Höga blodsocker som barn ökar risken för tidig död som ung vuxen

INTRODUCTION

Patients with type 1 diabetes mellitus diagnosed in childhood or adolescence are at increased risk of premature death compared to the general population.1 A systematic review by Morgan et al calculated standardized mortality ratios (SMRs) in 23 studies worldwide, ranging from 0 to 8.54, covering time periods from 1970 to 2007.2 Excess mortality was less marked in more recent studies2, 3 and in countries with higher health expenditure.2 A Swedish register study between the years 1977 and 2000 found an average SMR of 2.15 in young patients with type 1 diabetes.4 A more recent Norwegian study presented an average SMR of 3.6 from 1973 to 2012 (n = 7884),5 the same as a Finnish study of childhood‐onset (<15 years) diabetes covering the period 1970 to 2007 (n = 17 306),6 and a study from northern Ireland from 1989 to 2012 calculated an average SMR of 2.96.7 In Denmark, a cohort of 720 children was followed from 1987 to 2014, rendering an SMR of 4.8, where HbA1c in 1989 was found to be the only predictor for increased risk of death.8 An Australian study following subjects until the end of 2012 presented an average SMR of 3.3, 1.7 for men and 10.1 for women (n = 1309). Death during early adulthood was significantly associated with elevated mean HbA1c level, recurrent episodes of severe hypoglycemia, and low socio‐economic status.9

Sweden, after Finland, is the country with the highest annual incidence of type 1 diabetes in the world,10, 11 in 2014 44.7/100 000 and approximately 890 children were diagnosed.12 The Swedish pediatric diabetes care is well organized and nationwide population‐based data are provided in a quality register with high ascertainment rate, enabling benchmarking of the outcome of care and follow‐up of quality improvement. In spite of this, a high proportion of children and adolescents do not achieve the national goal of metabolic control.12

Intensive treatment is known to give better metabolic control, reduced morbidity, and lower mortality.13-15 An increasing number of studies illustrate the importance of good glycemic control early in the course of disease, in order to avoid future morbidity.16-19

Lind et al have shown an excess risk of death from any cause for adult Swedish patients with type 1 diabetes; a doubled risk even with good glycemic control, ≤ 52 mmol/mol (6.9%), and an almost 10 times higher mortality risk with a mean HbA1c above 83 mmol/mol (9.7%). Adults ≤34 years of age had an increased risk of premature death, and diabetic ketoacidosis and hypoglycemia contributed to 31.4% of this risk.20 It is not known how these subjects presented at onset, and what kind of metabolic control they experienced during childhood.

As type 1 diabetes is a common pediatric disease, with high mortality rates, it is important to increase the knowledge regarding mortality, and its risk factors in type 1 diabetes. The impact of metabolic control in childhood and adolescence on future mortality has not been well studied, and never using a nationwide population‐based pediatric quality register.

The aim of the present study was to calculate mortality rates in young persons (≤ 29 years) in Sweden, with type 1 diabetes diagnosed <18 years of age, and to study metabolic control in childhood related to cause of death.

4 DISCUSSION

In this nationwide, population‐based cohort of 12 652 young subjects with type 1 diabetes, there was a significantly higher mortality rate than in the general population. A high proportion of deaths were directly related to diabetes.

The subjects in this study were all younger than 30 years of age, and there was a remarkably increased risk of dying registered as being due to diabetes in those with poor metabolic control during childhood. Almost all diabetes‐related deaths were caused by acute and not micro‐ or macrovascular complications. As the cohort was young this is not surprising, and similar results have been shown in Norway by Gagnum et al.26 In 22 persons (32%), the cause of death was acute diabetes coma (hypo and hyperglycemic). HbA1c was significantly higher in those for whom diabetes was the immediate cause of death, compared to death from other causes, or compared to subjects still alive. This was true both regarding last registered HbA1c before referral to adult care, or before death, and mean HbA1c during childhood. Children with earlier onset year did not have an increased risk of premature death. However the study period is short. Guidelines regarding the treatment of type 1 diabetes are constantly being updated and the treatment of the disease has improved. The introduction of insulin pumps and Continuous Glucose Monitoring (CGM) systems might further contribute to decreased mortality rates. Today, a high percentage of Swedish children with diabetes have a CGM system attached to their body, and future studies are needed to evaluate the effect of CGM on the risk of acute death.

Most deaths occur after referral to adult diabetes care, which is why this might be a problem that is overlooked by the pediatric diabetes team. The transition to adult diabetes care is a sensitive period. There is need for a well‐structured transition care and it is important not to lose subjects from follow up.27 It must be emphasized that health professionals treating and supporting children and adolescents are aware of the importance of good metabolic control during childhood to reduce the risk of death in young patients with type 1 diabetes.

In a study of Swedish adults with type 1 diabetes Lind et al have shown an increased risk of premature death, clearly increasing with increasing HbA1c in adulthood.20 However, studies also including data regarding metabolic control during childhood are few. In an Australian cohort of 1309 subjects, Cooper et al have shown an association between increased HbA1c in childhood and death in early adulthood.9 Our results are in line with this. Furthermore, in some earlier studies, both the SWE, and the NDR (National Diabetes Register; the Swedish database for adults with diabetes) have shown that good metabolic control during childhood/adolescence reduced future morbidity.17, 19 This linkage of the two registries could also show that poor metabolic control during childhood/adolescence could not be compensated for with good metabolic control during early adulthood.19 Moreover, teenage girls with poor metabolic control face more complications in early adulthood than teenage boys.28However, we found no differences in the distribution between sex and cause of death. In absolute numbers, deaths were evenly distributed between males and females. When calculating SMRs, females with type 1 diabetes have an increased risk of death compared to the general population. In this material, this cannot be explained by worse metabolic control in females. Mostly, it is due to our finding that before 20 years of age the mortality rate in males with diabetes is almost equal to the mortality rate in males in the general population. We found no significant sex difference regarding HbA1c in those deceased, but this might be because there were few deaths.

As has been shown by Rawshani et al, age at diagnosis is an important risk factor for premature death, most emphasized in cardiovascular cause of death, raising the question whether cardioprotective medication should be considered earlier than in current practice.29 Our results compliment the picture as data regarding metabolic control in childhood were not available neither in the study by Rawshani et al or in the study by Lind et al.20, 29 As well as considering cardiovascular medication in young adults, efforts aimed to keep a low HbA1c during childhood is essential to increase survival.

A strength of the present study is the use of a register with very good coverage and completeness, and the access to data regarding HbA1c in childhood. However, as with all registry studies, data is based on registry information and relies on correct information being entered into the registry.

A weakness of the present study is the classification of deaths based only on ICD codes from the CDR. ICD codes do not differentiate hypoglycemic coma from hyperglycemic coma (ketoacidosis). There is a need for future studies where medical records are reviewed in order to achieve a more accurate classification. Robust data regarding death from hypoglycemia and ketoacidosis would be clinically interesting. In six cases, the immediate cause of death was accident. One can speculate on whether some of these were in fact suicides or hypoglycemic events. However, we found no increase of SMR regarding accidents, and the same was true for suicides and poisoning. Socioeconomic factors and their association to poor metabolic control in childhood and subsequent mortality need further research. The present study does not include data on adult glycemic control. Future similar studies should include adult HbA1c data in order to control for the impact of glycemic control in adulthood and assess the time‐dependent HbA1c related risk for mortality.

In conclusion, we have found an increased mortality in young subjects with type 1 diabetes, compared to the general population in Sweden. Female SMRs were higher than males. The SMRs increase with age. Mean HbA1c in childhood was significantly increased in those who died from diabetes‐related causes, mainly due to acute complications. To achieve and maintain good metabolic control in childhood and adolescence are one of the most essential and important factors to reduce the risk of acute death in young persons with type 1 diabetes.

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