr S, Walker TC, Price DA. Associations between HbA1c and continuous glucose monitoring-derived glycaemic variables. Diabet Med. 2019;36(12):1637-42. https://doi.org/10.1111/dme.14065 https://doi.org/10.1111/dme.14065...	S	S	UN	S	N	N	S	UN
^{Peterson, et al. (2019)}24. Petersson J, Åkesson K, Sundberg F, Särnblad S. Translating glycated hemoglobin A1c into time spent in glucose target range: A multicenter study. Pediatr Diabetes. 2019;20(3):339-44. https://doi.org/10.1111/pedi.12817 https://doi.org/10.1111/pedi.12817...	S	S	S	S	UN	UN	S	S
^{Tsuchiya, et al. (2020)}25. Tsuchiya T, Saisho Y, Murakami R, Watanabe Y, Inaishi J, Itoh H. Relationship between daily and visit-to-visit glycemic variability in patients with type 2 diabetes. Endocr J. 2020;67(8):877-81. https://doi.org/10.1507/endocrj.ej20-0012 https://doi.org/10.1507/endocrj.ej20-001...	S	S	N	S	S	N	S	S
^{Cutruzzola, et al. (2020)}26. Cutruzzolà A, Irace C, Parise M, Fiorentino R, Tripodi PFP, Ungaro S, et al. Time spent in target range assessed by self-monitoring blood glucose associates with glycated hemoglobin in insulin treated patients with diabetes. Nutr Metab Cardiovasc Dis. 2020;30(10):1800-5. https://doi.org/10.1016/j.numecd.2020.06.009 https://doi.org/10.1016/j.numecd.2020.06...	S	S	S	S	N	N	S	S
^{Urakami, et al. (2020)}27. Urakami T, Yoshida K, Kuwabara R, Mine Y, Aoki M, Suzuki J, et al. Individualization of recommendations from the international consensus on continuous glucose monitoring-derived metrics in Japanese children and adolescents with type 1 diabetes. Endocr J. 2020;67(10):1055-62. https://doi.org/10.1507/endocrj.ej20-0193 https://doi.org/10.1507/endocrj.ej20-019...	S	S	N	S	UN	UN	S	S
^{Valenzano, et al. (2021)}28. Valenzano M, Bertolotti IC, Valenzano A, Grassi G. Time in range-A1c hemoglobin relationship in continuous glucose monitoring of type 1 diabetes: a real-world study. BMJ Open Diabetes Res Care. 2021;9(1):e001045. https://doi.org/10.1136/bmjdrc-2019-001045 https://doi.org/10.1136/bmjdrc-2019-0010...	S	S	S	S	UN	UN	S	S
^{Ling, et al. (2021)}30. Ling P, Yang D, Gu N, Xiao X, Lu J, Liu F, et al. Achieving the HbA1c Target Requires Longer Time in Range in Pregnant Women With Type 1 Diabetes. J Clin Endocrinol Metab. 2021;106(11):e4309-e4317. https://doi.org/10.1210/clinem/dgab502 https://doi.org/10.1210/clinem/dgab502...	S	S	UN	S	UN	UN	S	S
^{Bosoni, et al. (2021)}32. Bosoni P, Calcaterra V, Tibollo V, Malovini A, Zuccotti G, Mameli C, et al. Exploring the inter-subject variability in the relationship between glucose monitoring metrics and glycated hemoglobin for pediatric patients with type 1 diabetes. J Pediatr Endocrinol Metab. 2021;34(5):619-25. https://doi.org/10.1515/jpem-2020-0725 https://doi.org/10.1515/jpem-2020-0725...	N	S	S	S	N	N	S	S
^{Babaya, et al. (2021)}33. Babaya N, Noso S, Hiromine Y, Taketomo Y, Niwano F, Yoshida S, et al. Relationship of continuous glucose monitoring-related metrics with HbA1c and residual β-cell function in Japanese patients with type 1 diabetes. Sci Rep. 2021;11(1):4006. https://doi.org/10.1038/s41598-021-83599-x https://doi.org/10.1038/s41598-021-83599...	S	N	S	S	N	N	S	S
^{Díaz-Soto, et al. (2022)}35. Díaz-Soto G, Bahíllo-Curieses MP, Jimenez R, Nieto MO, Gomez E, Torres B, et al. The relationship between glycosylated hemoglobin, time-in-range and glycemic variability in type 1 diabetes patients under flash glucose monitoring. Endocrinol Diabetes Nutr. 2021;68(7):465-71. https://doi.org/10.1016/j.endien.2021.11.006 https://doi.org/10.1016/j.endien.2021.11...	S	S	S	S	UN	UN	S	S
^{Kurozumi, et al. (2022)}36. Kurozumi A, Okada Y, Mita T, Wakasugi S, Katakami N, Yoshii H, et al. Associations between continuous glucose monitoring-derived metrics and HbA1c in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2022;186:109836. https://doi.org/10.1016/j.diabres.2022.109836 https://doi.org/10.1016/j.diabres.2022.1...	S	S	S	S	UN	UN	S	S
^{Alarcon, et al. (2022)}37. Alarcón PP, Felgueroso CA, Blanco JA, Sánchez PM, Goitia CL, Escobedo RR, et al. Correlation between glucose measurement parameters of continuous flash monitoring and HbA1c. Real life experience in Asturias. Endocrinol Diabetes Nutr. 2022;69(7):493-9. https://doi.org/10.1016/j.endien.2022.08.001 https://doi.org/10.1016/j.endien.2022.08...	S	S	S	N	N	N	S	S
%	92	92	61	92	8	0	100	92

Studies	Q1*	Q2 ^†	Q3 ^‡	Q4 ^§	Q5 ^\|\|	Q6 ^¶	Q7**	Q8 ^††	Q9 ^‡‡	Q10 ^§§	Q11 ^\|\|\|\|
^{Kuroda, et al. (2021)}29. Kuroda N, Kusunoki Y, Osugi K, Ohigashi M, Azuma D, Ikeda H, et al. Diabetes Hypoglycemia Cognition Complications (HDHCC) study group. Relationships between time in range, glycemic variability including hypoglycemia and types of diabetes therapy in Japanese patients with type 2 diabetes mellitus: Hyogo Diabetes Hypoglycemia Cognition Complications study. J Diabetes Investig. 2021;12(2):244-53. https://doi.org/10.1111/jdi.13336 https://doi.org/10.1111/jdi.13336...	UN	UN	S	N	N	S	S	S	S	N	S
^{Ohigashi, et al. (2021)}34. Ohigashi M, Osugi K, Kusunoki Y, Washio K, Matsutani S, Tsunoda T, et al. Association of time in range with hemoglobin A1c, glycated albumin and 1,5-anhydro-d-glucitol. J Diabetes Investig. 2021;12(6):940-9. https://doi.org/10.1111/jdi.13437 https://doi.org/10.1111/jdi.13437...	UN	UN	S	N	N	S	S	S	UN	N	S
^{Den Braber, et al. (2021)}31. den Braber N, Vollenbroek-Hutten MMR, Westerik KM, Bakker SJL, Navis G, van Beijnum BF, et al. Glucose Regulation Beyond HbA1c in Type 2 Diabetes Treated With Insulin: Real-World Evidence From the DIALECT-2 Cohort. Diabetes Care. 2021;44(10):2238-44. https://doi.org/10.2337/dc20-2241 https://doi.org/10.2337/dc20-2241...	S	S	S	UN	UN	S	S	S	UN	N	S
%	33	33	100	0	0	100	100	100	33	0	100

[1] Corresponding author:
Rafael Aparecido Dias Lima E-mail: rafael.aparecido.lima@usp.br https://orcid.org/0000-0002-5700-1333

Brasil

Brasil

Correlation between time on target and glycated hemoglobin in people with diabetes mellitus: systematic review ^* * This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) - Finance Code 001, Brazil.

Highlights:

Brasil

Brasil

Correlation between time on target and glycated hemoglobin in people with diabetes mellitus: systematic review * * This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) - Finance Code 001, Brazil.

Highlights:

Correlation between time on target and glycated hemoglobin in people with diabetes mellitus: systematic review ^* * This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) - Finance Code 001, Brazil.