From Gold Study

Marcus Lind, MD, PhD; William Polonsky, PhD; Irl B. Hirsch, MD; Tim Heise, MD; Jan Bolinder, MD, PhD;
Sofia Dahlqvist; Erik Schwarz, MD, PhD; Arndís Finna Ólafsdóttir, RN; Anders Frid, MD, PhD; Hans Wedel, PhD; Elsa Ahlén, MD; Thomas Nyström, MD, PhD; Jarl Hellman, MD

 

JAMA Continuous Glucose Monitoring vs Conventional Therapy for Glycemic Control in Adults With Type 1 Diabetes Treated With Multiple Daily Insulin Injections
The GOLD Randomized Clinical Trial

 

IMPORTANCE The majority of individuals with type 1 diabetes do not meet recommended glycemic targets.

 

OBJECTIVE Toevaluatetheeffectsofcontinuousglucosemonitoringinadultswithtype1 diabetes treated with multiple daily insulin injections.

 

DESIGN,SETTING,ANDPARTICIPANTS Open-labelcrossoverrandomizedclinicaltrial conducted in 15 diabetes outpatient clinics in Sweden between February 24, 2014, and June 1, 2016 that included 161 individuals with type 1 diabetes and hemoglobin A1c (HbA1c) of at least 7.5% (58 mmol/mol) treated with multiple daily insulin injections.

 

INTERVENTIONS Participantswererandomizedtoreceivetreatmentusingacontinuous glucose monitoring system or conventional treatment for 26 weeks, separated by a washout period of 17 weeks.

 

MAINOUTCOMESANDMEASURES DifferenceinHbA1cbetweenweeks26and69forthe2 treatments. Adverse events including severe hypoglycemia were also studied.

 

RESULTS Among161randomizedparticipants,meanagewas43.7years,45.3%werewomen, and mean HbA1c was 8.6% (70 mmol/mol). A total of 142 participants had follow-up data in both treatment periods. Mean HbA1c was 7.92% (63 mmol/mol) during continuous glucose monitoring use and 8.35% (68 mmol/mol) during conventional treatment (mean difference, −0.43% [95% CI, −0.57% to −0.29%] or −4.7 [−6.3 to −3.1 mmol/mol]; P < .001). Of 19 secondary end points comprising psychosocial and various glycemic measures, 6 met the hierarchical testing criteria of statistical significance, favoring continuous glucose monitoring compared with conventional treatment. Five patients in the conventional treatment group and 1 patient in the continuous glucose monitoring group had severe hypoglycemia. During washout when patients used conventional therapy, 7 patients had severe hypoglycemia.

 

CONCLUSIONSANDRELEVANCE Amongpatientswithinadequatelycontrolledtype1diabetes treated with multiple daily insulin injections, the use of continuous glucose monitoring compared with conventional treatment for 26 weeks resulted in lower HbA1c. Further research is needed to assess clinical outcomes and longer-term adverse effects.

 

TRIALREGISTRATION clinicaltrials.govIdentifier:NCT02092051

 

Intensive insulin therapy resulting in good glycemic con- trol has been shown to prevent and reduce the progres- sion of diabetes-related complications in patients with type 1 diabetes.1 Today, intensive glycemic control is generally achieved through multiple daily insulin injections or continu- ous subcutaneous insulin infusions through an insulin pump.2 Regular self-measured capillary blood glucose values have been crucial to optimal insulin dosing for good glycemic control.3-5

In recent years, continuous glucose monitoring (CGM) has become an option for optimal insulin dosing and other activities.6 The advantages of CGM include providing continu- ous feedback on estimated glucose values and illustrating glu- cose trends. CGM systems include a subcutaneous sensor with a transmitter attached and continuous reporting of glucose lev- els and trends to the patient by a handheld monitor.

 

Data from clinical trials of CGM have been mixed regard- ing its effect on glycemic control.7 Such trials have, for example, consisted only of patients with the following characteristics: (1) continuous subcutaneous insulin infusions; (2) initiated CGM and continuous subcutaneous insulin infusions simulta- neously; or (3) included patients with both multiple daily insu- lin injections and continuous subcutaneous insulin infusions.7-10 Post hoc findings have also been mixed, in that glycemic control appears to differ when CGM is combined with either multiple daily insulin injections or continuous subcutaneous insulin infusions.8-10 Although the majority of adults with type 1 dia- betes in the United States and Europe are treated with multiple daily insulin injections, to our knowledge, clinical trials evalu- ating CGM vs conventional therapy in persons treated with mul- tiple daily insulin injections have not been performed.

 

The aim of this study was to analyze the effect of CGM on glycemic control, hypoglycemia, well-being, and glycemic vari- ability in individuals with type 1 diabetes treated with mul- tiple daily insulin injections.

 

In this crossover study of persons with type 1 diabetes treated with multiple daily insulin injections, CGM was associated with a mean HbA1c level that was 0.43% (4.7 mmol/mol) less than conventional treatment. Moreover, glycemic variability was re- duced by CGM. Subjective well-being and treatment satisfac- tion were greater during CGM than conventional therapy.

The population evaluated in the current study differs to a great extent from earlier clinical trials of CGM.7-10,25,26 The cur- rent study aimed to include a more general population of per- sons with type 1 diabetes. In contrast to earlier trials, the cur- rent study had no upper limit of HbA1c for inclusion, which includes the group of patients with the greatest excess mortality27,28 and the highest risk of diabetic levels and diabetic complications.
ment options for reducing HbA1c in these patients is of great concern. Baseline HbA1c was also high (8.7%) in the current population, and not only was mean HbA1c reduced but fewer patients also had very high HbA1c levels during CGM therapy.

Also in contrast to earlier CGM-studies,7-10,25,26 the current trial had no limit on the number of self-measurement of blood glu- cose patients were required to perform for inclusion. Patients who do not perform self-measurement of blood glucose regularly have higher HbA1c levels.4 Despite the availability of free glucose me- ters and test strips in Sweden, less than 50% of patients perform self-measurement of blood glucose according to guidelines (>4 times/d). Hence, evaluating alternative glucose monitoring strat- egies for these patients is also important. In the present study, pa- tients performed self-measurement of blood glucose less during CGM than conventional therapy (2.7 vs 3.7 measurements/d).

When used in connection with an insulin pump, CGM may ease adjusting insulin doses with respect to observed CGM patterns.2 Certain processes in the pump can also be guided by CGM information, such as halting the insulin infusion during a rapid decline in glucose.26 Conversely, most adults with type 1 diabetes are treated with multiple daily insulin injections.29 Therefore, novel complementary treatment strategies are needed on a broad level. In the intervention/control sequence, HbA1c re- verted back to prestudy levels during the washout period (Figure 2), indicating that there was no carry-over effect. In ac- cordance with earlier findings,9 these results also suggest that the effectiveness of CGM depends on uninterrupted use during multiple daily insulin injections treatment. Our study in- creases knowledge in the field of type 1 diabetes in reporting that CGM may be a beneficial option for multiple daily insulin injec- tions–treated patients with respect to HbA1c levels.

A novel feature of this trial is a more comprehensive inves- tigation of psychosocial variables, which are now recognized as a high priority in clinical diabetes guidelines.30 To our knowledge, this trial is the first to demonstrate a significant improvement in subjective well-being and treatment satisfaction in adults using CGM in comparison with conventional therapy. The positive effect on well-being is consistent with previous studies that have shown a significant effect due to CGM on the physical component subscale of the SF-36 (Short Form Health Survey).10,31 In total, these psychosocial benefits may be at least partially due to the sig- nificant HbA1C improvement,32 as well as to the reduction in time spent in hypoglycemia. Indeed, less time in hypoglycemia is known to be associated with better quality of life33,34 and a lower risk of severe hypoglycemia.35,36 Furthermore, hypoglycemic con- fidence improved during CGM therapy, but it should be inter- preted with greater caution since this was an exploratory endpoint. Of note from a safety perspective, there were numerically more severe hypoglycemic episodes (5 vs 1) during conventional compared with CGM therapy. In addition, 7 severe hypoglycemia events occurred during the washout period of 4 months when pa- tients used conventional therapy.

 

This study had a number of limitations. First, 19 patients (approximately 12.0%) had no follow-up data in the second treat- ment period and were not included in the primary analysis. Gen- erally, in a parallel-group study, this can lead to an imbalance between groups. However, in the current study, patients served as their own controls and thus no such problem existed. It has therefore been proposed that the full analysis set population should be used in crossover studies as the main analysis.37 In ad- dition, with the crossover design, it can be determined whether results are going in the same direction during the first treat- ment period from a parallel design perspective. Sixteen of the 19 patients who had no follow-up data in the second treatment period had HbA1c data during the first follow-up period. Among these patients, those with CGM had a 1.0% decrease in HbA1c, whereas those with conventional therapy had an increase of 0.1%. There were more patients treated with CGM than conven- tional therapy who discontinued treatment during the first treat- ment period. This was due to patients wanting to continue CGM and therefore not completing the study while receiving conven- tional therapy in the second period and also due to patients ex- periencing device-related problems (Figure 1).

 

A second limitation is that the study could not be blinded and hence patients were aware of the intervention. It cannot be excluded that this, to some extent, could have influenced the treatment effect. Although the current reduction in HbA1c may be clinically important, other treatment alternatives are needed for persons with type 1 diabetes to obtain good glyce- mic control on a broad level. In addition, the current results are restricted to patients with HbA1c of at least 7.5%.

 

Among patients with inadequately controlled type 1 diabetes treated with multiple daily insulin injections, the use of CGM compared with conventional treatment for 26 weeks resulted in lower HbA1c. Further research is needed to assess clinical outcomes and longer-term adverse effects.

 

Adult patients with type 1 diabetes who use multiple daily insulin injections had a significant reduction in HbA1c levels with continuous glucose monitor (CGM) versus usual care, according to researchers.

 

There was a -0.6% mean change in A1c levels after 24 weeks of using a CGM compared with usual care (95% CI, -0.8% to -0.3%, P<0.001), reported by Roy W. Beck, MD, PhD, of the Jaeb Center for Health Research in Tampa, Fla., and colleagues.

Usual care was defined as self-monitored blood glucose testing for a minimum of four times per day, they reported in the Journal of the American Medical Association.

 

A separate Swedish study, also in JAMA, also reported benefits with CGM in a similar patient population but at 26 weeks.

In an accompanying editorial, Mayer B. Davidson, MD, of the Charles R. Drew University of Medicine and Science in Los Angeles, stated both studies were important in analyzing the benefits of CGM with self-monitoring of blood glucose.

The majority of patients with type 1 diabetes use daily insulin injections and adjust insulin administration based on preprandial and postprandial self-monitored blood glucose values," Davidson noted.

Real-time CGM "has the potential to improve diabetes control by limiting hyperglycemia, decreasing episodes of hypoglycemia, lowering glucose variability ... and enhancing patient satisfaction with glycemic treatment," he added.

 

End of JAMA Citation

____________________

 

Beck's group recruited adults (mean age 48) with type 1 diabetes, using daily insulin injections, from 24 endocrinology practices, and randomly assigned them to the CGM intervention (n=105) or the usual care control group (n=53). The CGM group used a Dexcom G4 Platinum CGM System, which measured glucose levels every 5 minutes. Data collected at baseline, 12, and 24 weeks on 147 participants was included in the statistical analysis.

 

Women made up 44% of the study population. The mean baseline HbA level was 8.6%, and the median duration of diabetes was 19 years (interquartile range 10-31 years). Almost all of the participants (98%) completed the study.

The authors reported a 1.1% mean reduction in A1c levels in the CGM group after 12 weeks versus 0.5% in the control group. After 24 weeks, the CGM group had a 1.0% mean reduction in A1c levels versus 0.4% in the control group (P<0.001 for both).

 

Duration of hypoglycemia nearly decreased by half among the CGM group, averaging 43 minutes per day (IQR 27-69) compared to 80 min per day (IQR, 36-111) in the usual care group (P=0.002).

 

No cases of diabetic ketoacidosis were reported, but severe hypoglycemia occurred in two participants from each group.

Beck told MedPage today that a previous project -- the Type 1 Diabetes Exchange, a registry including over 30,000 individuals with type 1 diabetes -- found CGM was only utilized in about 6% of patients using insulin injections.

"We wanted to do a clinical trial to determine whether CGM would be beneficial for patients with type 1 diabetes using insulin injections, with the expectation that if the results were positive that this would lead to greater use of CGM and better diabetes outcomes," he explained.

 

"Prior to conducting the trial, we did not know whether patients not using an insulin pump would be willing to wear a CGM sensor on a daily or near-daily basis long term since, unlike pump users, injection users are not accustomed to wearing a device," Beck added. "Additionally, we did not know how much CGM would be beneficial even if worn every day. Pump users have far greater flexibility in adjusting their insulin delivery in response to CGM glucose readings than do injection users."

Nonetheless, the volume of CGM use among participants was surprisingly high, comparable to what previous studies have reported among pump users, he said.

 

Among the CGM group, median use was 7.0 days/week (IQR, 7.0-7.0) before 24 weeks, which dropped slightly to 6 or more days/week for 93% of participants during month 6. Only 2% of participants discontinued use before 24 weeks.

The study had some limitations. The authors pointed out that the results may not apply to individuals with type 1 diabetes who are younger than 26 years or have HbA levels outside the range of 7.5% to 9.9%. The results also should not be applied to individuals with type 2 diabetes who receive multiple daily injections of insulin, they cautioned.

 

Individuals with uncontrolled type 1 diabetes using multiple daily insulin injections had lower HbA1c levels when using CGM versus convention treatment, reported Marcus Lind, MD, PhD, of the Diabetes Outpatient Clinic at Uddevalla Hospital in Sweden, and colleagues

The randomized clinical GOLD trial found individuals using a CGM with multiple daily insulin injections had an average A1c of 7.92% (180.7 mg/dL) versus 8.35% (193.9 mg/dL) with conventional treatment (mean difference -27.4 mg/dL, 95% CI -31.6 to -23.2 mg/dL, P<0.001). Levels were measured at baseline and weeks 4, 13, and 26.

The mean age of the 161 participants from 15 diabetes clinics was 43.7, and 45.3% were women, with a mean HbA of 8.6%. A total of 142 participants had follow-up data in both treatment periods. Participants were assigned to the CGM group (n=82), which used the same system as the DIAMOND trial, or the conventional treatment group (n=79), which involved self-monitored blood glucose testing.

A total of 142 participants were included in the statistical analysis. Following the 26-week intervention period, all participants were included in a 17-week washout period, during which they all used conventional treatment.

Nineteen secondary endpoints of psychosocial variables were also assessed, "which are now recognized as a high priority in clinical diabetes guidelines," according to the authors.

Variables reaching statistical significance included improved overall well-being among the CGM group, measured by the WHO-5 questionnaire (66.1 versus 62.7, P=0.02). The CGM group also reported less hypoglycemia fear, measured by the Hypoglycemia Confidence Questionnaire scale (3.40 versus 3.27, P<0.001). The Diabetes Treatment Satisfaction Questionnaire status version found the CGM group had higher treatment satisfaction versus conventional treatment (30.21 versus 26.62, P<0.001).

The authors suggest the improvement in the psychosocial variables may be a result of the "significant HbA1c improvement, as well as to the reduction in time spent in hypoglycemia," among the CGM group.

During the first phase of the trial, one CGM user and five control participants experienced severe hypoglycemia, while seven participants experienced severe hypoglycemia during the washout period.

The study had some limitations including a lack of blinding so patients were aware of the intervention, which may have influenced treatment effects.

 

'Several Caveats'

Davidson warned that "there are several caveats regarding the findings and the generalizability of the results."

Lastly, he also warned against generalizing the results of the studies to patients with type 2 diabetes.

Beck told MedPage Today that his group has conducted two follow-up studies, one of which analyzed the benefits of CGM use among type 2 diabetes patients using insulin, while the other assessed the benefit of insulin pump therapy among the same participant group from the DIAMOND trial.

Both follow-up studies will be presented at the Advanced Technologies and Treatments for Diabetes meeting in Paris in February, he said.

 

Click here for a 2016 consensus statement on CGM from thee American Association of Clinical Endocrinologists and American College of Endocrinology

https://www.aace.com/files/guidelines/PrePrintContinuousGlucoseMonitoring.pdf

 

The DIAMOND trial was funded by Dexcom. Beck disclosed relevant relationships with Dexacom and Abbott Diabetes Care. Co-authors disclosed multiple relevant relationships with industry including Dexacom, Medtronic, Novo Nordisk, Lexicon, Sanofi, AstraZeneca; Eli Lilly, and Janssen.

 

The GOLD trial was supported by theNU Hospital Group, Trollhättan and Uddevalla, Sweden.

From www.medpagetoday.com

 

 

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