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HbA1c level as a risk factor for retinopathy and nephropathy in children and adults with type 1 diabetes: Swedish population based cohort study

BMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l4894 (Published 28 August 2019) Cite this as: BMJ 2019;366:l4894

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No evidence for a change of the current HbA1c target level of ≤ 6.5% (48 mmol/mol) in children and adolescents with diabetes in Sweden and UK

We read with interest the article by Lind et al (1), interpreted by JDRF UK as ”Importantly, people with an HbA1c 6.5% or lower were also at an increased risk of severe hypoglycaemia (SH) and of developing severe retinopathy“ (2). However, Lind writes that they do not find any further reduction in microvascular complications risk at HbA1c levels <6.5% (<48 mmol/mol). This is in contrast DCCT/EDIC findings where there were still meaningful further reductions in risk as HbA1c was reduced toward the normal range (3, 4). The Lind study has more patients while the DCCT/EDIC study has a background in an extensive randomized study with a predefined selection of patients. In the Lind paper, individual clinicians have defined the type 1 diagnosis without detailed criteria. Persons with HbA1cAUC down to 4.8-5.3% (29-34 mmol/mol) were included. This indicates a non-type 1 diabetes diagnosis in lack of more specific documentation.

In fact, there may be other explanations for the finding of severe eye and kidney complications in patients with up to 10-11 years diabetes duration in the Lind study. Early worsening of retinopathy with improved control was seen in the DCCT (5). Severe retinopathy at HbA1c <48 mmol/l (6.5%) was in the Lind study present only in the groups with the shortest diabetes durations, which is remarkable and needs to be verified by medical records. A J-formed association between HbA1c-levels and complications could be explained by remaining confounding factors related to coexisting medical conditions. A total lack of severe retinopathy in the groups with 12-13 and 14-15 years duration both with HbA1c 6.5-7.0% (48-52 mmol/mol) and <6.5% (<48 mmol/mol) in Suppl Table 2.1 can be interpreted as a reversing of these complications by continued good metabolic control.

The follow-ups of both the DCCT (3) and the Lind paper are too short to give a long-term prognosis. In the 30-year DCCT/EDIC follow-up, proliferative retinopathy developed after in average 22 years (6). Our children and adolescents with diabetes have a much longer life-span awaiting them. The Swedish VISS-study that Lind refers to had 20-24 years follow-up and no patient with an average HbA1c <7.6% (<60 mmol/mol) developed proliferative retinopathy, but almost half of those with HbA1c <6.7% (<50 mmol/mol) had simplex retinopathy (7). With a continued HbA1c of 7.5% (58 mmol/mol), the risk of proliferative retinopathy within 5 years would be 2.5% according to EDIC (4) and with 8.0% (64 mmol/mol) increases to 3.5%, i.e. not negligible in a life-long perspective.

The Lind analysis of SH was done in patients from the Swedish childhood registry (SWEDIABKIDS), i.e. below age 18, while the 12 patients with HbA1c <6.5% and severe complications had a mean age of 20.2 (proliferative retinopathy) and 22.7 years (macroalbuminuria), i.e. were largely not from the same cohort. The total number of patient years for SH is 13,413 in Lind, a very low number for the period of 2008-2017. With more than 7,000 children and adolescents with diabetes in Sweden, the total number of patient years approximates 70,000 over 10 years. This indicates that the Lind data only covers approximately 20% of the pediatric population, which hardly is representative to draw conclusions on changing HbA1c targets from. The frequency of SH in SWEDIABKIDS has been stable around 3% since 2009 in spite of a considerable drop in HbA1c from 63.4 to 54.8 mmol/mol (7.9 to 7.2%) during this period (8, 9), yet Lind finds a SH rate of 10.3%.

The Nordic Registry study, including data from 2008 to 2012 with 8,806 patients and 29,715 patient years, 16,901 from Sweden (10), found the lowest risk of SH in the group with an HbA1c of ≤6.7% (≤50 mmol/mol), however not significant when controlled for gender, age and diabetes duration and a trend of higher risk of SH with higher HbA1c, i.e. the opposite results of the Lind et al study although both included data from SWEDIABKIDS during the same time period. We thus question the validity of the Lind results on an increase in SH in the low HbA1c segment. A study on SH in Germany, Austria, USA and Australia including 26,854 patients did not find an increase in SH at HbA1c <7.0% (<53 mmol/mol) (11).

Since children with diabetes inevitably will have their condition for a longer time compared to those diagnosed as adults, we strongly emphasize keeping HbA1c at a level that will minimize long-term complications according to the data of EDIC, the longest available follow-up study. Data from SWEDIABKIDS and other Nordic countries show that this can be achieved without an increase in SH. Families should not be discouraged when their children have an HbA1c <6.5% (<48 mmol/mol) when life quality is uncompromised with a low frequency of glucose readings <4 mmol/l (<72 mg/dl). CGM helps to make this possible in a growing number of children. According to SWEDIABKIDS, currently 95% of children and adolescents are using CGM, and 34% have an HbA1c of 48 mmol/l or lower (6.5%) (9). ISPAD recently lowered their recommended HbA1c target to <7.0% (< 53 mmol/mol) (12), adding: “A lower goal of 6.5% or 48 mmol/mol may be appropriate if achievable without excessive hypoglycemia, impairment of quality of life, and undue burden of care” (12).

In conclusion, we appreciate that Lind has taken on the important task of investigating the risk of complications risk at low HbA1c levels, but since the EDIC follow-up of the DCCT study finds lower complication rates at <6.5% compared to 6.5-6.9% (<48 and 48-52 mmol/mol) and the rate of SH in other studies from several countries is not increased at these HbA1c levels, we most convincingly do not find any arguments for a change of the current target level of ≤6.5% (≤48 mmol/mol) for children and adolescents in Sweden and UK.

Naturally, the individual HbA1c target needs to be individualized in each family with consideration taken to any current hypoglycaemia problems. The diabetes team should personalize the diabetes care and help families to make the best possible adjustment of each child’s health and life quality both in the short and long term.

References
1. Lind M, Pivodic A, Svensson AM, Olafsdottir AF, Wedel H, Ludvigsson J. HbA1c level as a risk factor for retinopathy and nephropathy in children and adults with type 1 diabetes: Swedish population based cohort study. BMJ. 2019;366:l4894.
2. . https://jdrforguk/news/hba1c-minimise-risks-type-1/.
3. DCCT Research Group. The absence of a glycemic threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial. Diabetes. 1996;45(10):1289–98.
4. Nathan DM, Bebu I, Hainsworth D, Klein R, Tamborlane W, Lorenzi G, et al. Frequency of Evidence-Based Screening for Retinopathy in Type 1 Diabetes. N Engl J Med. 2017;376(16):1507-16.
5. DCCT Research Group. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Archives of Ophthalmology. 1998;116(7):874–86.
6. Hainsworth DP, Bebu I, Aiello LP, Sivitz W, Gubitosi-Klug R, Malone J, et al. Risk Factors for Retinopathy in Type 1 Diabetes: The DCCT/EDIC Study. Diabetes Care. 2019;42:875-82.
7. Nordwall M, Abrahamsson M, Dhir M, Fredrikson M, Ludvigsson J, Arnqvist HJ. Impact of HbA1c, followed from onset of type 1 diabetes, on the development of severe retinopathy and nephropathy: the VISS Study (Vascular Diabetic Complications in Southeast Sweden). Diabetes Care. 2015;38(2):308-15.
8. Samuelsson U, Gudbjörnsdottir S, Hanberger L, Pundziute-Lycka A, Åkesson Elfvin K, Örtqvist E, et al. Data from the Swedish National Paediatric Diabetes Registry (SWEDIABKIDS). 2013. https://www.ndr.nu/pdfs/Arsrapport_Swediabkids_2013.pdf
9. Åkesson K, Eriksson E, Fureman A, Gudbjornsdottir S, Hanberger L, Pundziute-Lycka A, et al. SWEDIABKIDS yearly report 2018. https://www.ndr.nu/pdfs/Arsrapport_Swediabkids_2018.pdf
10. Birkebaek NH, Drivvoll AK, Aakeson K, Bjarnason R, Johansen A, Samuelsson U, et al. Incidence of severe hypoglycemia in children with type 1 diabetes in the Nordic countries in the period 2008-2012: association with hemoglobin A 1c and treatment modality. BMJ open diabetes research & care. 2017;5(1):e000377.
11. Haynes A, Hermann JM, Miller KM, Hofer SE, Jones TW, Beck RW, et al. Severe hypoglycemia rates are not associated with HbA1c: a cross-sectional analysis of 3 contemporary pediatric diabetes registry databases. Pediatr Diabetes. 2017;18(7):643-50.
12. DiMeglio LA, Acerini CL, Codner E, Craig ME, Hofer SE, Pillay K, et al. ISPAD Clinical Practice Consensus Guidelines 2018: Glycemic control targets and glucose monitoring for children, adolescents, and young adults with diabetes. Pediatr Diabetes.
2018;19 Suppl 27:105-14.

Corresponding author: Ragnar Hanas, MD, PhD, Department of Pediatrics, NU Hospital Group, 45180 Uddevalla, Sweden, ragnar.hanas@vgregion.se

Competing interests: No competing interests

27 November 2019
Ragnar Hanas
MD, PhD
Niels H Birkebaek5, Annelie Carlsson3,6, Gun Forsander 2,3,7, Anna-Lena Fureman3,4,8, Lena Hanberger4,9, Anna Olivecrona3,10,11, Eva Örtqvist3,4,12, Auste Pundziute-Lyckå4,7, Frida Sundberg2,7, Stefan Särnblad3,4,10,11, Fiona Campbell13, Karin Åkesson3,4,14, Ulf Samuelsson4,15 1Department of Pediatrics, NU Hospital Group, Uddevalla, Sweden 2Gothenburg University, Sahlgrenska Academy, Institute of Clinical Sciences, Gothenburg, Sweden. 3The Swedish Reference Group for National Guidelines 4The steering Committee of Swedish National Pediatric Diabetes Registry (SWEDIABKIDS) 5 Department of Pediatrics and Steno Diabetes Center Aarhus, Aarhus University Hospital, Denmark 6Department of Clinical Sciences, SUS, University Hospital, Lund University, Lund, Sweden 7The Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden 8Department of Pediatrics, Östersund Hospital, Sweden 9Division of Nursing, Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden 10School of Medical Sciences, Örebro University, Örebro, Sweden 11Department of Pediatrics, Örebro University Hospital, Örebro, Sweden 12Division of Pediatrics, Astrid Lindgrens Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden 13Children’s Diabetes Centre, St James’s University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK 14Department of Clinical and Experimental Medicine, Linköping University, Linköping, and Department of Pediatrics, Jönköping, Region Jönköping County, Sweden 15Division of Pediatrics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
1Department of Pediatrics, NU Hospital Group, Uddevalla, Sweden 2Gothenburg University, Sahlgrenska Academy, Institute of Clinical Sciences, Gothenburg, Sweden. 3The Swedish Reference Group for National Guidelines 4The Steering Committee of Swedish National Pediatric Diabetes Registry (SWEDIABKIDS)
Dept Paediatrics, NU Hospital Group, 45180 Uddevalla, Sweden