Hypoglycaemia is by far the most common complication among people with diabetes who are treated with insulin or insulin secretagogues, with frequencies averaging 2-3 events per week in those with type 1 and 2-3 events per month in those with type 2 diabetes. Hypoglycaemia is defined by three levels according to the International Hypoglycaemia Study Group (IHSG, 2017). Level 1 refers to glucose <3.9 mmol/l, level 2 to glucose <3.0 mmol/l and level 3 to severe hypoglycaemia. In addition, severe hypoglycaemia, defined by the need for external help because of cognitive decline and occurring at a yearly basis, puts these people at high risk of physical harm, including increased risk of mortality. Many people with diabetes and their family members fear hypoglycaemic events, often more so than (chronic) hyperglycaemia. As a consequence, hypoglycaemia is an important barrier to achieve optimal glucose control, thus maintaining high risks of micro- and macrovascular complications of diabetes. In itself, hypoglycaemia has been associated with increased risks of cardiovascular morbidity and mortality, probably in part through its pro-inflammatory effects. Current technology, i.e. continuous glucose monitoring and closed-loop systems, has been shown to be highly effective in reducing the incidence of (severe) hypoglycaemia among people with type 1 diabetes. Whether and to what extent this is also the case for people with type 2 diabetes is less clear.

•rtCGM

¹Mean results per treatment group were not reported for continuous outcomes, only mean differences between group.

• isCGM/FGM

¹Mean results per treatment group were not reported for continuous outcomes, only mean differences between group.

Description of studies

One study (systematic review) was included in the analysis of the literature (Jancev, 2024). Important study characteristics and results of the individual studies are summarized in table 2. The assessment of the risk of bias of the individual studies is summarized in Figure 2 of the supplementary file of Jancev (2024).

Jancev (2024) searched Embase, MEDLINE (via PubMed), Web of Science, Scopus and ClinicalTrials for relevant articles from inception until 2 May 2023. Studies were eligible if they compared CGM (rtCGM or isCGM) to SMBG (or isCGM when rtCGM was the main intervention, although no trials were included fort his reason) and reported HbA1c as an outcome measure. RCTs with a minimum intervention period of 6 weeks of consecutive or intermittent use of CGM among adults with type 2-diabetes (irrespective of diabetes treatment) in an outpatient setting were included. Studies with pregnant women or individuals with type 1-diabetes, studies that investigated GlucoWatch or a professional CGM (pCGM) device (e.g. Abbott Freestyle Libre Pro IQ or Dexcom G6 Pro) or an intervention that consisted of CGM combined with an additional glucose-lowering treatment strategy were excluded. A total of twelve RCT’s were included in the systematic review, of which eight trials investigated the effectivity of rtCGM versus SMBGand four trials investigated isCGM. Risk of bias was rated using the Cochrane risk-of-bias tool version 2. Eight individual studies were rated as ‘some concerns for risk of bias’ (Bergenstal, 2022; Cosson, 2009; Haak, 2017; Moon, 2022; Price, 2021; Vigersky, 2012; Yaron, 2019; Yoo, 2008) while the remaining four studies were rated as ‘low risk’ (Ajjan, 2023; Beck, 2017; Martens, 2021; Wada, 2020). 

Table 2. Characteristics of included studies

*For further details, see Figure 2 in supplementary file by Jancev (2024).

Results

The results are reported separately for rtCGM and isCGM/FGM. For the outcomes Time in range (TIR), time below range (TBR) and time above range (TAR), the following definitions were used in the review by Jancev (2024):

TIR: percentage of time glucose between 3.9–10mmol/l [70–180 mg/dl]

TBR: percentage of time glucose <3.9 mmol/l [<70 mg/dl]

TAR percentage of time glucose >10 mmol/l [>180 mg/dl]

•rtCGM

Severe hypoglycemia

A total of five studies that investigated the effectivity of rtCGM in the review by Jancev (2024) reported on severe hypoglycemia (definition not reported), although in only one study events of severe hypoglycemia occurred. Martens (2021), reported severe hypoglycemia in 1/116 (0.9%) patients of the intervention group, compared to 1/59 (1.7%) patients in the control group.

Hypoglycemia

A total of two studies reported on hypoglycemia events. Price (2021) reported no events of hypoglycemia in the intervention group (n=46), compared to one event of hypoglycemia in the control group (n=24). However, it was not reported which cut-off point was used to define hypoglycemia.

Martens (2021) reported on hypoglycemia as event rate/week, in which a hypoglycemic event was defined as 15 consecutive minutes with a sensor glucose value below 3.0 mmol/l (at least 2 sensor values <3 mmol/L that are ≥15 minutes apart plus no intervening values of ≥3 mmol/L are required to define an event). The end of the hypoglycemic event was defined as a minimum of 30 consecutive minutes with a sensor glucose concentration of 3.9 mmol/l or greater (at least 2 sensor values ≥3.9mmol/L that are ≥30 minutes apart with no intervening values <3.9 mmol/L were required to define the end of an event).

The hypoglycemia event rate/week was 0.0 (± 0.0) in the intervention group, compared to 0.2 (± 0.4) in the control group. With a follow-up of eight months, this indicates zero events in the intervention group (n = 116) and seven events in the control group (n = 59). As only events were reported and not the number of patients in which these events occurred, a risk ratio cannot be calculated. 

Time in range (TIR)

A total of five studies in the review by Jancev (2024) reported on TIR, see Figure 1. The mean change (MD, 95%CI) in TIR was 7.48 (2.83 to 12.13), in favor of the intervention group, which is considered clinically relevant.

Figure 1. Forest plot of pooled analysis of change in TIR in patients with type DM2 using rtCGM vs. SMBG.

Time below range (TBR)

A total of six studies that investigated the effectivity of rtCGM in the review by Jancev (2024) reported on TBR, see Figure 2. The mean change (MD, 95%CI) in TBR was -0.48 (-0.88 to -0.08), in favor of the intervention group, which is not considered clinically relevant.

Figure 2. Forest plot of pooled analysis of change in TBR in patients with type DM2 using rtCGM vs. SMBG.

Time above range (TAR)

A total of five studies that investigated the effectivity of rtCGM in the review by Jancev (2024) reported on TAR, see Figure 3. The mean change (MD, 95%CI) in TAR was -6.84           (-11.63 to -2.05), in favor of the intervention group, which is considered clinically relevant.

Figure 3. Forest plot of pooled analysis of change in TAR in patients with type DM2 using rtCGM vs. SMBG.

HbA1c

All eight studies that investigated the effectivity of isCGM in the review by Jancev (2024) reported on HbA1c. The MD (95%CI) in HbA1c level was -3.95 (-5.46 to -2.44), in favor of the intervention group. In percentage, the mean difference was -0.36%, which is not considered clinically relevant. See Figure 1 in the study article by Jancev (2024) for details on the results.

Jancev (2024) also performed subanalyses for the effectivity of isCGM compared to SMBG on HbA1c.

•HbA1c levels

No clinically relevant differences were found for patients with a HbA1c level > 69 mmol/mol (MD -3.19 (95%CI -5.41 to -0.97)) and a HbA1c level <69 mmol/mol (MD -3.53 (95%CI -5.35 to -1.71)).

•Intervention duration

No clinically relevant differences were found for intervention duration ≤ 12 weeks (MD -4.04 (95%CI -5.70 to -2.39)) and intervention duration > 12 weeks (MD -2.66 (95%CI -5.32 to -0.01)).

•Age

No clinically relevant differences were found for patients aged >58.9 years (MD -2.30 (95%CI -4.59 to -0.01)) and patients aged <58.9 years (MD -4.17 (95%CI -5.79 to -2.55)).

•Insulin use

No clinically relevant differences were found for patients who use insulin (MD -3.27 (95%CI -6.22 to -0.31)), patients who do not use insulin (MD -3.22 (95%CI -5.39 to -1.05)) and patients who use insulin or other glucose lowering medication (MD -3.65 (95%CI -6.14 to -1.15)). In this last group, studies were included in which patients used insulin and/or glucose lowering medication (in contrast to the first group). 

•isCGM/FGM

Severe hypoglycemia

All four studies that investigated the effectivity of isCGM in the review by Jancev (2024) reported on severe hypoglycemia, although in only two studies events of severe hypoglycemia occurred (Ajjan, 2023; Haak, 2017). Ajjan (2023), reported severe hypoglycemia in 0/69 (0%) patients of the intervention group, compared to 2/72 (2.8%) patients in the control group.

Hypoglycemia

A total of three studies reported on hypoglycemia. Wada (2020) reported a total of three hypoglycemia adverse events, experienced by three participants (2/49 in the intervention group and 1/51 in the control group). However, it was not reported which cut-off point was used.

Yaron (2019) reported the number of patients with one or more hypoglycemic events separately for glucose levels <3.9 mmol/L and glucose levels <3.0 mmol/L.

•Hypoglycemia <3.9 mmol/L

A total of 15/52 (28%) patients in the intervention group had one or more hypoglycemic events (glucose level <3.9 mmol/L), compared to 16/44 (36%) patients in the control group. The corresponding risk ratio (95% CI) is 0.79 (0.44 to 1.42), in favor of the intervention group, which is not considered clinically relevant.

•Hypoglycemia <3.0 mmol/L

A total of 6/52 (11%) patients in the intervention group had one or more hypoglycemic events (glucose level <3.0 mmol/L, compared to 4/44 (9%) patients in the control group. The corresponding risk ratio (95% CI) is 1.27 (0.38 to 4.21), in favor of the control group, which is considered clinically relevant.

Haak (2017) reported the mean differences in number of hypoglycemic events/day between the intervention and control group, separately for glucose levels <3.9 mmol/L and glucose levels <3.1 mmol. However, no baseline values were reported. 

•Hypoglycemia <3.9 mmol/L

Haak reported that the frequency of events with glucose <3.9 mmol/L was 28% less (-0.16 ± 0.065 per day mean ± SE) in the intervention group compared with the control group. This is considered clinically relevant.

•Hypoglycemia <3.0 mmol/L

The frequency of events <3.1 mmol/L was 44% less (-0.12 ± 0.037) in the intervention group compared with the control group. This is considered clinically relevant.

The total number of patients experiencing hypoglycemic adverse events was 10/149 (6.7%) in the intervention group compared to 7/75 (9.3%) in the control group. The corresponding risk ratio (95% CI) is 0.72 (0.29 to 1.81), in favor of the intervention group, which is considered clinically relevant. However, it was not reported which cut-off point was used.

Time in range (TIR)

A total of three studies that investigated the effectivity of isCGM in the review by Jancev (2024) reported on TIR, see Figure 4. The mean change (MD, 95%CI) in TIR was 4.97 (-3.96 to 13.91), in favor of the intervention group, which is not considered clinically relevant.

Figure 4. Forest plot of pooled analysis of change in TIR in patients with type DM2 using isCGM vs. SMBG.

Time below range (TBR)

A total of three studies that investigated the effectivity of isCGM within the review by Jancev (2024) reported on TBR, see Figure 5. The mean change (MD, 95%CI) in TBR was -1.60 (-5.48 to 2.28), in favor of the intervention group, which is considered clinically relevant.

Figure 5. Forest plot of pooled analysis of change in TBR in patients with type DM2 using isCGM vs. SMBG.

Time above range (TAR)

A total of three studies that investigated the effectivity of in the review by Jancev (2024) reported on TAR, see Figure 6. The mean change (MD, 95%CI) in TAR was -3.64 (-16.70 to 9.42), in favor of the intervention group, which is not considered clinically relevant.

Figure 6. Forest plot of pooled analysis of change in TAR in patients with type DM2 using isCGM vs. SMBG.

HbA1c

All four studies that investigated the effectivity of isCGM in the review by Jancev (2024) reported on HbA1c. The MD (95%CI) in HbA1c level was -1.79 (-5.28 to 1.69), in favor of the intervention group. In percentage, the mean difference was -0.16%, which is not considered clinically relevant. See Figure 1 in the study article by Jancev (2024) for details on the results.

A systematic review of the literature was performed to answer the following question(s):

What is the effectivity of continuous glucose monitoring (CGM) and flash glucose monitoring (FGM) in the prevention of hypoglycemia compared to self-monitoring of blood glucose (SMBG) in adult patients with diabetes mellitus type 2?

Table 1. PICO

Relevant outcome measures

The guideline panel considered (severe) hypoglycemia as a critical outcome measure for decision making; and TBR, TIR, TAR and HbA1c as an important outcome measure for decision making.

A priori, the guideline panel did not define the outcome measures listed above but used the definitions used in the studies. For the definition of hypoglycaemia, the 3-level IHSG classification was used in which level 1 refers to glucose <3.9 mmol/l, level 2 to glucose <3.0 mmol/l and level 3 to severe hypoglycaemia as defined above

The guideline panel defined the following cut-off points as a minimal clinically (patient) important difference:

Hypoglycemia/severe hypoglycemia: Difference of 25%

TBR: Absolute difference of 1%

TIR and TAR: Absolute difference of 5%

HbA1c: Difference of 5 mmol/mol (~0.5%)

Search and select (Methods)

A systematic literature search was performed by a medical information specialist using the following bibliographic databases: Embase.com and Ovid/Medline. Both databases were searched from 2004 to 11 December 2024 for systematic reviews, RCTs and observational studies. Systematic searches were completed using a combination of controlled vocabulary/subject headings (e.g., Emtree-terms, MeSH) wherever they were available and natural language keywords. The overall search strategy was derived from three primary search concepts: (1) diabetes mellitus; (2) continuous glucose monitoring; (3) hypoglycemia. Duplicates were removed using EndNote software. After deduplication a total of 359 records were imported for title/abstract screening. Initially, 25 studies were selected based on title and abstract screening. After reading the full text, 24 studies were excluded (see the exclusion table under the tab ‘Evidence tabellen’), and 1 study was included.

1. Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545-59. doi: 10.1056/NEJMoa0802743. Epub 2008 Jun 6. PMID: 18539917; PMCID: PMC4551392.
2. ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2560-72. doi: 10.1056/NEJMoa0802987. Epub 2008 Jun 6. PMID: 18539916.
3. Ajjan RA, Heller SR, Everett CC, et al. Multicenter randomized trial of intermittently scanned continuous glucose monitoring versus self-monitoring of blood glucose in individuals with type 2 diabetes and recent-onset acute myocardial infarction: results of the LIBERATES trial. Diabetes Care. 2023;46(2):441–449. doi: 10.2337/dc22-1219.
4. Beck RW, Riddlesworth TD, Ruedy K, et al. Continuous glucose monitoring versus usual care in patients with type 2 diabetes receiving multiple daily insulin injections. Ann Intern Med. 2017;167(6):365–374. doi: 10.7326/M16-2855.
5. Bergenstal RM, Mullen DM, Strock E, Johnson ML, Xi MX. Randomized comparison of self-monitored blood glucose (BGM) versus continuous glucose monitoring (CGM) data to optimize glucose control in type 2 diabetes. J Diabetes Complications. 2022;36(3):108106. doi: 10.1016/j.jdiacomp.2021.108106.
6. Cosson E, Hamo-Tchatchouang E, Dufaitre-Patouraux L, Attali JR, Pariès J, Schaepelynck-Bélicar P. Multicentre, randomised, controlled study of the impact of continuous sub-cutaneous glucose monitoring (GlucoDay®) on glycaemic control in type 1 and type 2 diabetes patients. Diabetes Metab. 2009;35(4):312–318. doi: 10.1016/j.diabet.2009.02.006.
7. Haak T, Hanaire H, Ajjan R, Hermanns N, Riveline J-P, Rayman G. Flash glucose-sensing technology as a replacement for blood glucose monitoring for the management of insulin-treated type 2 diabetes: a multicenter, open-label randomized controlled trial. Diabetes Ther. 2017;8(1):55–73. doi: 10.1007/s13300-016-0223-6.
8. International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/l (54 mg/dl) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2017 Jan;60(1):3-6. doi: 10.1007/s00125-016-4146-6. Erratum in: Diabetologia. 2017 Feb;60(2):377. doi: 10.1007/s00125-016-4168-0. PMID: 27872948; PMCID: PMC6518070.
9. Jancev M, Vissers TACM, Visseren FLJ, van Bon AC, Serné EH, DeVries JH, de Valk HW, van Sloten TT. Continuous glucose monitoring in adults with type 2 diabetes: a systematic review and meta-analysis. Diabetologia. 2024 May;67(5):798-810. doi: 10.1007/s00125-024-06107-6. Epub 2024 Feb 16. PMID: 38363342; PMCID: PMC10954850.
10. Martens T, Beck RW, Bailey R et al (2021) Effect of continuous glucose monitoring on glycemic control in patients with type 2 diabetes treated with basal insulin: a randomized clinical trial. JAMA 325(22):2262–2272. 10.1001/jama.2021.7444.
11. Moon SJ, Kim KS, Lee WJ, Lee MY, Vigersky R, Park CY. Efficacy of intermittent short-term use of a real-time continuous glucose monitoring system in non-insulin–treated patients with type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2023;25(1):110–120. doi: 10.1111/dom.14852.
12. Price DA, Deng Q, Kipnes M, Beck SE. Episodic real-time CGM use in adults with type 2 diabetes: results of a pilot randomized controlled trial. Diabetes Ther. 2021;12(7):2089–2099. doi: 10.1007/s13300-021-01086-y.
13. Vigersky RA, Fonda SJ, Chellappa M, Walker MS, Ehrhardt NM. Short- and long-term effects of real-time continuous glucose monitoring in patients with type 2 diabetes. Diabetes Care. 2012;35(1):32–38. doi: 10.2337/dc11-1438.
14. Wada E, Onoue T, Kobayashi T, et al. Flash glucose monitoring helps achieve better glycemic control than conventional self-monitoring of blood glucose in non-insulin-treated type 2 diabetes: a randomized controlled trial. BMJ Open Diabetes Res Care. 2020;8(1):10–17. doi: 10.1136/bmjdrc-2019-001115.
15. Yaron M, Roitman E, Aharon-Hananel G, et al. Effect of flash glucose monitoring technology on glycemic control and treatment satisfaction in patients with type 2 diabetes. Diabetes Care. 2019;42(7):1178–1184. doi: 10.2337/dc18-0166.
16. Yoo HJ, An HG, Park SY, et al. Use of a real time continuous glucose monitoring system as a motivational device for poorly controlled type 2 diabetes. Diabetes Res Clin Pract. 2008;82(1):73–79. doi: 10.1016/j.diabres.2008.06.015.