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. Author manuscript; available in PMC: 2019 Dec 1.
Published in final edited form as: J Diabetes Complications. 2018 Sep 1;32(12):1097–1099. doi: 10.1016/j.jdiacomp.2018.08.015

Real life evidence that impaired awareness of hypoglycemia persists for years in patients with type 1 diabetes

K Zekarias 1, A Kumar 1, A Moheet 1, E Seaquist 1
PMCID: PMC6289863  NIHMSID: NIHMS1509104  PMID: 30301594

Abstract

Aims

To determine if impaired awareness of hypoglycemia in patients with type 1 diabetes persists over time and to assess if continuous glucose monitoring use was associated with improved awareness of hypoglycemia in our population

Methods

Thirty-six with type 1 diabetes and impaired awareness of hypoglycemia who participated in studies on impaired awareness of hypoglycemia between 2009 – 2015 were contacted to complete an online survey. The survey included the Cox/Clarke and Gold hypoglycemia questionnaires and questions about continuous glucose monitoring use.

Results

23 of 36 (63%) subjects contacted completed the survey. (12 M, 11 F; median age 51 years, median diabetes duration 34 years). One had had an islet cell transplant and was excluded. Persistent impaired awareness of hypoglycemia was found in 19/22 (86%) using the Cox questionnaire and 18/22 (82%) using the Gold questionnaire. Consistent use of continuous glucose monitoring over the last six months defined as using a device ≥75% of time over the last 6 months was reported by 67% (12/18) and 68% (13/19) of participants with persistent impaired awareness of hypoglycemia as measured by Gold and Cox; respectively. Nineteen of the 22 participants (86%) reported severe hypoglycemia over the last six months.

Conclusion

Impaired awareness of hypoglycemia persisted in more than 80% of the subjects with type 1 diabetes we studied between 2009–2015. While the consistent use of continuous glucose monitoring among our participants was high; it did not translate into restoration of hypoglycemia awareness in this population. This real world data shows that severe hypoglycemia continues to be a frequent problem in this patient population.

Keywords: Hypoglycemia, Impaired awareness of hypoglycemia, Severe hypoglycemia, Continuous glucose monitor, Type 1 diabetes

Introduction

Impaired awareness of hypoglycemia is common in patients with Type 1 diabetes1,2. It occurs because recurrent episodes of hypoglycemia in a short period of time lowers the glucose level required to elicit the counterregulatory response necessary to generate the symptoms associated with hypoglycemia. As a result, patients with impaired awareness of hypoglycemia experience neuroglycopenic symptoms as the first sign of hypoglycemia and rely on the assistance of others to manage their episodes of hypoglycemia. Impaired awareness of hypoglycemia is associated with a 6-fold increase in the risk of severe hypoglycemia1, which in turn has been linked to increases in overall mortality3.

Several studies have shown that impaired awareness of hypoglycemia may be reversible.4–7 Strict avoidance of hypoglycemia over the course of a few weeks has been show to reverse clinical symptoms of impaired awareness of hypoglycemia 6,8, but this is very difficult to achieve in clinical practice. The U.K. DAFNE study demonstrated that a structured education program improves impaired awareness of hypoglycemia in both the short- and long-term9, but such programs are not widely available to patients in the United States. Islet cell transplant restores hypoglycemia awareness in patients with type 1 diabetes and impaired awareness of hypoglycemia4, but some view the risk associated with immunosuppression to be greater than that associated with hypoglycemia. Whether impaired awareness of hypoglycemia persists in community dwelling patients with type 1 diabetes found to have impaired awareness of hypoglycemia at one point in time has not been determined. The aim of this study was to determine if impaired awareness of hypoglycemia persists in real life patients with type 1 diabetes who have not participated in a formal intervention program to address this problem.

Real-time continuous glucose monitoring has become an important tool in the management of patients with diabetes and current data suggest that it may reduce the incidence of hypoglycemia10. If so, use of continuous glucose monitoring may reverse impaired awareness of hypoglycemia in some patients. Therefore, a secondary aim of our study was to determine if use of continuous glucose monitoring in our subjects was associated with a change in their hypoglycemia awareness status.

Materials and Methods

Study population and selection criteria: From our research registry, we selected patients 18 years and older with a diagnosis of type 1 diabetes who were previously categorized as being hypoglycemia unaware between 2009–2015. Hypoglycemia awareness was assessed using standardized Cox/Clarke14 and/or Gold14 questionnaires. We invited all participants with previous Cox/Clarke scores of 4 and above. An exclusion criterion was islet or pancreas transplantation.

After IRB approval; a total of thirty-six potential study participants were selected from our registry. They were contacted by email in 2017 and asked to complete a onetime online survey using a REDCap software. Participants were also provided the option of completing the survey in paper format; if they choose to do so. The survey included the Cox/Clarke and Gold hypoglycemia awareness assessment instruments, questions about continuous glucose monitoring use, details of current diabetes treatment, status of microvascular complications, and duration of diagnosis. The survey is included in the Supplemental material.

Data were analyzed using descriptive statistics.

Results

Out of 36 participants contacted, 23 (12 males, 11 females) completed the online survey. One study participant indicated that he had had an islet transplant since our last contact and therefore was excluded from the analysis. The median age of respondents was 51 years and the median duration of diabetes was 34 years.

Using the Cox and Gold questionnaires; 19/22 (86%) and 18/22 (82%) of the participants reported persistent impaired awareness of hypoglycemia; respectively. Sixty-four (14/22) percent of the participants reported consistent continuous glucose monitoring use, defined as using the device more than 75% of the time over the last six months. Consistent use of continuous glucose monitoring was reported 67% (12/18) and 68% (13/19) of participants with impaired awareness of hypoglycemia as measured by GOLD and Cox/Clarke questionnaires; respectively.

Eighty two percent of the participants (18/22) reported using an insulin pump for the management of diabetes. None were using a hybrid closed loop system. Eighteen percent (4/22) reported using multiple daily injections (MDI). Seventy-seven percent (16/22) reported having HbA1c within three months preceding the survey. Twenty one out of twenty-two had HbA1c checked within six months preceding the survey. Only one participant reported HbA1c checked greater than six months ago and one participant didn’t report HbA1c status. The median of the reported HbA1c values was 6.8 ± 1%; 64% had HbA1c 7% and below. None of the participants reported chronic kidney disease. Eighteen percent (4/22) of the participants reported diabetic retinopathy and 9% (2/22) reported diabetic neuropathy.

Nineteen of the twenty-two participants (86%) answered that they had experienced severe hypoglycemia over the last six months, including 17 of 19 (84%) of subjects with impaired awareness of hypoglycemia using Cox questionnaire. Consistent continuous glucose monitoring use was reported in 11/22 of those who experienced severe hypoglycemia and in 2 of the 3 who did not over the last six months.

Discussion

These observations show that persistent impaired awareness of hypoglycemia is common in type 1 diabetes. While the consistent use of continuous glucose monitoring among our study participants was high, it did not translate into restoration of hypoglycemia awareness in this population. The prevalence of severe hypoglycemia in this population was also very high, even in patients who consistently used continuous glucose monitoring.

Interventions to reduce severe hypoglycemia and restore hypoglycemia awareness have been tested around the world. Diabetes education appears to provide the greatest impact on these conditions, as was demonstrated by Yeoh et al in a recent systematic review and meta analysis. The U.K. DAFNE experience9 in particular showed a strong association between a structured education and reduction in self-reported severe hypoglycemia and improvement in hypoglycemia recognition among those with history of impaired awareness of hypoglycemia. Technology has also been tested as an intervention and a recent study by Rickels and et al10 reported continuous glucose monitoring improves hypoglycemia unawareness. However, in the HypoCOMPaSS study12 there was no difference between the different treatment modalities and monitoring techniques, insulin pump vs multiple daily injections or self-monitored blood glucose vs continuous glucose monitoring on restoration of hypoglycemia awareness. Similarly, a study by Heinemann et al17; showed there was no difference on self-reported hypoglycemia unawareness in patients randomized to real time continuous glucose monitoring vs self monitored blood glucose testing.

In summary, our study indicated that most patients with long standing type 1 diabetes and impaired awareness of hypoglycemia have persistent impaired awareness of hypoglycemia . This continues to put them at risk for experiencing severe hypoglycemia. The consistent use of continuous glucose monitoring in the real world did not translate into restoring impaired awareness of hypoglycemia, similar to findings in RCT trials.12,13,17 Future studies that focus exclusively on restoring awareness of hypoglycemia are necessary to develop ways to manage this very serious complication of insulin treatment.

Supplementary Material

1

Table 1.

Persistent impaired awareness of hypoglycemia and severe hypoglycemia status by consistent use of continuous glucose monitoring

Consistent use of continuous glucose monitoring defined as more than 75% of the time over the last six months No consistent use of continuous glucose monitoring
Participants with persistent impaired awareness of hypoglycemia (n = 18/22 using Gold) 12 6
Participants with persistent impaired awareness of hypoglycemia (n = 19/22 using Cox) 13 7
Participants without persistent impaired awareness of hypoglycemia (n= 4/22 using Gold) 2 2
Participants without persistent impaired awareness of hypoglycemia (n= 3/22 using Cox) 1 2
Participants with severe HG in 6 months before survey (n = 19/22) 11 8
Participants without severe HG in 6 months before survey (n = 3/22) 2 1
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Data are given in numbers

Highlights.

  • We Report on the role of continuous glucose monitor in reversing impaired awareness of Hypoglycemia in a real-world setting.

  • Persistent impaired awareness of hypoglycemia is common in patients with Type 1 Diabetes.

  • Consistent use of CGM did not translate into restoration of impaired awareness of hypoglycemia in our study population.

Acknowledgment

The study participants were selected from previous studies funded by ADA 7–09-DCS-02 (07/1/2009 – 06/30/2013); Hypoglycemia Unawareness in Patients with Type 1 Diabetes: Pilot Study of Naltrexone Therapy and NIH R01DK62440 (09/03/2002 – 09/30/2010); Cerebral Responses to Insulin-Induced Hypoglycemia. The authors didn’t receive any funding for the study presented here.

Footnotes

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Declaration of interests

The authors declare that there are no conflicts of interest.

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Associated Data

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Supplementary Materials

1
NIHMS1509104-supplement-1.pdf (465.4KB, pdf)

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