Articles
Continuous glucose monitoring for patients with type 1 diabetes and impaired awareness of hypoglycaemia (IN CONTROL): a randomised, open-label, crossover trial

https://doi.org/10.1016/S2213-8587(16)30193-0Get rights and content

Summary

Background

Patients with type 1 diabetes who have impaired awareness of hypoglycaemia have a three to six times increased risk of severe hypoglycaemia. We aimed to assess whether continuous glucose monitoring (CGM) improves glycaemia and prevents severe hypoglycaemia compared with self-monitoring of blood glucose (SMBG) in this high-risk population.

Methods

We did a randomised, open-label, crossover trial (IN CONTROL) at two medical centres in the Netherlands. Eligible participants were patients diagnosed with type 1 diabetes according to American Diabetes Association criteria, aged 18–75 years, with impaired awareness of hypoglycaemia as confirmed by a Gold score of at least 4, and treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections and doing at least three SMBG measurements per day. After screening, re-education about diabetes management, and a 6-week run-in phase (to obtain baseline CGM data), we randomly assigned patients (1:1) with a computer-generated allocation sequence (block size of four) to either 16 weeks of CGM followed by 12 weeks of washout and 16 weeks of SMBG, or 16 weeks of SMBG followed by 12 weeks of washout and 16 weeks of CGM (where the SMBG phase was the control). During the CGM phase, patients used a real-time CGM system consisting of a Paradigm Veo system with a MiniLink transmitter and an Enlite glucose sensor (Medtronic, CA, USA). During the SMBG phase, patients were equipped with a masked CGM device, consisting of an iPro 2 continuous glucose monitor and an Enlite glucose sensor, which does not display real-time glucose values. The number of SMBG measurements per day and SMBG systems were not standardised between patients, to mimic real-life conditions. During both intervention periods, patients attended follow-up visits at the centres each month and had telephone consultations 2 weeks after each visit inquiring about adverse events, episodes of hypoglycaemia, etc. The primary endpoint was the mean difference in percentage of time spent in normoglycaemia (4–10 mmol/L) over the total intervention periods, analysed on an intention-to-treat basis. Severe hypoglycaemia (requiring third party assistance) was a secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01787903.

Findings

Between March 4, 2013, and Feb 9, 2015, we recruited and randomly assigned 52 patients to either the CGM–SMBG sequence (n=26) or the SMBG–CGM sequence (n=26). The last patient visit was on March 21, 2016. Time spent in normoglycaemia was higher during CGM than during SMBG: 65·0% (95% CI 62·8–67·3) versus 55·4% (53·1–57·7; mean difference 9·6%, 95% CI 8·0–11·2; p<0·0001), with reductions in both time spent in hypoglycaemia (ie, blood glucose ≤3·9 mmol/L [6·8% vs 11·4%, mean difference 4·7%, 3·4–5·9; p<0·0001]) and time spent in hyperglycaemia (ie, blood glucose >10 mmol/L [28·2% vs 33·2%, mean difference 5·0%, 3·1–6·9; p<0·0001]). During CGM, the number of severe hypoglycaemic events was lower (14 events vs 34 events, p=0·033). Five serious adverse events other than severe hypoglycaemia occurred during the trial, but all were deemed unrelated to the trial intervention. Additionally, no mild to moderate adverse events were related to the trial intervention.

Interpretation

CGM increased time spent in normoglycaemia and reduced severe hypoglycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia, compared with SMBG. Our results support the concept of using CGM in this high-risk population.

Funding

Eli Lilly and Sanofi.

Introduction

Maintaining near-normal glucose concentrations lowers the risk of microvascular and macrovascular complications and reduces mortality in patients with type 1 diabetes.1, 2 However, satisfactory glycaemic control is difficult to achieve3 and hypoglycaemia is a major limiting factor in reaching glycaemic targets.4

Hypoglycaemia has important physical and psychological consequences5, 6 and can even be fatal.7 In adults with type 1 diabetes, the mean incidence of mild hypoglycaemia is one to two events per patient per week, and the incidence of severe hypoglycaemia (ie, hypoglycaemia requiring third-party assistance for recovery) is about 0·2 to 3·2 events per patient per year.6 The risk of severe hypoglycaemia increases with increasing duration of type 1 diabetes. In patients who have had the disease for a long time (>15 years), a prevalence of up to 46% for severe hypoglycaemia, and a mean frequency of 3·2 episodes per patient-year have been reported.8 Recurrent hypoglycaemia induces defective glucose counter-regulation and impaired awareness of hypoglycaemia.9 This impaired awareness occurs in roughly 25% of adult patients with type 1 diabetes10 and renders patients at a three to six times increased risk of severe hypoglycaemia.10, 11

Research in context

Evidence before this study

We searched the PubMed database up to May 9, 2016, using the search terms “continuous glucose monitoring”, “sensor-augmented pump therapy”, “low-glucose insulin suspension”, predictive low-glucose suspension”, “automated insulin pump suspension”, “threshold insulin pump interruption”, and “diabetes mellitus, type 1” for full reports of observational trials, randomised controlled trials and systematic reviews that investigated the effect of continuous glucose monitoring (CGM) on glycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia. Our search identified one observational study and two randomised controlled trials. Findings from the observational study showed a reduction of severe hypoglycaemia in patients with impaired awareness of hypoglycaemia, reinforcing the need for randomised studies in patients with such impaired awareness. Investigators of one of the randomised trials reported improved hypoglycaemia awareness and glycaemic control from baseline to endpoint (24 weeks), which did not seem related to use of CGM, but was rather attributed to extensive interventions including weekly contact, monthly follow-up visits, and use of a bolus calculator to determine the insulin dose, whether or not an insulin pump was used. Moreover, sensors were used for a median of 57% of the time; only 17 of the 42 individuals achieved the 80% sensor usage threshold, which is often considered the frequency required for meaningful benefit. Findings from the second randomised controlled trial, which used CGM with low-glucose suspend, showed a reduction in severe hypoglycaemia in patients with impaired awareness of hypoglycaemia, but the population studied was quite young (mean age 18·6 years) and the reduction of severe hypoglycaemia lost significance when two outliers in the youngest age groups were excluded from the analysis. Since most patients with impaired awareness of hypoglycaemia are usually older than 40 years and have more than 25 years of diabetes duration, whether CGM adds any benefit (such as less hypoglycaemia and improved glycaemic control) in patients with impaired awareness of hypoglycaemia is still unknown.

Added value of this study

We report the findings from our randomised, crossover trial assessing the effect of CGM without low-glucose suspend on glycaemic control in adult patients with type 1 diabetes affected by impaired awareness of hypoglycaemia. CGM improved percentage of time patients spent in normoglycaemia compared with self-monitoring of blood glucose, by reducing both the percentage of time spent in hypoglycaemia and percentage of time spent in hyperglycaemia. Importantly, the results also showed CGM reduced severe hypoglycaemia in this typical population of patients with type 1 diabetes with impaired awareness of hypoglycaemia. In addition, the absence of an interaction between insulin treatment modality (multiple daily injections or continuous subcutaneous insulin infusion), and both the percentage of time spent in normoglycaemia and the proportion of patients affected by at least one severe hypoglycaemic event are of clinical importance.

Implications of all the available evidence

In earlier trials, CGM did not live up to the expectations of the diabetes community regarding its ability to reduce severe hypoglycaemia. However, our findings here support the benefit of CGM, both with and without combining it with continuous subcutaneous insulin infusion, for improving glycaemic control and diminishing severe hypoglycaemia in adult patients with type 1 diabetes and impaired awareness of hypoglycaemia, who are at highest risk of severe hypoglycaemia.

Continuous glucose monitoring (CGM) reduces HbA1c without increasing hypoglycaemia, with the largest effect in patients with the highest HbA1c at baseline.12 Current marketed CGM systems are used as standalone devices, or are connected to insulin pumps (sensor-augmented pump therapy), with or without a (predicted) low-glucose suspend feature, which automatically interrupts insulin administration for up to 2 h when glucose concentration falls below a pre-set threshold.13

Findings from an observational study14 have suggested that CGM reduces the risk of severe hypoglycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia. This finding was supported by results from a randomised controlled trial using sensor-augmented pump therapy with low-glucose suspension.15 However, the population studied in the trial was quite young (mean age 18·6 years) and the reduction of severe hypoglycaemia was not significant when two outliers in the youngest age groups were excluded from the analysis. Since most patients with impaired awareness of hypoglycaemia are older than 40 years and have had diabetes for more than 25 years,16 whether CGM improves glycaemia more than self-monitoring of blood glucose (SMBG) in a typical adult type 1 diabetes population with impaired awareness of hypoglycaemia has yet to be determined.17

Therefore, the primary objective of this trial was to investigate the effect of CGM compared with SMBG on glycaemic control in adult patients with type 1 diabetes and impaired awareness of hypoglycaemia.

Section snippets

Study design and participants

A detailed description of the study protocol has been previously published.18 Briefly, we did a two-centre, randomised, crossover, open-label trial (IN CONTROL) at the VU University Medical Center (Amsterdam, Netherlands) and the Medical Center Haaglanden (The Hague, Netherlands). Ethical approval was granted by the medical ethical committee of the VU University Medical Center.

We recruited patients from the outpatient clinics of both medical centres, and from outpatient clinics at affiliated

Results

Between March 4, 2013, and Feb 9, 2015, 57 patients attended the screening visit, and 52 were randomly assigned to either the CGM-to-SMBG sequence (n=26) or to the SMBG-to-CGM sequence (n=26; figure 1). The first patient was enrolled on March 4, 2013, and the final patient's last visit was on March 21, 2016. Five patients were deemed ineligible: two had a Gold score of 3, one had type 2 diabetes, one had a malignancy, and one was deemed unable to adhere to the study protocol, because he could

Discussion

The results from our randomised controlled crossover trial in adult patients with type 1 diabetes and impaired awareness of hypoglycaemia showed that a 16-week intervention with CGM (without low-glucose suspension) significantly improved time that the patients spent in a normoglycaemic state, with less time spent in hypoglycaemia and hyperglycaemia, compared with SMBG. Additionally, CGM decreased the frequency of severe hypoglycaemic events in this high-risk population, and produced less

References (32)

  • DM Nathan et al.

    Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes

    N Engl J Med

    (2005)
  • TJ Orchard et al.

    Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality

    JAMA

    (2015)
  • KM Miller et al.

    Current state of type 1 diabetes treatment in the US: updated data from the T1D Exchange clinic registry

    Diabetes Care

    (2015)
  • PE Cryer

    Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes

    Diabetologia

    (2002)
  • BM Frier

    How hypoglycaemia can affect the life of a person with diabetes

    Diabetes Metab Res Rev

    (2008)
  • BM Frier

    Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications

    Nat Rev Endocrinol

    (2014)
  • RG Feltbower et al.

    Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes: results from the Yorkshire Register of diabetes in children and young adults

    Diabetes Care

    (2008)
  • Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration

    Diabetologia

    (2007)
  • PE Cryer

    Diverse causes of hypoglycemia-associated autonomic failure in diabetes

    N Engl J Med

    (2004)
  • J Geddes et al.

    Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes

    Diabet Med

    (2008)
  • AE Gold et al.

    Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia

    Diabetes Care

    (1994)
  • JC Pickup et al.

    Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data

    BMJ

    (2011)
  • RM Bergenstal et al.

    Threshold-based insulin-pump interruption for reduction of hypoglycemia

    N Engl J Med

    (2013)
  • P Choudhary et al.

    Real-time continuous glucose monitoring significantly reduces severe hypoglycemia in hypoglycemia-unaware patients with type 1 diabetes

    Diabetes Care

    (2013)
  • TT Ly et al.

    Effect of sensor-augmented insulin pump therapy and automated insulin suspension vs standard insulin pump therapy on hypoglycemia in patients with type 1 diabetes: a randomized clinical trial

    JAMA

    (2013)
  • P Choudhary et al.

    Frequency of biochemical hypoglycaemia in adults with Type 1 diabetes with and without impaired awareness of hypoglycaemia: no identifiable differences using continuous glucose monitoring

    Diabet Med

    (2010)
  • Cited by (0)

    Prof Diamant died on April 9, 2014

    View full text