DIABETICMedicine DOI: 10.1111/dme.12730
Research: Treatment Weight-based hypoglycaemia treatment protocol for adults with Type 1 diabetes: a randomized crossover clinical trial L. McTavish1, J. D. Krebs1,2, M. Weatherall2 and E. Wiltshire3 1 Endocrine, Diabetes and Research Centre, Capital and Coast District Health Board, 2Department of Medicine, University of Otago and 3Department of Paediatrics and Child Health, University of Otago Wellington, Wellington, New Zealand
Accepted 9 February 2015
Abstract Aim To determine whether a weight-based hypoglycaemia treatment using 0.3 g/kg (or 0.2 g/kg) glucose effectively treats adults with Type 1 diabetes mellitus compared with an internationally recommended 15-g treatment. Methods Patients with frequent hypoglycaemia were recruited from hospital-based diabetes clinics. The treatment for each hypoglycaemic episode, defined as capillary glucose 18 years with Type 1 diabetes attending the Capital & Coast District Health Board diabetes clinics, with a history of recent, recurrent episodes of hypoglycaemia. Exclusion criteria included adrenal insufficiency, uncompensated hypothyroidism, clinical autonomic neuropathy, coeliac disease and living alone. Methods
Participants gave written informed consent when they attended the Endocrine, Diabetes and Research Centre at Wellington Regional Hospital, Wellington, New Zealand. A questionnaire was used to gather relevant clinical information, including duration of diabetes, most recent HbA1c
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value, a list of current medications and medical history. Each participant’s height and weight was measured and an individualized quantity of glucose was calculated for the 0.2- and 0.3-g/kg treatment doses for each participant, rounded to the nearest 1.5 g (half a DextroTM tablet; Dextro Energy, Krefeld, Germany). Our comparison treatments were chosen as follows: 0.2 g/kg to mimic the current standard of 15 g glucose for an average patient weighing 75 kg, but to provide more flexibility for variation in weight, and 0.3 g/kg because of the effectiveness of this dose in our previous study in children [14]. Each treatment was written on five capillary glucose record forms, with each form placed into an envelope and sealed. Using a previously generated randomization sequence downloaded from sealedenvelop.com, the Research Trial Coordinator then assigned a number between 1 and 15 to each envelope and wrote the assigned number on the outside. This was thus a crossover study with each participant planned to have, in random order, five treatments per treatment protocol. The participants were also given an Accu-chek Performa (Nano; Roche Diagnostics, Mannheim, Germany) capillary glucose meter, 150 Performa blood test strips (Roche Diagnostics), a calculated supply of glucose Dextro tablets, a stopwatch, a quantity of foil-wrapped 20-g complex carbohydrate packets, 15 stamped envelopes and capillary glucose recording forms to mail back to the principal investigator. Once a participant identified a symptomatic hypoglycaemic event, defined as a capillary glucose value of < 4.0 mmol/l [17], they were instructed to open the next envelope in consecutive ascending order to determine the treatment protocol for that episode (Fig. 1). Time zero was defined as the time of ingesting the nominated treatment. After treatment, the participant waited 10 min before completing a second capillary glucose recording. A third and final blood test was taken at 5 min after the resolution of the hypoglycaemic event to investigate whether immediate rebound hyperglycaemia occurred. If the second capillary glucose was ≥ 4.0 mmol/l, then the participant followed the normal guidelines of either consuming 20 g of complex carbohydrate or the usual meal if it was due. If the recording remained < 4.0 mmol/l, then the participant would repeat the treatment until resolution of the event. Each blood test time and level was recorded by participants on the respective data sheet, along with actual number of Dextro tablets consumed, together with any symptoms, then the participant mailed this back to the lead investigator. The primary outcome was the capillary glucose after 10 min adjusted for baseline capillary glucose. The main secondary outcomes were the proportion of participants with capillary glucose > 8 mmol/l after 10 min and the proportion needing more than one treatment. A post hoc analysis was also carried out to examine if there was an interaction between the response to treatment and the sex of participant.
ª 2015 The Authors. Diabetic Medicine ª 2015 Diabetes UK
Research article
DIABETICMedicine
FIGURE 1 Study flow diagram.
Sample size and analysis
In a two-arm trial, 75 participants per arm are needed for 80% power to detect an effect size of 0.5. We assumed an intraclass correlation coefficient of 0.1 for repeated measures of capillary glucose. After adjustment for the intraclass correlation coefficient and planning for five measurements per treatment clustered within participants, this would require 135 measurements per treatment. We aimed for the present three-arm study to have 30 participants with 50 measurements per treatment for a total of 450 measurements to allow for 10% missing data. Mixed linear models for capillary glucose values, and generalized mixed linear models for proportions of participants achieving particular capillary glucose measurements after 10 min, were used to estimate the effect of treatment compared with the 15-g treatment, and to take into account the clustering of measurements within participants. For the main outcome variable of capillary glucose after 10 min, baseline capillary was used as a continuous covariate. In the post hoc analysis by sex this was used as an interaction term with treatment SAS version 9.3 and SPSS version 22 software were used for the analyses.
Results The flow of participants through the study is shown in Fig. 2. The characteristics of the 34 participants are shown in Table 1. Completion of all 15 planned glucose treatments occurred in 24 participants and the other 10 participants completed between four and 11 glucose treatments. Two participants, while randomized to use 0.3 g/kg for a particular hypoglycaemic episode reported using fewer than the randomized number of Dextro tablets, as they had insufficient
ª 2015 The Authors. Diabetic Medicine ª 2015 Diabetes UK
tablets to hand. Two participants withdrew because they did not like the taste of the Dextro tablets and were not included in the analysis as they had no relevant data. One further participant substituted their own sweets for the randomized treatment and was also excluded from the analysis data set. For seven episodes the 10-min capillary glucose values were missing. A total of 409 episodes at 10 min were included in the analysis data set: 132 in the 0.2-g/kg treatment protocol, 141 in the 0.3-g/kg treatment protocol and 136 in the 15-g treatment protocol. For the episodes of symptomatic hypoglycaemia the mean capillary glucose overall was 3.1 mmol/l. The median (range) dose of glucose consumed was 15 (10.5–18) g for the 0.2-g/ kg treatment and 24 (15–30) g for the 0.3-g/kg treatment. The summary capillary glucose results, unadjusted for clustering within participants, are shown in Table 2. After 10 min, adjusted for baseline glucose and clustering, the difference (95% CI) between the 0.3-g/kg and 15-g doses was significant: 0.26 (0.04 to 0.48) mmol/l (P = 0.02), but not between 15g and 0.2 g/kg; -0.07 (-0.29 to 0.16) mmol/l (P = 0.56). Glucose was > 8 mmol/l after 10 min for only three treatments, one in the 15-g group and two in the 0.3-g/kg group, suggesting that rebound hyperglycaemia is rare with the doses used. At 5 min after the consumption of complex carbohydrate, the number of episodes for which capillary glucose concentration was >8 mmol/l were: 17/132 episodes (12.9%) for 15 g, 18/125 episodes (14.4%) for 0.2 g/kg and 28/128 episodes (21.9%) for 0.3 g/kg. In comparison with the 15-g treatment of glucose the odds ratio for the proportion of episodes for which the final capillary glucose concentration was >8 mmol/l were 1.25 (95% CI 0.57–2.76; P = 0.57) for 0.2 g/kg and 2.05 (95% CI 0.98 – 4.29; P = 0.056) for 0.3 g/kg.
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Weight-based hypoglycaemia treatment in adults with Type 1 diabetes L. McTavish et al.
DIABETICMedicine
FIGURE 2 Treatment protocol during study.
Table 1 Characteristics of study participants
Age, years Duration of diabetes, years Weight, kg BMI, kg/m2 Total daily insulin, units Glucose dose 0.2 g/kg Glucose dose 0.3 g /kg HbA1c mmol/mol %
Discussion
Male, (n = 21)
Female (n = 13)
43.4 21.1 79.5 25.0 54.5 15.1 22.9 63
44.0 24.8 70.6 23.8 45.4 14.0 21.2 63
(15.1) (14.1) (10.4) (3.1) (17.9) (2.0) (3.1) (10.5)
7.9 (0.9)
(15.0) (14.1) (10.5) (3.2) (17.7) (2.1) (3.1) (10.4)
7.9 (0.9)
Values are mean (SD).
The need for more than one treatment occurred in 50/134 hypoglycaemia episodes (37.3%) of the 15-g group, 51/130 (39.2%) of the 0.2-g/kg group and 41/142 (28.9%) of the 0.3g/kg group. There was no evidence of a difference in proportions of participants in each treatment group needing more than one treatment (P = 0.18). The odds ratio, adjusted for clustering, for 0.3 g/kg compared with 15 g was 0.65 (95% CI 0.37 to 1.12), and for 0.2 g/kg compared with 15 g it was 1.03 (95% CI 0.60 to 1.78). The raw capillary glucose means by sex are shown in Table 3. There was no interaction between sex and response to treatment (P = 0.39), so that there was no evidence that the response to treatment differed by the sex of the participants.
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In the present study we investigated the efficacy of two different weight-based treatment protocols in comparison with the current standard international guideline of 15 g glucose for correcting insulin-induced hypoglycaemia in adolescents and adults in the community setting. Our results show that treatment of insulin-induced hypoglycaemia with 0.3 g/kg of glucose more effectively resolves hypoglycaemia within 10 min than either 15 g glucose or 0.2 g/kg glucose in most adolescents and adults. The unadjusted rise in capillary glucose averaged 1.5 mmol/l per treatment in the 0.3-g/kg glucose group, compared with 1.2 mmol/l in the 15-g group and 1.1 mmol/l in the 0.2-g/kg group. We use the term ‘treatment’ as one individualized weight-based dose of a glucose preparation. These results are similar to those observed in children with Type 1 diabetes, although children had a greater mean rise in glucose concentration (2.5 mmol/l with 0.3 g/kg glucose) [14]. Other recent studies have also concluded that current international guidelines for the management of hypoglycaemia require reviewing in light of recent research findings [11,16]. Most of the international recommendations are based on the 1984 study by Brodows et al. [12] and the study by Slama [13] in 1990, who used euglycaemic clamps to determine the effectiveness of carbohydrate preparations for resolving insulin-induced hypoglycaemia. Slama induced hypoglycaemia in 41 adult volunteers with Type 1 diabetes, who at 62.1 1.5 kg were lighter than the patients in the ª 2015 The Authors. Diabetic Medicine ª 2015 Diabetes UK
Research article
DIABETICMedicine
Table 2 Mean capillary glucose (mmol/l) and change over time by treatment group, unadjusted for clustering Glucose treatment 0.2 g/kg Median (range) actual glucose dose, g Mean (SD) glucose, mmol/l Baseline
0.3 g/kg
15 (10.5 to 19.5)
24 (15 to 30)
3.15 (0.52) n = 133 4.29 (0.94) n = 132 1.15 (0.89) n = 132
10 min Change from baseline
15 g (control) 15
3.17 (0.55) n = 143 4.67 (1.25) n = 141 1.48 (1.19) n = 141
3.11 (0.55) n = 140 4.37 (0.99) n = 136 1.25 (0.99) n = 136
Table 3 Mean capillary glucose and change over time by sex and treatment group, unadjusted for clustering Glucose treatment 0.2 g/kg
Mean (SD) glucose, mmol/l Baseline 10 min Mean (SD) change from baseline
0.3 g/kg
Male
Female
Male
Female
Male
Female
3.10 (0.50) n = 87 4.24 (0.95) n = 87 1.14 (0.88) n = 87
3.23 (0.54) n = 46 4.38 (0.94) n = 45 1.15 (0.92) n = 45
3.18 (0.58) n = 92 4.76 (1.23) n = 90 1.56 (0.18) n = 90
3.17 (0.49) n = 51 4.51 (1.29) n = 51 1.35 (1.20) n = 51
3.03 (0.56) n = 91 4.37 (0.94) n = 88 1.33 (0.91) n = 88
3.27 (0.51) n = 49 4.38 (1.08) n = 48 1.11 (1.12) n = 48
present study, on average, and randomized them to seven different carbohydrate preparations, aiming to find the optimum preparation to treat insulin-induced hypoglycaemia rather than the optimum amount of simple carbohydrate to use. Upon the onset of hypoglycaemia, the participants in the present study were given 15 g of study preparation, with blood drawn at specific time intervals until alleviation of symptoms. This appears to be the primary basis for current international guidelines suggesting 15 g carbohydrate for hypoglycaemia. The study concluded that glucose and sucrose were more effective than other preparations, that the exact choice of hypoglycaemia treatment could be left to the individual and that 15 g of a glucose- or sucrose-containing preparation provided an effective glycaemic response within 20 min. Similar results were found in a recent study investigating the effectiveness of 15 g of glucose, sucrose and fructose in treating hypoglycaemia in children with Type 1 diabetes, with fructose-containing preparations less effective than either sucrose or glucose [11]. Our earlier study in children varied the amount of carbohydrate preparation based on the child’s weight and found glucose-containing preparations to be the most efficacious [14]. A recent Australian study involving 92 people treated with insulin, living in the community, has also challenged the 15-g recommendation, suggesting 20 g may be better [16]. In that study, 15 g glucose provided a lower (63.2%) resolution rate at 10 min ª 2015 The Authors. Diabetic Medicine ª 2015 Diabetes UK
15 g (control)
than did the 20 g treatment (89.3%), consistent with the outcome of the present study. A second treatment was more frequently required if the capillary glucose was < 3.1 mmol/l. In light of this finding, a larger initial treatment dose may be required in this setting. We would suggest 0.3 g/kg glucose as the best treatment if capillary glucose is 3.1–3.9 mmol/l and 0.6 g/kg if capillary glucose is < 3.1 mmol/l, although a further study would be required to specifically test this. The present study has some limitations. It was not possible to blind the treatment protocols, but the amount of the treatment preparation was randomized and, once a treatment was selected, identical procedures were used for follow-up. We used the American Diabetes Association threshold of 3.9 mmol/l (70 mg/dl) to classify hypoglycaemia in the present study, whereas other studies use 3.5 mmol/l. It is possible that participants did not adhere to the randomized treatment, given the neurocognitive effects of mild hypoglycaemia, however, all subjects recorded the actual number of Dextro tablets consumed and capillary glucose measurements for each episode, so this is unlikely to have been a major limitation. It also reflects ‘real world’ management of hypoglycaemia. The study population was relatively small, but similar in size to previous studies in this area. A further limitation is that there were few individuals with obese range body weights included. It is conceivable that a weight-based glucose dose may be excessive in those with morbid obesity.
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Weight-based hypoglycaemia treatment in adults with Type 1 diabetes L. McTavish et al.
Whilst this is uncommon in Type 1 diabetes, it can occur. Weight-based treatment in Type 2 diabetes may also be worth further study, but was beyond the scope of the present study. In summary, weight-based treatment of hypoglycaemia using 0.3 g/kg glucose is more effective in resolving hypoglycaemia than 15 g or 0.2 g/kg. It should be considered as part of a person’s individualized self-management education plan. All adolescents and adults with Type 1 diabetes attending a diabetes clinic should be weighed as part of their overall diabetes assessment and, as a routine, could have an individualized quantity of simple carbohydrate calculated as a recommended treatment of prospective mild to moderate hypoglycaemic events. A dose of 0.3 g/kg glucose should increase capillary glucose by 1.5 mmol/l on average, over 10 min. Initial recordings below 3.1 mmol/l may require a higher dose, but this requires further study.
Funding sources
This study was funded by grants from The New Zealand Society for the Study of Diabetes (NZSSD) 2011 Eli Lilly Diabetes Nursing Research Grant (awarded to LM), and the Wellington Medical Research Foundation.
Competing interests
None declared.
Acknowledgements
We thank the Research Assistants at the Endocrine, Diabetes & Research Centre, Wellington Regional Hospital, Wellington, New Zealand and the New Zealand Society for the Study of Diabetes for the 2011 Eli Lilly Diabetes Nursing Research Grant (awarded to L.M.), as well as the Wellington Medical Research Foundation. This study was presented in part at the International Diabetes Federation World Diabetes Congress, Melbourne, Australia. December 2013 (Abstract number ME: 0132)
References 1 Diabetes Control and Complications Trial Research Group. Effect of intensive diabetes treatment on the development of long-term complications in adolescents with insulin dependent diabetes mellitus: Diabetes Control and Complications Trial. J Pediatr 1994; 125: 177–188.
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2 Davis EA, Keating B., Byrne GC, Russell M, Jones TW. Impact of improved glycaemic control on rates of hypoglycaemia in insulin dependent diabetes mellitus. Arch Dis Child 1998; 78: 111–115. 3 Epidemiology of diabetes interventions and complications (EDIC) Research Group. Beneficial effects of intensive therapy of diabetes during adolescence: outcomes after the conclusion of the diabetes control and complications trial (DCCT. J Pediatr 2001; 139: 804– 812. 4 Diabetes Control and Complications Trial Research Group. The effect of intensive treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N.Engl J Med 1993; 329: 977–986. 5 Cryer PE. Hypoglycaemia: The limiting factor in the Glycaemic management of Type 1 and Type 2 Diabetes. Diabetologia 2002; 45: 937–948. 6 National Institute for Health and Clinical Excellence (NICE) CG15 Type1 diabetes in children and young people. 23 July 2004. Available at http://guidance.nice.org.uk. Last accessed 1 August 2010. 7 American Diabetes Association. Evidence-based nutritional principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 2002; 25: 148– 198. 8 Canadian Diabetes Association Clinical Practice Guidelines for the. Prevention and Management of Hypoglycaemia in Diabetes. Can J, Diabetes 2001; 26: 22–35. 9 Diabetes Australia, Diabetes Management in General Practice. Available at http://www.diabetesaustralia.com.au/For-HealthProfessionals/Diabetes-National-Guidelines/#Diabetes-Managementin-General-Practice. Last accessed 1 August 2010. 10 American Diabetes Association. Defining and Reporting Hypoglycaemia in Diabetes. Diabetes Care 2005; 28: 1245–1249. 11 Husband AC, Crawford S, McCoy LA, Pacaud D. The effectiveness of glucose, sucrose, and fructose in treating hypoglycaemia in children with type 1 diabetes. Pediatr Diabetes 2009; 11: 154– 158. 12 Brodows RG, Williams C, Amatruda M. Treatment of insulin reactions in diabetics. JAMA 1984; 252: 3378–3381. 13 Slama G. The Search for an optimized treatment of hypoglycaemia: carbohydrates in tablets, solution, or gel for the correction of insulin reactions. Arch Intern Med 1990; 150: 589–593. 14 McTavish L, Wiltshire E. Effective treatment of hypoglycaemia in children with type 1 diabetes; a randomized controlled clinical trial. Pediatr Diabetes 2011; 12: 381–387. 15 Vindedzis S, Marsh B, Sherriff J, Dhaliwal S, Stanton K. Dietary treatment of hypoglycaemia: should the Australian recommendation be increased? Int Med J 2012; 42: 830–833. 16 Bryden KS, Neil A, Mayou RA, Peveler RC, Fairburn CG, Dunger DB. Eating habits, bodyweight, and insulin misuse. A longitudinal study of teenagers and young adults with type 1 diabetes. Diabetes Care 1999; 22: 1956–1960. 17 Endocrine Society. Hypoglycaemia and Diabetes: A report of a workgroup of the American Diabetes Association and The Endocrine Society. J. Clin Endocrinol Metabol 2013; 98: 1845–1859.
ª 2015 The Authors. Diabetic Medicine ª 2015 Diabetes UK
Research: Treatment Weight-based hypoglycaemia treatment protocol for adults with Type 1 diabetes: a randomized crossover clinical trial L. McTavish1, J. D. Krebs1,2, M. Weatherall2 and E. Wiltshire3 1 Endocrine, Diabetes and Research Centre, Capital and Coast District Health Board, 2Department of Medicine, University of Otago and 3Department of Paediatrics and Child Health, University of Otago Wellington, Wellington, New Zealand
Accepted 9 February 2015
Abstract Aim To determine whether a weight-based hypoglycaemia treatment using 0.3 g/kg (or 0.2 g/kg) glucose effectively treats adults with Type 1 diabetes mellitus compared with an internationally recommended 15-g treatment. Methods Patients with frequent hypoglycaemia were recruited from hospital-based diabetes clinics. The treatment for each hypoglycaemic episode, defined as capillary glucose 18 years with Type 1 diabetes attending the Capital & Coast District Health Board diabetes clinics, with a history of recent, recurrent episodes of hypoglycaemia. Exclusion criteria included adrenal insufficiency, uncompensated hypothyroidism, clinical autonomic neuropathy, coeliac disease and living alone. Methods
Participants gave written informed consent when they attended the Endocrine, Diabetes and Research Centre at Wellington Regional Hospital, Wellington, New Zealand. A questionnaire was used to gather relevant clinical information, including duration of diabetes, most recent HbA1c
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value, a list of current medications and medical history. Each participant’s height and weight was measured and an individualized quantity of glucose was calculated for the 0.2- and 0.3-g/kg treatment doses for each participant, rounded to the nearest 1.5 g (half a DextroTM tablet; Dextro Energy, Krefeld, Germany). Our comparison treatments were chosen as follows: 0.2 g/kg to mimic the current standard of 15 g glucose for an average patient weighing 75 kg, but to provide more flexibility for variation in weight, and 0.3 g/kg because of the effectiveness of this dose in our previous study in children [14]. Each treatment was written on five capillary glucose record forms, with each form placed into an envelope and sealed. Using a previously generated randomization sequence downloaded from sealedenvelop.com, the Research Trial Coordinator then assigned a number between 1 and 15 to each envelope and wrote the assigned number on the outside. This was thus a crossover study with each participant planned to have, in random order, five treatments per treatment protocol. The participants were also given an Accu-chek Performa (Nano; Roche Diagnostics, Mannheim, Germany) capillary glucose meter, 150 Performa blood test strips (Roche Diagnostics), a calculated supply of glucose Dextro tablets, a stopwatch, a quantity of foil-wrapped 20-g complex carbohydrate packets, 15 stamped envelopes and capillary glucose recording forms to mail back to the principal investigator. Once a participant identified a symptomatic hypoglycaemic event, defined as a capillary glucose value of < 4.0 mmol/l [17], they were instructed to open the next envelope in consecutive ascending order to determine the treatment protocol for that episode (Fig. 1). Time zero was defined as the time of ingesting the nominated treatment. After treatment, the participant waited 10 min before completing a second capillary glucose recording. A third and final blood test was taken at 5 min after the resolution of the hypoglycaemic event to investigate whether immediate rebound hyperglycaemia occurred. If the second capillary glucose was ≥ 4.0 mmol/l, then the participant followed the normal guidelines of either consuming 20 g of complex carbohydrate or the usual meal if it was due. If the recording remained < 4.0 mmol/l, then the participant would repeat the treatment until resolution of the event. Each blood test time and level was recorded by participants on the respective data sheet, along with actual number of Dextro tablets consumed, together with any symptoms, then the participant mailed this back to the lead investigator. The primary outcome was the capillary glucose after 10 min adjusted for baseline capillary glucose. The main secondary outcomes were the proportion of participants with capillary glucose > 8 mmol/l after 10 min and the proportion needing more than one treatment. A post hoc analysis was also carried out to examine if there was an interaction between the response to treatment and the sex of participant.
ª 2015 The Authors. Diabetic Medicine ª 2015 Diabetes UK
Research article
DIABETICMedicine
FIGURE 1 Study flow diagram.
Sample size and analysis
In a two-arm trial, 75 participants per arm are needed for 80% power to detect an effect size of 0.5. We assumed an intraclass correlation coefficient of 0.1 for repeated measures of capillary glucose. After adjustment for the intraclass correlation coefficient and planning for five measurements per treatment clustered within participants, this would require 135 measurements per treatment. We aimed for the present three-arm study to have 30 participants with 50 measurements per treatment for a total of 450 measurements to allow for 10% missing data. Mixed linear models for capillary glucose values, and generalized mixed linear models for proportions of participants achieving particular capillary glucose measurements after 10 min, were used to estimate the effect of treatment compared with the 15-g treatment, and to take into account the clustering of measurements within participants. For the main outcome variable of capillary glucose after 10 min, baseline capillary was used as a continuous covariate. In the post hoc analysis by sex this was used as an interaction term with treatment SAS version 9.3 and SPSS version 22 software were used for the analyses.
Results The flow of participants through the study is shown in Fig. 2. The characteristics of the 34 participants are shown in Table 1. Completion of all 15 planned glucose treatments occurred in 24 participants and the other 10 participants completed between four and 11 glucose treatments. Two participants, while randomized to use 0.3 g/kg for a particular hypoglycaemic episode reported using fewer than the randomized number of Dextro tablets, as they had insufficient
ª 2015 The Authors. Diabetic Medicine ª 2015 Diabetes UK
tablets to hand. Two participants withdrew because they did not like the taste of the Dextro tablets and were not included in the analysis as they had no relevant data. One further participant substituted their own sweets for the randomized treatment and was also excluded from the analysis data set. For seven episodes the 10-min capillary glucose values were missing. A total of 409 episodes at 10 min were included in the analysis data set: 132 in the 0.2-g/kg treatment protocol, 141 in the 0.3-g/kg treatment protocol and 136 in the 15-g treatment protocol. For the episodes of symptomatic hypoglycaemia the mean capillary glucose overall was 3.1 mmol/l. The median (range) dose of glucose consumed was 15 (10.5–18) g for the 0.2-g/ kg treatment and 24 (15–30) g for the 0.3-g/kg treatment. The summary capillary glucose results, unadjusted for clustering within participants, are shown in Table 2. After 10 min, adjusted for baseline glucose and clustering, the difference (95% CI) between the 0.3-g/kg and 15-g doses was significant: 0.26 (0.04 to 0.48) mmol/l (P = 0.02), but not between 15g and 0.2 g/kg; -0.07 (-0.29 to 0.16) mmol/l (P = 0.56). Glucose was > 8 mmol/l after 10 min for only three treatments, one in the 15-g group and two in the 0.3-g/kg group, suggesting that rebound hyperglycaemia is rare with the doses used. At 5 min after the consumption of complex carbohydrate, the number of episodes for which capillary glucose concentration was >8 mmol/l were: 17/132 episodes (12.9%) for 15 g, 18/125 episodes (14.4%) for 0.2 g/kg and 28/128 episodes (21.9%) for 0.3 g/kg. In comparison with the 15-g treatment of glucose the odds ratio for the proportion of episodes for which the final capillary glucose concentration was >8 mmol/l were 1.25 (95% CI 0.57–2.76; P = 0.57) for 0.2 g/kg and 2.05 (95% CI 0.98 – 4.29; P = 0.056) for 0.3 g/kg.
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Weight-based hypoglycaemia treatment in adults with Type 1 diabetes L. McTavish et al.
DIABETICMedicine
FIGURE 2 Treatment protocol during study.
Table 1 Characteristics of study participants
Age, years Duration of diabetes, years Weight, kg BMI, kg/m2 Total daily insulin, units Glucose dose 0.2 g/kg Glucose dose 0.3 g /kg HbA1c mmol/mol %
Discussion
Male, (n = 21)
Female (n = 13)
43.4 21.1 79.5 25.0 54.5 15.1 22.9 63
44.0 24.8 70.6 23.8 45.4 14.0 21.2 63
(15.1) (14.1) (10.4) (3.1) (17.9) (2.0) (3.1) (10.5)
7.9 (0.9)
(15.0) (14.1) (10.5) (3.2) (17.7) (2.1) (3.1) (10.4)
7.9 (0.9)
Values are mean (SD).
The need for more than one treatment occurred in 50/134 hypoglycaemia episodes (37.3%) of the 15-g group, 51/130 (39.2%) of the 0.2-g/kg group and 41/142 (28.9%) of the 0.3g/kg group. There was no evidence of a difference in proportions of participants in each treatment group needing more than one treatment (P = 0.18). The odds ratio, adjusted for clustering, for 0.3 g/kg compared with 15 g was 0.65 (95% CI 0.37 to 1.12), and for 0.2 g/kg compared with 15 g it was 1.03 (95% CI 0.60 to 1.78). The raw capillary glucose means by sex are shown in Table 3. There was no interaction between sex and response to treatment (P = 0.39), so that there was no evidence that the response to treatment differed by the sex of the participants.
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In the present study we investigated the efficacy of two different weight-based treatment protocols in comparison with the current standard international guideline of 15 g glucose for correcting insulin-induced hypoglycaemia in adolescents and adults in the community setting. Our results show that treatment of insulin-induced hypoglycaemia with 0.3 g/kg of glucose more effectively resolves hypoglycaemia within 10 min than either 15 g glucose or 0.2 g/kg glucose in most adolescents and adults. The unadjusted rise in capillary glucose averaged 1.5 mmol/l per treatment in the 0.3-g/kg glucose group, compared with 1.2 mmol/l in the 15-g group and 1.1 mmol/l in the 0.2-g/kg group. We use the term ‘treatment’ as one individualized weight-based dose of a glucose preparation. These results are similar to those observed in children with Type 1 diabetes, although children had a greater mean rise in glucose concentration (2.5 mmol/l with 0.3 g/kg glucose) [14]. Other recent studies have also concluded that current international guidelines for the management of hypoglycaemia require reviewing in light of recent research findings [11,16]. Most of the international recommendations are based on the 1984 study by Brodows et al. [12] and the study by Slama [13] in 1990, who used euglycaemic clamps to determine the effectiveness of carbohydrate preparations for resolving insulin-induced hypoglycaemia. Slama induced hypoglycaemia in 41 adult volunteers with Type 1 diabetes, who at 62.1 1.5 kg were lighter than the patients in the ª 2015 The Authors. Diabetic Medicine ª 2015 Diabetes UK
Research article
DIABETICMedicine
Table 2 Mean capillary glucose (mmol/l) and change over time by treatment group, unadjusted for clustering Glucose treatment 0.2 g/kg Median (range) actual glucose dose, g Mean (SD) glucose, mmol/l Baseline
0.3 g/kg
15 (10.5 to 19.5)
24 (15 to 30)
3.15 (0.52) n = 133 4.29 (0.94) n = 132 1.15 (0.89) n = 132
10 min Change from baseline
15 g (control) 15
3.17 (0.55) n = 143 4.67 (1.25) n = 141 1.48 (1.19) n = 141
3.11 (0.55) n = 140 4.37 (0.99) n = 136 1.25 (0.99) n = 136
Table 3 Mean capillary glucose and change over time by sex and treatment group, unadjusted for clustering Glucose treatment 0.2 g/kg
Mean (SD) glucose, mmol/l Baseline 10 min Mean (SD) change from baseline
0.3 g/kg
Male
Female
Male
Female
Male
Female
3.10 (0.50) n = 87 4.24 (0.95) n = 87 1.14 (0.88) n = 87
3.23 (0.54) n = 46 4.38 (0.94) n = 45 1.15 (0.92) n = 45
3.18 (0.58) n = 92 4.76 (1.23) n = 90 1.56 (0.18) n = 90
3.17 (0.49) n = 51 4.51 (1.29) n = 51 1.35 (1.20) n = 51
3.03 (0.56) n = 91 4.37 (0.94) n = 88 1.33 (0.91) n = 88
3.27 (0.51) n = 49 4.38 (1.08) n = 48 1.11 (1.12) n = 48
present study, on average, and randomized them to seven different carbohydrate preparations, aiming to find the optimum preparation to treat insulin-induced hypoglycaemia rather than the optimum amount of simple carbohydrate to use. Upon the onset of hypoglycaemia, the participants in the present study were given 15 g of study preparation, with blood drawn at specific time intervals until alleviation of symptoms. This appears to be the primary basis for current international guidelines suggesting 15 g carbohydrate for hypoglycaemia. The study concluded that glucose and sucrose were more effective than other preparations, that the exact choice of hypoglycaemia treatment could be left to the individual and that 15 g of a glucose- or sucrose-containing preparation provided an effective glycaemic response within 20 min. Similar results were found in a recent study investigating the effectiveness of 15 g of glucose, sucrose and fructose in treating hypoglycaemia in children with Type 1 diabetes, with fructose-containing preparations less effective than either sucrose or glucose [11]. Our earlier study in children varied the amount of carbohydrate preparation based on the child’s weight and found glucose-containing preparations to be the most efficacious [14]. A recent Australian study involving 92 people treated with insulin, living in the community, has also challenged the 15-g recommendation, suggesting 20 g may be better [16]. In that study, 15 g glucose provided a lower (63.2%) resolution rate at 10 min ª 2015 The Authors. Diabetic Medicine ª 2015 Diabetes UK
15 g (control)
than did the 20 g treatment (89.3%), consistent with the outcome of the present study. A second treatment was more frequently required if the capillary glucose was < 3.1 mmol/l. In light of this finding, a larger initial treatment dose may be required in this setting. We would suggest 0.3 g/kg glucose as the best treatment if capillary glucose is 3.1–3.9 mmol/l and 0.6 g/kg if capillary glucose is < 3.1 mmol/l, although a further study would be required to specifically test this. The present study has some limitations. It was not possible to blind the treatment protocols, but the amount of the treatment preparation was randomized and, once a treatment was selected, identical procedures were used for follow-up. We used the American Diabetes Association threshold of 3.9 mmol/l (70 mg/dl) to classify hypoglycaemia in the present study, whereas other studies use 3.5 mmol/l. It is possible that participants did not adhere to the randomized treatment, given the neurocognitive effects of mild hypoglycaemia, however, all subjects recorded the actual number of Dextro tablets consumed and capillary glucose measurements for each episode, so this is unlikely to have been a major limitation. It also reflects ‘real world’ management of hypoglycaemia. The study population was relatively small, but similar in size to previous studies in this area. A further limitation is that there were few individuals with obese range body weights included. It is conceivable that a weight-based glucose dose may be excessive in those with morbid obesity.
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Weight-based hypoglycaemia treatment in adults with Type 1 diabetes L. McTavish et al.
Whilst this is uncommon in Type 1 diabetes, it can occur. Weight-based treatment in Type 2 diabetes may also be worth further study, but was beyond the scope of the present study. In summary, weight-based treatment of hypoglycaemia using 0.3 g/kg glucose is more effective in resolving hypoglycaemia than 15 g or 0.2 g/kg. It should be considered as part of a person’s individualized self-management education plan. All adolescents and adults with Type 1 diabetes attending a diabetes clinic should be weighed as part of their overall diabetes assessment and, as a routine, could have an individualized quantity of simple carbohydrate calculated as a recommended treatment of prospective mild to moderate hypoglycaemic events. A dose of 0.3 g/kg glucose should increase capillary glucose by 1.5 mmol/l on average, over 10 min. Initial recordings below 3.1 mmol/l may require a higher dose, but this requires further study.
Funding sources
This study was funded by grants from The New Zealand Society for the Study of Diabetes (NZSSD) 2011 Eli Lilly Diabetes Nursing Research Grant (awarded to LM), and the Wellington Medical Research Foundation.
Competing interests
None declared.
Acknowledgements
We thank the Research Assistants at the Endocrine, Diabetes & Research Centre, Wellington Regional Hospital, Wellington, New Zealand and the New Zealand Society for the Study of Diabetes for the 2011 Eli Lilly Diabetes Nursing Research Grant (awarded to L.M.), as well as the Wellington Medical Research Foundation. This study was presented in part at the International Diabetes Federation World Diabetes Congress, Melbourne, Australia. December 2013 (Abstract number ME: 0132)
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ª 2015 The Authors. Diabetic Medicine ª 2015 Diabetes UK
