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A Randomized Clinical Trial of the Effect of Continuous Glucose Monitoring on Nocturnal Hypoglycemia, Daytime Hypoglycemia, Glycemic Variability, and Hypoglycemia Confidence in Persons with Type 1 Diabetes Treated with Multiple Daily Insulin Injections (GOLD-3)
Ólafsdóttir Arndís F., Polonsky William, Bolinder Jan, Hirsch Irl B, Dahlqvist Sofia, Wedel Hans, Nyström Thomas, Wijkman Magnus, Schwarcz Erik, Hellman Jarl, Heise Tim and Lind Marcus
Diabetes Technology & Therapeutics, April 2 2018
To evaluate the effects of continuous glucose monitoring (CGM) on nocturnal and daytime hypoglycemia in persons with type 1 diabetes treated with multiple daily insulin injections (MDI); we also evaluated factors related to differences in hypoglycemia confidence in this population.
Evaluations were performed from the GOLD randomized trial, an open-label multicenter crossover randomized clinical trial (n = 161) over 69 weeks comparing CGM to self-measurement of blood glucose (SMBG) in persons with type 1 diabetes treated with MDI. Masked CGM and the hypoglycemia confidence questionnaire were used for evaluations.
Time with nocturnal hypoglycemia, glucose levels <70 mg/dL was reduced by 48% (10.2 vs. 19.6 min each night, P < 0.001) and glucose levels <54 mg/dL by 65%. (3.1 vs. 8.9 min, P < 0.001). For the corresponding glucose cutoffs, daytime hypoglycemia was reduced by 40% (29 vs. 49 min, P < 0.001) and 54% (8 vs. 18 min., P < 0.001), respectively. Compared with SMBG, CGM use improved hypoglycemia-related confidence in social situations (P = 0.016) and confidence in more broadly avoiding serious problems due to hypoglycemia (P = 0.0020). Persons also reported greater confidence in detecting and responding to decreasing blood glucose levels (thereby avoiding hypoglycemia) during CGM use (P = 0.0033) and indicated greater conviction that they could more freely live their lives despite the risk of hypoglycemia (P = 0.022).
CGM reduced time in both nocturnal and daytime hypoglycemia in persons with type 1 diabetes treated with MDI and improved hypoglycemia-related confidence, especially in social situations, thus contributing to greater well-being and quality of life. Trial registration: ClinicalTrials.gov, number NCT02092051.
CGM minskar nattliga och dagliga hypoglykemier, glykemisk variation, samt ökar tryggheten runt hypoglykemier för personer med typ 1 diabetes och behandlade med flerdos insulin (GOLD – 3)
Målet med studien var att utvärdera effekten av CGM på nattliga och dagliga hypoglykemier för personer med typ 1 diabetes behandlade med flerdos insulin samt utvärdera faktorer relaterade till trygghetskänsla runt hypoglykemier.
Data kommer från randomiserad studie GOLD, en multicenter, randomiserad crossover studie (n=161). Studien genomfördes under 69 veckor på 15 olika sjukhus i Sverige och jämförde CGM med kapillära blodsocker kontroller för personer med typ 1 diabetes som var behandlade med flerdos insulin. Blindad CGM användes för hypoglykemi analyserna samt hypoglycemia confidence questionnaire för att analysera trygghetskänslan runt hypoglykemier.
Studien visade, att
• CGM användning minskade nattliga hypoglykemier för glukos värden < 3,9mmol/l med 48% (10,2 vs 19,6 minuter p<0,001) och
• för glukos värden < 3mmol/l minskade det med 65% (3,1 vs 8,9 min p<0,001).
• För hypglykemier under dagtid minskade glukosvärden < 3,9mmol/l med 40% (29 vs 49 min p>0,001) och
• med 54% (8 vs 18 min p>0,001) för glukosvärden > 3,0mmol/l vid CGM användning jämfört med kapillära blodglukos prover.
Den positiva effekten av CGM var enbart påvisbar under aktiv CGM behandling och försvann snabbt när CGM behandlingen avslutades.
Användning av CGM förbättrade tryggheten runt hypoglykemier i sociala situationer (p=0,016) och förbättrade generellt tryggheten i att undvika svåra problem pga hypoglykemier (p=0,002).
Tryggheten för att upptäcka och reagera i tid när blodglukosen sjunker och på så sätt undvika hypoglykemi (p=0,0033) och ökade känslan att kunna leva sina liv som de ville trotts risken för hypoglykemi (p=0,022).
CGM minskar både tid med nattliga och dagliga hypoglykemier för personer med typ 1 diabetes och behandlade med flerdos insulin samt ökade tryggheten runt hypoglykemier, särskilt i sociala situationer och genom detta ett ökat välbefinnande och livskvalité.
Conventional intensive insulin therapy resulting in good glycemic control has been shown to prevent and reduce the progression of diabetes-related complications in persons with type 1 diabetes.1,2 Intensive glycemic control is generally achieved through multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusions (CSII) through an insulin pump.3 Regular capillary self-measurement of blood glucose (SMBG) values has been crucial for optimal insulin dosing and good glycemic control.4–6 While lowering mean glucose levels by this conventional intensive regime, the risk of hypoglycemia associated with impaired well-being and acute risks simultaneously increases.1 Hence, conventional intensive therapy has drawbacks when it comes to the risk of hypoglycemia.
In a recent randomized crossover trial, we showed that intensive therapy in adults with type 1 diabetes treated with MDI could be more effective in improving glycemic control by using continuous glucose monitoring (CGM).7 Among other factors, CGM also improved overall hypoglycemia confidence. Hemoglobin A1c (HbA1c) was reduced by 0.43% (4.7 mmol/mol) and participants needed continual use of CGM to have a sustained effect on HbA1c. Regarding hypoglycemia, only overall estimates were presented as 40 min/24 h during CGM therapy and 69 min/24 h during conventional therapy. Differences regarding time in nocturnal and daytime hypoglycemia, episodes or how the effect changes when CGM therapy discontinues were not analyzed.
There were two main aims of the current study: (1) To increase understanding of CGM's effects on hypoglycemia in persons with type 1 diabetes treated with MDI, and (2) To improve the understanding of CGM's effects on hypoglycemia confidence in daily life in this population.
The current evaluations from a randomized crossover trial shows that intensive insulin treatment with MDI and CGM, compared with MDI and SMBG, among adults with type 1 diabetes led to reduced time and episodes of nocturnal and daytime hypoglycemia, whereas HbA1c was also reduced. Continuous use of CGM was needed to obtain these effects. Moreover, our current analyses of the Hypoglycemia Confidence Scale indicate that when using CGM, participants experience greater confidence regarding hypoglycemia in social situations and less limitations in their daily life. Participants felt more confident in detecting and responding to low glucose values, thereby avoiding hypoglycemia.
The DIAMOND study evaluated nocturnal and daytime hypoglycemia for persons on MDI using CGM versus SMBG and found that time in hypoglycemia (<70 mg/dL/3.9 mmol/L) was significantly lower for those with CGM both during day and night time.11 Previous randomized multicenter CGM trials have been performed either with persons on CSII therapy or persons with either CSII or MDI.12,14–19 In the STAR-3 study, initiating CGM simultaneously as insulin pump treatment compared with persons continuing on MDI showed no effect on hypoglycemia, although HbA1c was lowered,.14 In the JDRF CGM study, including both persons with insulin pumps and treated with MDI, no effect was found on hypoglycemia although glucose readings were available only for a few days.15 In its follow-up study, investigators found there was a greater reduction in time with glucose values ≤70 mg/dL (<3.9 mmol/L) over a 6-month period for those with CGM.16 In the SWITCH study, participants were randomized in a crossover design to CGM or SMBG during insulin pump treatment and showed that hypoglycemia was reduced with CGM for glucose levels <70 mg/dL along with HbA1c-lowering effect.17 In the IN CONTROL study, which included persons with hypoglycemic unawareness, CGM significantly increased time in euglycemia and reduced severe hypoglycemia.12 Another randomized study, including both persons with CSII and MDI, showed that time spent with glucose values <63 mg/dL was significantly reduced during CGM.18 It should be noted the hypoglycemia confidence questionnaire is relatively new and has generally not been evaluated in other multicenter randomized trials.9,12,14–19
In the current study, extensive evaluations on the effect of hypoglycemia were performed using two glucose level cutoffs, 70 mg/dL (<3.9 mmol/L) and 54 mg/dL (<3.0 mmol/L), and two-time frames for nocturnal and daytime hypoglycemia, with both evaluating time and episodes of hypoglycemia. All analyses showed consistent results of CGM substantially reducing both time and episodes of hypoglycemia. We recently showed that to obtain an effect of CGM on HbA1c in persons with type 1 diabetes and treated with MDI, continuous use is needed,7 which has also been shown for insulin pump users.12,14 In the present study, we found that continuous use of monitoring is needed to obtain beneficial effects on reducing hypoglycemia. When CGM use was stopped during the washout period, time in hypoglycemia reverted to levels similar with conventional therapy (Fig. 1). Therefore, a key issue for CGM therapy to be able to improve both HbA1c and time in hypoglycemia long term is continuous use of the system.
A likely explanation for the reduced time in both nocturnal and daytime hypoglycemia with CGM is that participants receive continuous information about glucose values, including whether these values are rising or decreasing.20 With this information, it is possible to take early preventive actions in many situations, for example, easily checking glucose levels and trends before physical activity or bed time and deciding whether carbohydrates are needed if the glucose trend is decreasing or taking an extra insulin dose if increasing. The alarms are also likely to be an important function in signaling before glucose values get too low or high. In contrast using SMBG for information about glucose levels, only a very small proportion of the continuous glucose curve is retrieved and does not provide information about trends.4–6 Current analyses of CV, as a measure of glycemic variability, was significantly less during both day and nighttime with CGM therapy, which further supports the glucose-stabilizing effect of CGM. Of note, the CGM system used in the study (Dexcom G4), has shown high accuracy and treatment experience in short-term comparative trials, which may be essential for the current results.21–23This study has shown that CGM improves both time in hypoglycemia and glycemic variability, but it is important to note that other factors can also lead to improvements.24,25
The current study implies that for adults treated with MDI, a more efficient way to improve HbA1c is now available, which at the same time reduces both nocturnal and daytime hypoglycemia. The fact that CGM patients felt more confident that hypoglycemia was not limiting their daily lives or negatively impacting social situations and that they were generally more confident regarding their ability to avoid hypoglycemia is of critical importance. Since this is the first study to examine the specific features of hypoglycemic confidence resulting from CGM use in a randomized setting, it is of value to consider these findings and their potential implications in greater detail. It seems likely that the key result was that CGM patients gained a greater sense of self-efficacy that they could avoid and/or detect and respond to mild hypoglycemia before it grew more serious. Consequently, they felt more secure in their ability to participate in daily activities (including social activities) without worrying about hypoglycemia. This would seem to be an essential benefit of CGM, to make life easier for patients, and allows them to feel more confident about participating in their own lives with fewer restrictions and worries. It is likely that this is a key contributor to broader quality of life benefits and may largely explain the significantly greater overall well-being and treatment satisfaction earlier that was described in the original study report.7
Given these findings, however, it is difficult to explain why CGM patients did not feel more confident while driving, sleeping, or exercising. It is possible that factors that we could not control for may have influenced these findings, such as how frequently patients were driving and/or whether patients were living alone or with a partner (which may have influenced confidence regarding hypoglycemia while sleeping). It is also possible that most patients already felt generally confident in these specific situations at baseline (therefore leaving little room for additional improvement). We plan to examine this latter possibility in future analyses of this dataset.
In total, we would suggest that, together with the earlier reported findings of improved well-being and treatment satisfaction, the current results further support the use of CGM for adults with type 1 diabetes.
A limitation of the study is that treatment could not be blinded, thus participants were aware of the intervention. This may have influenced the treatment effects to some extent. Although the current reduction in nocturnal and daytime hypoglycemia is clinically important, other treatment alternatives are needed for persons with type 1 diabetes to fully avoid hypoglycemia on a broad level. In addition, the current results are restricted to adults with HbA1c > 7.5% (58 mmol/mol).
In conclusion, CGM reduces both nocturnal and daytime hypoglycemia as well as the number of hypoglycemic episodes while lowering HbA1c in adults with type 1 diabetes treated with MDI. In addition, both daytime and nighttime glycemic variability is reduced by CGM in persons with T1D treated with MDI. As a result, persons reported greater confidence detecting and managing hypoglycemia, especially in social situations, and indicated greater conviction that they could live more freely and safely despite the risk of hypoglycemia.
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