GLYCEMIC VARIABILITY INDICATORS BY CONTINUOUS GLUCOSE MONITORING AND HYPOGLYCEMIA RISK IN CHILDREN AND YOUNG ADULTS WITH TYPE 1 DIABETES
Main Article Content
Abstract
Background: Hypoglycemia is the main barrier to optimizing insulin treatment in people with type 1 diabetes, different risk factors have been studied and one of the mechanisms involved is glycemic variability.
Aims: To assess hypoglycemia risk showed by the glycemic variability metrics: coefficient of variation (CV), continuous overlapping net glycemic action (CONGA), low blood glucose index (LBGI) and lability index (LI) in a group of children, adolescents, and young adults with type 1 diabetes.
Methods: A group of 31 subjects with type 1 diabetes under 25 years were evaluated, data from professional continuous glucose monitoring records were studied, glycemic variability metrics, including CV, CONGA24, LBGI, and LI, were calculated. Correlation with percentage time of hypoglycemia under 54mg% was assessed. Multiple linear regression models were generated, univariate and multivariate analysis was also performed, area under curve of glycemic variability metrics was obtain from ROC curves analysis, the optimal cutoff points were calculated.
Results: The average age was 14.5 years with a range of 5 to 24 years. The mean duration of diabetes was 6.6 ± 3.7 years, and the glycated hemoglobin mean value was 8.2% ± 2.1%. The average percentage of time for hypoglycemia alert was 4.23% (0.2 to 13%), while for clinically significant hypoglycemia was 4.55% (0 to 17.1%). LBGI with R= 0.913 and CV with R= 0.735 (p < 0.0001) expressed the highest degree of correlation with percentage of time in hypoglycemia, furthermore, after multivariate analysis, they showed the highest predictive load. CV expressed an AUC of 0.97, while LBGI was 0.95, both statistically significant (p<0.0005). The cut-off point for CV of 38% had sensitivity of 93% and specificity of 74% in detection of time in hypoglycemia under 54mg/dl, and the cut-off point for LBGI of 5.4 expressed sensitivity of 87% and specificity of 94%.
Conclusions: Glycemic variability metrics studied outperformed the clinical variables as indicators of risk of hypoglycemia, and those with the greatest predictive power of hypoglycemia risk were LBGI and CV above 38%.
Article Details
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
2. Urakami T. Severe Hypoglycemia: Is It Still a Threat for Children and Adolescents With Type 1 Diabetes? Front Endocrinol (Lausanne). 2020; 11: 609. DOI: 10.3389/fendo.2020.00609. [PubMed: 33042005].
3. Dagogo-Jack SE, Craft S, Cryer PE. Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. J Clin Invest. 1993; 91(3): 819-828. DOI: 10.1172/JCI116302. [PubMed: 8450063].
4. Perantie DC, Lim A, Wu J, Weaver P, Warren SL, Sadler M, White NH, Hershey T. Effects of prior hypoglycemia and hyperglycemia on cognition in children with type 1 diabetes mellitus. Pediatr Diabetes. 2008; 9(2): 87-95. DOI: 10.1111/j.1399-5448.2007.00274.x. [PubMed: 18208449].
5. Villalobos J, Hernández-Sandoval G, Paz JJ, Finol M, Colina JL. Variabilidad glucémica como parámetro de control metabólico en pacientes con diabetes tipo 1. Rev Venez Endocrinol Metab. 2020; 18(3): 107-120. Available in: http://ve.scielo.org/scielo.php?script=sci_arttext&pid=S1690-31102020000300107&lng=es.
6. Monnier L, Colette C, Owens DR. The application of simple metrics in the assessment of glycaemic variability. Diabetes Metab. 2018; 44(4): 313-319. DOI: 10.1016/j.diabet.2018.02.008. [PubMed: 29602622].
7. Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, DeVries JH, Garg S, Heinemann L, Hirsch I, Amiel SA, Beck R, Bosi E, Buckingham B, Cobelli C, Dassau E, Doyle FJ 3rd, Heller S, Hovorka R, Jia W, Jones T, Kordonouri O, Kovatchev B, Kowalski A, Laffel L, Maahs D, Murphy HR, Nørgaard K, Parkin CG, Renard E, Saboo B, Scharf M, Tamborlane WV, Weinzimer SA, Phillip M. International Consensus on Use of Continuous Glucose Monitoring. Diabetes Care. 2017; 40(12): 1631-1640. DOI: 10.2337/dc17-1600. [PubMed: 29162583].
8. DeVries JH. Glucose variability: where it is important and how to measure it. Diabetes. 2013; 62(5): 1405-1408. DOI: 10.2337/db12-1610. [PubMed: 23613566].
9. Monnier L, Colette C, Wojtusciszyn A, Dejager S, Renard E, Molinari N, Owens DR. Toward Defining the Threshold Between Low and High Glucose Variability in Diabetes. Diabetes Care. 2017; 40(7): 832-838. DOI: 10.2337/dc16-1769. [PubMed: 28039172].
10. Service FJ. Glucose variability. Diabetes. 2013; 62(5): 1398-1404. DOI: 10.2337/db12-1396. [PubMed: 23613565].
11. Kovatchev B, Cobelli C. Glucose Variability: Timing, Risk Analysis, and Relationship to Hypoglycemia in Diabetes. Diabetes Care. 2016; 39(4): 502-510. DOI: 10.2337/dc15-2035. [PubMed: 27208366].
12. Vantyghem MC, Press M. Management strategies for brittle diabetes. Ann Endocrinol (Paris). 2006; 67(4): 287-296. DOI: 10.1016/s0003-4266(06)72600-2. [PubMed: 17072232].
13. Ryan EA, Shandro T, Green K, Paty BW, Senior PA, Bigam D, Shapiro AM, Vantyghem MC. Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation. Diabetes. 2004; 53(4): 955-962. DOI: 10.2337/diabetes.53.4.955. [PubMed: 15047610].
14. Piona C, Marigliano M, Mozzillo E, Di Candia F, Zanfardino A, Iafusco D, Maltoni G, Zucchini S, Delvecchio M, Maffeis C. High Glycemic Variability Is Associated with Worse Continuous Glucose Monitoring Metrics in Children and Adolescents with Type 1 Diabetes. Horm Res Paediatr. 2021; 94(9-10): 369-373. DOI: 10.1159/000521430. [PudMed: 34915493].
15. Liu X. Classification accuracy and cut point selection. Stat Med. 2012; 31(23): 2676-2686. DOI: 10.1002/sim.4509. [PubMed: 22307964].
16. Oliver N, Gimenez M, Calhoun P, Cohen N, Moscardo V, Hermanns N, Freckmann G, Reddy M, Heinemann L. Continuous Glucose Monitoring in People With Type 1 Diabetes on Multiple-Dose Injection Therapy: The Relationship Between Glycemic Control and Hypoglycemia. Diabetes Care. 2020; 43(1): 53-58. DOI: 10.2337/dc19-0977. [PubMed: 31530662].
17. Unger J, Parkin C. Recognition, prevention, and proactive management of hypoglycemia in patients with type 1 diabetes mellitus. Postgrad Med. 2011; 123(4): 71-80. DOI:10.3810/pgm.2011.07.2306. [PubMed: 21680991].
18. Šoupal J, Petruželková L, Grunberger G, Hásková A, Flekač M, Matoulek M, Mikeš O, Pelcl T, Škrha J Jr, Horová E, Škrha J, Parkin CG, Svačina Š, Prázný M. Glycemic Outcomes in Adults With T1D Are Impacted More by Continuous Glucose Monitoring Than by Insulin Delivery Method: 3 Years of Follow-Up From the COMISAIR Study. Diabetes Care. 2020; 43(1): 37-43. DOI: 10.2337/dc19-0888. [PubMed: 31530663].
19. Di Molfetta S, Rossi A, Assaloni R, Cherubini V, Consoli A, Di Bartolo P, Guardasole V, Laurenzi A, Lombardo F, Maffeis C, Scaramuzza A, Irace C; AMD-SID-SIEDP Working group on Diabetes and Technology. A guide for the use of LibreView digital diabetes platform in clinical practice: Expert paper of the Italian Working Group on Diabetes and Technology. Diabetes Res Clin Pract. 2022; 187: 109867. DOI: 10.1016/j.diabres.2022.109867. [PubMed: 35405166].
20. Di Molfetta S, Caruso I, Cignarelli A, Natalicchio A, Perrini S, Laviola L, Giorgino F. Professional continuous glucose monitoring in patients with diabetes mellitus: A systematic review and meta-analysis. Diabetes Obes Metab. 2023; 25(5): 1301-1310. DOI: 10.1111/dom.14981. [PubMed: 36661362].
21. Wright LA, Hirsch IB. Metrics Beyond Hemoglobin A1C in Diabetes Management: Time in Range, Hypoglycemia, and Other Parameters. Diabetes Technol Ther. 2017; 19(S2): S16-S26. DOI: 10.1089/dia.2017.0029. [PubMed: 28541136].
22. Advani A. Positioning time in range in diabetes management. Diabetologia. 2020; 63(2): 242-252 . DOI: 10.1007/s00125-019-05027-0. [PubMed: 31701199].
23. Geddes J, Schopman JE, Zammitt NN, Frier BM. Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes. Diabet Med. 2008; 25(4): 501-504. DOI: 10.1111/j.1464-5491.2008.02413.x. [PubMed: 18387080].
24. Battelino T, Danne T, Bergenstal RM, Amiel SA, Beck R, Biester T, Bosi E, Buckingham BA, Cefalu WT, Close KL, Cobelli C, Dassau E, DeVries JH, Donaghue KC, Dovc K, Doyle FJ 3rd, Garg S, Grunberger G, Heller S, Heinemann L, Hirsch IB, Hovorka R, Jia W, Kordonouri O, Kovatchev B, Kowalski A, Laffel L, Levine B, Mayorov A, Mathieu C, Murphy HR, Nimri R, Nørgaard K, Parkin CG, Renard E, Rodbard D, Saboo B, Schatz D, Stoner K, Urakami T, Weinzimer SA, Phillip M. Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International Consensus on Time in Range. Diabetes Care. 2019; 42(8): 1593-1603. DOI: 10.2337/dci19-0028. [PubMed: 31177185].
25. Huang B, Jiang Q, Wu T, Shen Q, Wang W, Wang S, Huang Y, Wang S, Huang P, Lin M, Shi X, Li X. Hypoglycemia unawareness identified by continuous glucose monitoring system is frequent in outpatients with type 2 diabetes without receiving intensive therapeutic interventions. Diabetol Metab Syndr. 2022; 14(1): 180. DOI: 10.1186/s13098-022-00959-x. [PubMed: 36443872].
26. Johansen A, Kanijo B, Fredheim S, Olsen B, Hertz B, Lauridsen MH, Andersen ML, Mortensen HB, Svensson J; Danish Society for Diabetes in Childhood. Prevalence and predictors of severe hypoglycemia in Danish children and adolescents with diabetes. Pediatr Diabetes. 2015; 16(5): 354-360. DOI: 10.1111/pedi.12171. [PubMed: 25039921].
27. Fredheim S, Johansen A, Thorsen SU, Kremke B, Nielsen LB, Olsen BS, Lyngsøe L, Sildorf SM, Pipper C, Mortensen HB, Johannesen J, Svensson J; Danish Society for Diabetes in Childhood and Adolescence. Nationwide reduction in the frequency of severe hypoglycemia by half. Acta Diabetol. 2015; 52(3): 591-599. DOI: 10.1007/s00592-014-0697-5. [PubMed: 25528006].
28. Rama Chandran S, Tay WL, Lye WK, Lim LL, Ratnasingam J, Tan ATB, Gardner DSL. Beyond HbA1c: Comparing Glycemic Variability and Glycemic Indices in Predicting Hypoglycemia in Type 1 and Type 2 Diabetes. Diabetes Technol Ther. 2018; 20(5): 353-362. DOI: 10.1089/dia.2017.0388. Erratum in: Diabetes Technol Ther. 2019; 21(5): 303. [PudMed: 29688755].
29. Monnier L, Wojtusciszyn A, Molinari N, Colette C, Renard E, Owens D. Respective Contributions of Glycemic Variability and Mean Daily Glucose as Predictors of Hypoglycemia in Type 1 Diabetes: Are They Equivalent? Diabetes Care. 2020; 43(4): 821-827. DOI: 10.2337/dc19-1549. [PubMed: 31988062].
30. Gómez AM, Henao DC, Imitola Madero A, Taboada LB, Cruz V, Robledo Gómez MA, Rondón M, Muñoz-Velandia O, García-Jaramillo M, León Vargas FM. Defining High Glycemic Variability in Type 1 Diabetes: Comparison of Multiple Indexes to Identify Patients at Risk of Hypoglycemia. Diabetes Technol Ther. 2019; 21(8): 430-439. DOI: 10.1089/dia.2019.0075. [PubMed: 31219350].
31. Tan HK, Little SA, Leelarathna L, Walkinshaw E, Lubina-Solomon A, Hosking J, Speight J, Kerr D, Heller SR, Evans ML, Shaw JA, Flanagan D. Low-Blood Glucose Avoidance Training Improves Glycemic Variability in Adults With Type 1 Diabetes Complicated by Impaired Awareness of Hypoglycemia: HypoCOMPaSS Trial. Diabetes Care. 2016; 39(4): e56-8. DOI: 10.2337/dc15-2431. [PubMed: 26953169].