Abstract

Objective To evaluate if the lowest target level for glycated haemoglobin (HbA_1c) of <6.5% is associated with lower risk for retinopathy and nephropathy than less tight control in children and adults with type 1 diabetes.

Design Population based cohort study.

Setting Swedish National Diabetes Registry, 1 January 1998 to 31 December 2017.

Participants 10 398 children and adults with type 1 diabetes followed from diagnosis, or close thereafter, until end of 2017.

Main outcome measures Relative risk (odds ratios) for retinopathy and nephropathy for different mean levels of HbA_1c.

Results Mean age of participants was 14.7 years (43.4% female), mean duration of diabetes was 1.3 years, and mean HbA_1c level was 8.0% (63.4 mmol/mol). After adjustment for age, sex, duration of diabetes, blood pressure, blood lipid levels, body mass index, and smoking, the odds ratio for mean HbA_1c <6.5% (<48 mmol/mol) compared with 6.5-6.9% (48-52 mmol/mol) for any retinopathy (simplex or worse) was 0.77 (95% confidence interval 0.56 to 1.05, P=0.10), for preproliferative diabetic retinopathy or worse was 3.29 (0.99 to 10.96, P=0.05), for proliferative diabetic retinopathy was 2.48 (0.71 to 8.62, P=0.15), for microalbuminuria or worse was 0.98 (0.60 to 1.61, P=0.95), and for macroalbuminuria was 2.47 (0.69 to 8.87, P=0.17).

Compared with HbA_1c levels 6.5-6.9%, HbA_1clevels 7.0-7.4% (53-57 mmol/mol) were associated with an increased risk of any retinopathy (1.31, 1.05 to 1.64, P=0.02) and microalbuminuria (1.55, 1.03 to 2.32, P=0.03). The risk for proliferative retinopathy (5.98, 2.10 to 17.06, P<0.001) and macroalbuminuria (3.43, 1.14 to 10.26, P=0.03) increased at HbA_1c levels >8.6% (>70 mmol/mol).

The risk for severe hypoglycaemia was increased at mean HbA_1c <6.5% compared with 6.5-6.9% (relative risk 1.34, 95% confidence interval 1.09 to 1.64, P=0.005).

Conclusions Risk of retinopathy and nephropathy did not differ at HbA_1c levels <6.5% but increased for severe hypoglycaemia compared with HbA_1c levels 6.5-6.9%. The risk for severe complications mainly occurred at HbA_1c levels >8.6%, but for milder complications was increased at HbA_1c levels >7.0%.

1. Marcus Lind, professor12,  
2. Aldina Pivodic, statistician3,  
3. Ann-Marie Svensson, associate register director14,  
4. Arndis F Ólafsdóttir, diabetes nurse12,  
5. Hans Wedel, professor5,  
6. Johnny Ludvigsson, professor67

Introduction

Type 1 diabetes is the predominant form of diabetes diagnosed in childhood and is characterised by increased blood glucose levels resulting from insulin deficiency. Treatment in developed countries generally comprises exogenous insulin by injections or insulin pump as guided by capillary testing or use of continuous glucose monitoring to estimate blood glucose levels. Intensive treatment with better glycaemic control has been shown to reduce the risk of retinopathy and nephropathy, with a strong association between glycated haemoglobin (HbA_1c) level and diabetes complications.

Multiple studies in several countries have confirmed that a higher HbA_1c level is an independent risk factor for diabetes complications.

Few studies have followed patients from diagnosis, therefore large contemporary population based studies evaluating the relation between HbA_1c levels and diabetes complications would complement earlier studies to help understand the risks of complications during modern glucose lowering treatments.

The evidence for HbA_1c levels and diabetes complications is interpreted differently by organisations such as the American Diabetes Association and International Society for Paediatric and Adolescent Diabetes, resulting in guidelines that differ between organisations and countries—current guidelines range between 6.5% (48 mmol/mol) and 7.5% (58 mmol/mol). HbA_1c targets also differ within countries for children and adults. Reaching lower HbA_1c levels requires greater effort from people with diabetes and their families and can be associated with more stress and possibly an increased risk of hypoglycaemia, which in itself can be burdensome and lead to unconsciousness. If major risk reductions of long term complications could be obtained with low HbA_1c levels this might outweigh a potentially increased risk of hypoglycaemia and the efforts needed to achieve low levels.

To understand better the relation between HbA_1c level and microvascular complications in people with type 1 diabetes, we utilised the paediatric and adult diabetes registries in Sweden. Participants were followed-up regarding retinopathy and nephropathy for 8-20 years from diagnosis.

Discussion

This study of 10 398 children and adults followed for 8-20 years from diagnosis of type 1 diabetes or shortly thereafter did not find any statistically significant differences in risk for retinopathy or nephropathy for a mean glycated haemoglobin (HbA_1c) level of <6.5% (<48 mmol/mol) compared with 6.5-6.9% (48-52 mmol/mol). Any retinopathy (defined as simplex or worse) and microalbuminuria became slightly more common at mean HbA_1c levels greater than 7.0% (53 mmol/mol), whereas increasing risk of preproliferative diabetic retinopathy (moderately severe) started at HbA_1c levels around 7.5% (58 mmol/mol). Severe complications in the form of proliferative diabetic retinopathy and macroalbuminuria first became apparent at mean HbA_1c levels >8.6% (>70 mmol/mol). Severe hypoglycaemia increased with lower HbA_1c levels and was greater at levels <6.5% (<48 mmol/mol) compared with 6.5-6.9% (48-52 mmol/mol).

Comparison with other studies

Multiple studies of HbA_1c related to diabetes complications, both microvascular and macrovascular, have been performed.12345678910 To fully understand the impact of HbA_1c levels, studies should preferentially be performed in larger populations and follow participants from childhood, when onset of type 1 diabetes generally occurs, to adulthood, when complications most often exist.3410 The Diabetes Control and Complications Trial is evaluating participants in the primary prevention cohort (n=726) from diagnosis or closely thereafter and showed the strongest relations between HbA_1c and complications in this cohort compared with the secondary intervention cohort including people with longer duration of diabetes and existing complications.1224 About half of the participants in the Diabetes Control and Complications Trial were treated with multiple dose insulin injections or insulin pumps, whereas the rest had only basal insulin. Because relatively few complications occurred at lower HbA_1c levels, however, it is difficult to distinguish between differences in risk at low HbA_1c levels, such as <6.5% (<48 mmol/mol) compared with <7.0% (<53 mmol/mol). A study that followed 451 participants from diagnosis to 20-24 years onwards found no cases of proliferative diabetic retinopathy at a mean HbA_1c level of <7.6% (<60 mmol/mol), and no participant developed macroproteinuria at HbA_1c <8.4% (<68 mmol/mol).4 The current study complements earlier studies as it is larger, population based, and includes participants who used modern glucose lowering treatments.

HbA_1c targets

Currently, HbA_1c targets vary in diabetes guidelines worldwide.11121314 In the US, the American Diabetes Association guidelines recommend an HbA_1c of <7.5% (<58 mmol/mol) for children and <7.0% (<53 mmol/mol) for adults.11 In the UK, the National Institute for Health and Care Excellence recommends <6.5% (<48 mmol/mol) for both children and adults, whereas Swedish guidelines recommend <6.5% (<48 mmol/mol) for children and <7.0% (<53 mmol/mol) for adults.1213 The International Society for Pediatric and Adolescent Diabetes has recently lowered the HbA_1c target from <7.5% (<58 mmol/mol) to <7.0% (<53 mmol/mol).14

Clinical implications

Reaching lower HbA_1c targets is associated with increased effort by people with type 1 diabetes15 and not least for carers of children with diabetes.16 Glucose levels must be checked often, insulin administered frequently, and certain things undertaken, such as following a suitable diet or ensuring physical activity. Both children and their parents often need to make substantial efforts in their daily lives, which can include overnight glucose monitoring and extra insulin doses to reach HbA_1c targets. People with type 1 diabetes can be frustrated from having to monitor the disease, and diabetes can be associated with increased stress.1516 It is therefore clinically important to know if a low HbA_1c target of <6.5% (<48 mmol/mol) can prevent microvascular complications more than a HbA_1c target of <7.0% (<53 mmol/mol).

In this study, preproliferative diabetic retinopathy or worse occurred in seven participants with a mean HbA_1c level of <6.5% (<48 mmol/mol), which was associated with an increased risk of borderline significance (P=0.05) versus an HbA_1c level of 6.5-6.9% (48-52 mmol/mol), and seven participants developed macroalbuminuria. It seems unlikely that low HbA_1c levels indicating glucose levels close to normal should be harmful in themselves; however, preclinical studies have indicated that microvascular complications might be promoted by frequent hypoglycaemia, as is possibly the case with rapid glucose fluctuations that can be related to hypoglycaemia.2526 Moreover, we observed an increased risk of severe hypoglycaemia with HbA_1c levels <6.5% (<48 mmol/mol) compared with 6.5-6.9% (48-52 mmol/mol).

Hence the current findings suggest that clinicians should be extra vigilant about ensuring people with diabetes do not spend considerable time in hypoglycaemia and that treatment is related to good quality of life at HbA_1c levels <6.5% (<48 mmol/mol) or else aim at higher levels of 6.5-6.9% (48-52 mmol/mol). The rationale being that we do not find any further reduction of risk for microvascular complications at HbA_1clevels <6.5% (<48 mmol/mol) in this large cohort compared with levels of 6.5-6.9% (48-52 mmol/mol).

Future studies

In future studies it will be important to include data based on continuous and flash glucose monitors over a long period.27 In such studies it will also be important to evaluate complementary glycaemic metrics to HbA_1c, including measures for euglycaemia, time in hypoglycaemia, and glycaemic variability.

HbA_1c levels and cardiovascular disease

When discussing at what HbA_1c levels clinicians should be aware that risk reductions exist and evidence from guidelines it is essential to also discuss relations between HbA_1c level and cardiovascular disease. In a recent study of more than 30 000 people with type 1 diabetes, risk estimates for myocardial infarction were in principle identical for those with mean HbA_1c levels <6.5% (<48 mmol/mol) compared with 6.5-7.0% (48-53 mmol/mol).9 Although information on mean level of HbA_1c was available over about nine years, a limitation was that glycaemic control further back in the patient´s history was not known in many patients, known to be crucial for future complications termed metabolic memory or legacy effects.28

HbA_1c levels and advanced microvascular complications

In the current study, complications were statistically significantly more advanced in participants with HbA_1c levels >8.6% (>70 mmol/mol)—that is, proliferative diabetic retinopathy and macroalbuminuria at 10-20 years after diagnosis. Also, the tendency was for more advanced complications to appear after 16-20 years at lower HbA_1c levels. Hence clinicians need to focus on lowering high HbA_1c levels at least to moderately increased levels in addition to targeting HbA_1c.

Exposure time and risk

The risk association between HbA_1c level and complications increased with longer follow-up, and relative risks were generally higher than earlier described.12345678 During follow-up of 16-20 years, a 1% (10 mmol/mol) increase in HbA_1c level resulted in an odds ratio of 2.87 for proliferative diabetic retinopathy and of 3.83 for macroalbuminuria. This is important for economic analyses and decision making about diabetes treatments as an essential part of health economic analyses within the specialty of diabetes is the association between HbA_1c level and risk of complications.

Future treatments

Treatments for type 1 diabetes are emerging that could influence the possibilities of reaching low HbA_1clevels with a low risk of hypoglycaemia in the future. Continuous glucose monitoring, in conjunction both with and without an insulin pump, have shown beneficial effects in reducing both HbA_1c levels and time in hypoglycaemia and is becoming more commonly used among people with type 1 diabetes.29303132Moreover, oral treatment with sodium-glucose cotransporter 2 inhibitors has shown beneficial effects in reducing HbA_1c levels without increasing the risk of hypoglycaemia when added to insulin treatment in adults with type 1 diabetes.3334 This treatment will likely soon be introduced in clinical practice. However, broad use might initially be limited owing to increased risk of diabetes ketoacidosis before it can be better understood who is at risk and how ketoacidosis can best be prevented.

Strengths and limitations of this study

The main strength of this study is follow-up of a large nationwide population from diagnosis of type 1 diabetes, with data collection up to 31 December 2017. Treatments have shifted over time and risk patterns might differ during recent decades, with more people receiving modern insulin analogues and continuous glucose monitoring known to reduce the risk of hypoglycaemia while lowering HbA_1clevels.3536 Although relatively few advanced complications occurred, the study was relatively highly powered to detect these, as shown by the narrow confidence intervals. Limitations include the decreasing number of people with longer follow-up and retrospective study design; the lack of more detailed information on hypoglycaemia, including continuous glucose monitoring results for time in hypoglycaemia; and information on insulin doses, pregnancy, and concurrent illnesses. Moreover, information on quality of life was not available. The current study did not include macrovascular endpoints since these events generally occur later in life and would require long follow-up. Microalbuminuria and macroalbuminuria evaluated here are some of the strongest risk factors for future cardiovascular risk and mortality.937 A further limitation is that we cannot exclude the influence of other renal diseases on albuminuria levels in certain cases. However, the strong risk gradients found between HbA_1c level and nephropathy indicate a high overall quality of data, and the variables have been used in multiple earlier studies based on Swedish registry data.91337

Conclusions

We found no difference in risk of retinopathy and nephropathy at HbA_1c levels <6.5% (<48 mmol/mol) but an increased risk of severe hypoglycaemia compared with levels of 6.5-6.9% (48-52 mmol/mol). Severe complications mainly occurred at HbA_1c levels >8.6% (>70 mmol/mol), whereas the risk of milder complications increased at HbA_1c levels >7.0% (>53 mmol/mol). In people with HbA_1c levels <6.5% (<48 mmol/mol), clinicians should focus on avoidance of frequent hypoglycaemia and obtaining good diabetes related quality of life, or else increase the target level to 6.5-6.9% (48-52 mmol/mol). Other measures, including time in range, time in hypoglycaemia, and variation in glycaemia will be essential complementary measures to HbA_1c in clinical practice and future studies.

What is already known on this topic

• Poor glycaemic control (high glycated haemoglobin (HbA_1c) levels) is associated with increased risk of diabetes complications
• Targets for glycaemic control in children and adults differ between developed countries
• Low HbA_1c levels could increase the risk of hypoglycaemia

What this study adds

• This study found no decreased risk of diabetic retinopathy and nephropathy associated with HbA_1clevels <6.5% (<48 mmol/mol) compared with 6.5-6.9% (48-52 mmol/mol) but an increased risk for severe hypoglycaemia—severe complications mainly occurred at HbA_1c >8.6% and milder complications increased at >7.0%
• The current findings support a general target of HbA_1c <7.0% in people with type 1 diabetes
• People who achieve HbA_1c levels <6.5% should be vigilant about not spending too much time in hypoglycaemia and achieve a good diabetes related quality of life