A systematic review on clinical implication of continuous glucose monitoring in diabetes management

Abstract

INTRODUCTION Diabetes Mellitus (DM) is one of the most prevalent endocrine disorders worldwide with several short-term and long-term complications including macro- and microvascular disorders.[1] It is estimated that approximately 592 million people will be affected with diabetes mellitus by 2035.[2] The health-disease burden showed increasing trends over the past decade[2] and to improve health-related quality of life, along with diabetic care, extensive monitoring guidelines should also be implemented.[12345] Literature showed dominant prevalence of type 2 diabetes mellitus (T2DM) over type 1 diabetes mellitus (T1DM) all around the world.[14,5] There are several challenges in the management of diabetes mellitus in the health-care system.[6] The effect and management outcomes based on multifactorial concept including demographic variability, disease and social functioning, and self-care behavior are the strong influencers in treatment plan.[45] Disease control or progression based on continuous/frequent blood glucose monitoring[456] will further facilitate the process of rational prescribing.[36] Several studies showed that self-care behavior specific to glucose monitoring plays a vital role in the management of glycemic levels.[23456] The continuous glucose monitoring (CGM) has led to a clinical shift in the management of DM.[7] This technique is based on real-time glycemic monitoring, glucose levels trending alerts, condition-related predictive notifications, and the ability to make care plan on glycemic levels without the use of conventional self-monitoring blood glucose (SMBG).[89] This automated system has helped patients with T1DM with insulin dosing process; however, its success is based on users’ perspectives to wear such device in terms of easiness, comfortability, cost, and potential benefits over SMBG. It is found that consistent use of CGM provides sustained glycated hemoglobin (HbA1c) reduction of 0.5%–1.2%.[789] The clinical implications of CGM and its application in clinical practice are based on the patient-related factors. Several studies have proposed the beneficial outcomes of CGM in the practice but limited to T1DM only. The patients’ and health-care professionals’ perspectives toward the use of device are still undermining. Therefore, this study aimed to evaluate the literature for clinical implication of CGM in different population (i.e., geriatric, adult, and pregnancy) and understand the users’ perspectives on the CGM use compared with standard SMBG and also identify the areas of application to CGM with limited literature. MATERIALS AND METHODS Eligibility criteria Continuous glucose monitoring CGM is the monitoring parameter for patients with DM. SMBG SMBG is also a self-care model for patients with diabetes mellitus but implication and practice are limited to individual behavior. Clinical implications of CGM Studies that focused on CGM-based monitoring among patients with diabetes mellitus and evaluate the clinical outcomes in terms of safety and/or efficacy profile. HbA1c and eA1c These are the predictive markers in the treatment of diabetes mellitus. Studies evaluating glycated hemoglobin values are considered for systematic review. Users perceptions/perspectives Studies evaluating the personnel perception or perspectives toward the use of CGM are also considered in this study. Literature search Articles were searched from different databases and individual journal websites including Google Scholar, ScienceDirect, Sagepub, Libertpub, American Diabetes Association (Diabetes Care), Wiley Online Library, EndocrineWeb, touchENDOCRINOLOGY, PROSPERO, Biomed Central (BMC), Diabetes Technology and Therapeutics, The San Diego Union-Tribune, PubMed(ncbi), Clinical Trials List, SCOPUS, and Elsevier. Search keywords The following were the search keywords: “CGM (continuous glucose monitoring)”, “safety”, “efficacy”, “type 2 DM”, “comorbidities”, “elderly”, “benefits”, “improved”, “glycemic”, and “outcomes” Study selection and data extraction Abstracts and conference proceedings were screened to exclude that do not involve in the following inclusion criteria. The articles should be published between 2017 and 2019. Primary literature would be specific only for T1DM and T2DM. In addition, the literature should also focus on the safety and efficacy of CGM. Also, studies evaluating users (both health-care providers’ and patients’) perspectives were included in the systematic review. Quality assessment Mixed-method appraisal tool (MMAT)[10] checklist is a comprehensive tool for quality assessment of different research design articles in the systematic review. It contains five domains on research design, each with five specific item appraisal questions. The appraisal tool consists of four sub-domains; data collection and recording, methodological design, study population and statistical analysis in-between groups.[10] RESULTS AND DISCUSSION General data This systematic review looks into 17 articles that were taken from 2017 to 2019. Five (29%) studies were from the USA, three (17%) studies were from the UK, one from South America, one from Japan, one from India, one from France, one from Italy, one from Belgium, one from Germany, one from Slovenia, and one from Georgia [Supplementary Table 1]. The quality was assessed using MMAT guidelines, according to which 11 (64%) studies were low-risk and 6 (35%) were mid-risk studies [Figure 1].Supplementary Table 1: Systematic review of studies included in the studyFigure 1: Preferred reporting items for systematic reviews and Meta-analyses (PRISMA) diagram of systematic reviewClinical themes In this systematic review, some of the things discussed are the discrepancy between calculated estimated A1c (eA1c) and HBA1c, how CGM is user friendly and is less time-consuming than conventional methods for blood glucose monitoring, and how pregnant women with diabetes mellitus also benefit from CGM [Table 1].Table 1: Content and subtheme analysis of systematic reviewThe review addresses “Clinical relevance of HBA1c in monitoring,” “Clinical controversies of HB1Ac,” “CGM used in TD1 than TD2,” “Limitations of CGM in clinical practice,” “Patient and HCPs perception on CGM,” “Future implications of CGM,” and “Glucose variability” [Figure 2].Figure 2: Systematic review blueprintClinical relevance of glycated hemoglobin HbA1c is the classic method for assessing the glucose levels.[111213] Most organizations that have been assessing glucose levels using this method have set a recommended target of 7.0% (53 mmol/mol) for adults and 7.5% (58 mmol/mol) for children; however, some other organizations suggest a different target value for HbA1c such as 6.5% for adults as well as for children.[12] Nonetheless, all the organizations agree that HbA1c limit should be set person to person rather than a generalized limit.[13] Considering the importance of HBA1c value and the increased use of CGM has introduced a new term eA1c, which is supposed to be an equivalent to HBA1c (laboratory generated); it uses the mean glucose data from CGM or SBGM to produce a value. However, due to lack of agreement between the lab A1C and eA1c, U.S. Food and Drug Administration (US FDA) suggested changing the nomenclature of eA1c to Glucose Management Indicator (GMI) and also derived a formula to convert the CGM readings of mean blood glucose to GMI.[14] The formula that is used to calculate the GMI is derived from a regression line by plotting a graph of “mean glucose concentration” on the x-axis and “simultaneously measured A1C” on y-axis. The very first study to generate eA1c value was A1c-derived average glucose study conducted in 2006–2007.[14] A more recent study by Beck et al.[14] generated an equation which was validated later by HypoDE study. The equation was GMI (%) = 3.31+0.02392x (mean glucose in mg/dL). Real-time continuous glucose monitoring (RT-CGM) was carried out, in which patients received various therapies that involved diet, lifestyle, and different combinations of antihyperglycemic therapies including basal insulin therapy.[26] As the trial proceeded, HbA1c reduction was observed despite of the lower doses given to the patients. RT-CGM study was considered as it will avoid the energy burnout of T2DM people, hence less chances of error in the results, even to those people who use insulin and along all this HbA1c reduction is observed.[26] Major changes are seen in those whose HbA1c values were high at baseline.[26] However, when this study was carried out on a mixed T1DM and T2DM, there were no significant results for HbA1c.[26] Another study was run on a sample of population consisting of 50 units. These units were 50 pregnant females who were divided into two groups, 25 females in each group where CGM, SMBG, and capillary blood glucose were observed in order to check how these variables affect and how much they affect the HbA1c concentration. These females were kept under study from the beginning of their pregnancy and also, they were to take their values three times a week and the results recorded are shown in Figure 3.[19]Figure 3: Continuous glucose monitoring (CGM) implication in pregnant women vs. self-monitoring of blood glucose (SBGM) for adverse drug reaction. As shown in the above the graph, the increase in Hb1Ac level in Group 1 (CGM and SMBG) is almost insignificant, whereas in Group 2 (control group) the increase in Hb1Ac level is approximately 0.5%Clinical controversies of glycated hemoglobin The conventional method for evaluating glycemic control has been the measurement of HbA1c. Although this method is still being used, there are several drawbacks of using it. Intra- and interday glycemic excursions are not considered[13] that give rise to acute events such as hypoglycemia and postprandial hyperglycemia, which remains undetected on a daily basis. Moreover, it is an erratic measure in the case of anemic patients,[13] iron deficiency,[13] hemoglobinopathies,[13] and pregnancy.[13] HbA1c values are also questionable due to racial differences as it affects the accuracy.[13] Another extensively used method for blood glucose monitoring to detect the hypoglycemia, which is undetected by HbA1c,[7] is SBGM. It provides a single “point-in-time” measurement.[1213] Although patients particularly on insulin therapy are at a greater risk of experiencing hypoglycemia, frequent testing is required which may or may not be performed by the patient.[1317] There are chances of misreporting,[17] and it also does not recognize nocturnal and asymptomatic hypoglycemia,[13] which is why SBGM is also not a very good method for achieving glycemic control. eA1c is another way of evaluating glycemic control when newer technologies such as CGM and FLASH are used but there is usually a discrepancy between the laboratory (HBA1c) and the eA1c, which makes this value unreliable and insufficient to be used for safe and effective clinical management.[14] As the use of CGM becomes significant, this inconsistency in comparison of HBA1c and eA1c leads to a new term being introduced by members of the Center for Devices and Radiological Health (CDRH), a division of the U.S. FDA, who is responsible for the regulation of medical devices, “GMI”.[14] The disagreement between HBA1c and eA1c will be overcome by considering other measurements such as fructosamine, glycated albumin, and SMBG along with HbA1c and the use of GMI, when sufficient data are available [Figure 4].Figure 4: Comparison of continuous glucose monitoring (CGM) glucose monitoring (CGM) outcomePazos-Couselo et al.[18] completed an observational, prospective study of 63 patients with T2DM on insulin in which the patients were asked to take two SMBG readings for 8 weeks and in the 9th week they wore blinded CGM and the results clearly showed that CGM is an important tool for detecting hypoglycemia and nocturnal hypoglycemia, which are undetectable by SBGM. Continuous glucose monitoring used in type 1 diabetes mellitus and in type 2 diabetes mellitus CGM is considered to be a very useful method to help patients who have T1DM or TD2 and also in pregnant women as it shows patterns in hypoglycemia, hyperglycemia, and glucose variability (GV).[1419] The CGM data therefore provide information regarding the variables aforementioned and record the interstitial glucose every 5min, which would help the doctors in making strategies to help the patients with diabetes mellitus manage their glucose levels.[1721] CGM helps clinicians and patients decide how lifestyle changes such as diet, exercise, and stress management can help in managing diabetes mellitus. It is observed that the use of CGM in patients with TD1 causes a major decrease in the HbA1c levels compared to TD2 for which more evidence is required. CGM is beneficial in the use of TD2 including elderly patients as it gives information regarding GV as well as HbA1c levels, although it is advised to be used in a limited manner. This is mainly because TD2 patients are more likely to benefit from insulin therapy (as in TD2 insulin is not made or is made abnormally) or lifestyle modifications, whereas frequent glucose monitoring is required more in TD1 (insulin is produced in a minimal amount) due to which CGM is preferred in TD1 than TD2.[18] A most important clinical use of CGM is to evaluate the results and compare different types of treatment in both patients with T1DM and T2DM; it is clinically beneficial not only in patients with T1DM but also in patients with T2DM. Patients with T2DM for whom basal–bolus insulin therapy is essential are considered as almost the same as patients with T1DM. Patients with Hirata’s disease (anti-insulin antibodies) and inconsistent glycemic levels benefit the most from CGM.[21] CGM is more helpful for patients with TD1 than TD2 especially in those patients who use insulin and for pregnant women as it reduces both important factors: hypoglycemia and hyperglycemia, whereas in TD2 no significant change in the reduction of HbA1c levels was observed. In addition, more evidence or clinical trials are required to confirm that CGM is beneficial in TD2.[1214,17] Limitations of continuous glucose monitoring in clinical practice CGM gives a very thorough idea of the glucose changes compared to the traditional methods such as SBMG; however, it is a relatively new technology and requires more clinical data to be proven safe and accurate. The limitations that contribute to CGM’s limited use at present are as follows [Figure 5]:Figure 5: Randomized controlled trial (RCT) comparison between self-monitoring of blood glucose (SBMG) and continuous (1) The lack of internationally accepted standards for CGM system performance unlike older devices.[13] For example, the mean absolute relative difference MARD values that provide an average of the absolute error still does not have an exact threshold for rendering the CGM device as accurate.[13] (2) They are not affordable[12] to be set up in clinics and it requires HCPs that need to be aware of multiple software and should be capable of understanding the complex nature of the tool,[18] hence limiting the accessibility to patients who could be receiving benefits from it.[1718] (3) Need for calibration of CGM systems still remains an issue as it relies on SMBG for calibration[17] and this adds up to one of the crucial reasons for hesitancy of using CGM alone to make treatment decisions.[17] Research gap More clinical trials can be performed for TD2 and for pregnant women.[17] More research will be conducted especially for patients with TD2 regarding optimal frequency, timing, and duration of CGM [Figure 6].[18]Figure 6: Comparison of glycated hemoglobin (HbA1c) reduction among type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM): (1) the study conducted between 515 patients with T1DM from 0 to 12 months showed Hb1Ac reduction of 0.3%,[22] (2) the study conducted between 25 patients with T1DM from 0 to 3 months showed Hb1Ac reduction of 0.3%,[17] (3) the study conducted between 224 patients with from 0 to 6 months showed Hb1Ac reduction of 0.2%,[18] and (4) the study conducted between 515 patients with T1DM from 0 to 3 months showed Hb1Ac reduction of 0.3%[20]Future implications of continuous glucose monitoring CGM has been around since mid-1970s and was commercially available by 1999; however, they are clinically still in its infancy.[23] According to many studies, there are insufficient data on TD2 so for its more abundant use in future, more studies need to be carried out on that. Furthermore, comparison and evaluation of new therapeutic agents is one of the main applications for patients with TD1 and TD2.[1821] In addition, these systems may also be used later by individuals affected by prediabetes and may also be used by weight-loss programs for obese people and athletes.[11] In addition, the target population for CGM is changing focus from just self-monitoring for diabetics to older patients who have comorbidities, intensive care unit (ICU) patients, inpatient care, and pregnant women with T1DM or gestational DM. Figure 7 showed the user and healthcare perspectives on CGM.Figure 7: Users perspectives on continuous glucose monitoring (CGM)Elderly patients who are diabetics and have comorbidities are at greater risk for a hypoglycemic attack and this must be prevented as it may lead to cognitive impairment,[23] falling, stroke, and even death[1622] and CGM is useful in this case as it provides close glucose monitoring.[2224] Figure 8 shows data from 3 different studies that suggests that above the age of 50, elderly are at a greater risk of experiencing hypoglycemia.Figure 8: Risk of hypoglycemia among geriatricsFor ICU patients, who may not be diabetics, it is debatable if glucose monitoring must be performed. However, a study shows reduced mortality in cases such as stress-related hyperglycemia[26] as use of CGM allows rapid adjustability of insulin infusions as the changes in glucose concentrations are more easily identified.[25] Inpatient hypoglycemia is more easily detected in insulin-treated patients as it allows better supervision because the alerts are sent to the nursing stations through a monitoring device.[1519] Due to the ongoing improvement in accuracy of these tools, use in hospitalized patients seems to be promising.[21] There are some but not enough data present for pregnancy-related use of CGM; it has been reported to enhance the glycemic control[17] of the mother but does not reduce the risk of macrosomia, which means that the fetus is significantly larger; this is a common complication in women with diabetes mellitus.[2021] Moreover, better neonatal outcomes are also observed when CGM in used in mothers with CGM is also clinically useful when it to with other such as diabetes mellitus with glycemic excursions seen following evaluation of hypoglycemia to Hirata’s disease (anti-insulin and to to the insulin Due to such uses of CGM, should be more likely to for these technologies and provide to more patients in if they that the is beneficial for their members and diabetic Glucose variability GV to the of the blood glucose levels the including and As it is and understanding it is GV is also a for increased GV is with mortality in the intensive care as well as older patients with T2DM with lower glucose levels or greater GV the risk of CGM is the tool to measure glycemic as it the interstitial glucose levels very and this has reported reduction in of hypoglycemia, and hence Another study also reported that of of GV were reduced weeks of use of CGM.[21] In addition, the study also that GV was reduced as the of of CGM used week This study suggested that although HbA1c is as the of glycemic there are several limitations to this method which is why HCPs are more and more in using only HbA1c for diabetes mellitus SBGM is another useful method but insufficient data as it only gives a single in of blood glucose level hence hypoglycemia or may which may be CGM is to have a role in the management of with glucose It is a safe and effective method for T1DM and T2DM, and it should be used to therapies for the patients. Although the calibration and of the device still it is still a very tool for people with diabetes mellitus as it is less to use and they do not have to be readings as with traditional methods such as SBGM. and of There are no of

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