Type 1 diabetes mellitus affects thousands of children, and causes high sugar levels because of low insulin production. In places with good access to medical care, blood glucose is first measured by capillary blood testing or continuous monitoring. Insulin is given as required by subcutaneous injection or insulin pump.
Doctors have long recommended intensive control of blood sugar to reduce the frequency of complications. However, a new study reveals that somewhat less keeping blood glucose at moderate levels is just as useful, while being much less burdensome.
A new study looked at the association between blood glucose levels and risks of organ impairment in people with type 1 diabetes. The study titled 'HbA1c level as a risk factor for retinopathy and nephropathy in children and adults with type 1 diabetes: Swedish population based cohort study', is published in the current issue of the BMJ (British Medical Journal).
Diabetic measuring level of glucose in the blood. Image Credit: Goffkein.pro / Shutterstock
Researcher Marcus Lind says, “We were unable to see that fewer instances of organ damage occurred at these lower levels. As for loss of consciousness and cramp, which are unusual, low blood glucose caused a 30 percent rise in risk. Patients with low HbA1c need to make sure they don't have excessively low glucose levels, fluctuations or efforts in managing their diabetes.”
Typically, glycated hemoglobin (HbA1C) is the risk factor measured since it shows average blood glucose level over a period of weeks rather than days. However, studies validating different HbA1C levels dating from the time of diagnosis are lacking. Secondly, the recommended HbA1C remains a somewhat controversial issue, with different guidelines being established by different expert bodies such as the American Diabetes Association and the International Society for Pediatric and Adolescent Diabetes.
Patients also find it more difficult to maintain very low HbA1C levels, which may induce more frustration and diabetes distress, and could lead to a higher number of potentially dangerous hypoglycemic episodes. Another researcher, Johnny Ludvigsson, explains: “Attaining a low HbA1c value may, in some cases, require children to be woken up several times a night, plus extra glucose monitoring and strict attention to diet and physical activity day after day, which can be extremely burdensome.”
Thus the question is whether intensive control of HbA1C is relevant in long-term reduction of complication risk. The current study set out to explore the link between HbA1C and microvascular complications in adults and children with T1DM, from the time of diagnosis. This will help determine whether a particular intervention is cost-effective.
How was the study performed?
The data for this study came from the combined Swedish medical registry for adults and children, which has details on more than 95% of T1DM patients in this country. All children and adults who had diabetes for five or less years were included, for a total of almost 10 400 patients. The average age was about 15 years, and about 43% were females. The patients were followed up for 8-20 years, depending on their registry entry date, and the date when an endpoint occurred or they ceased to be a part of the study.
The following outcomes were taken as endpoints:
- Any retinopathy (simplex, preproliferative or proliferative)
- Preproliferative diabetic retinopathy or worse
- Proliferative retinopathy (proliferative vessels or previously performed laser photocoagulation)
- Microalbuminuria: albumin:creatinine ratio of 3-30 mg/mmol or albumin of 20-200 µg/min (20-300 mg/L)
- Macroalbuminuria : albumin:creatinine ratio >30 mg/mmol or urinary albumin >200 µg/min (>300 mg/L)
What did the study show?
About 33% of these patients developed retinopathy of any severity. About 3% and 1% showed preproliferative and proliferative retinopathy respectively.
Risk in relation to HbA1C
The chances of any retinopathy were no different with strict control (HbA1C below 6.5%) compared with a level of 6.5% to 6.9%. However, the risk began to rise with an HbA1C above 7% to 7.4%. The highest risk was at above 7.5%, similar to the risk with preproliferative retinopathy. Proliferative retinopathy was most common with HbA1C above 8.6%. More severe complications were also observed to occur at increased rates with HbA1C below 6.5%, paradoxically.
That is, HbA1C below 6.5% did not reduce the risk of complications but increased the risk of severe hypoglycemia by 30%.
With respect to kidney damage, microalbuminuria and macroalbuminuria occurred in about 8% and 1.5% of patients respectively. Here again, there was no difference in the risk between HbA1C <6.5% and the next higher category. The microalbuminuria risk went up 1.5 times and 2.6 times, at HbA1C above 7% and 8.6% respectively.
Meanwhile, macroalbuminuria risk was 3.4 times greater at levels above 8.6%.
Risk in relation to HbA1C levels over time
For each 1% increase in HbA1C the risk of diabetic complications increased over time. The overall retinopathy risk increased only slightly over follow-up periods of 8-10 years and 10-20 years respectively. However, more severe complications like proliferative retinopathy increased three-fold at 8-10 years follow-up but the risk was more than doubled by 16-20 years. Severe retinopathy occurred at lower HbA1C levels over time, indicating the need to bring down HbA1C levels to at least moderately increased levels.
With each 1% increase in HbA1C, microalbuminuria risk doubled at 16-20 years follow-up compared to 8-10 years, while the risk of macroalbuminuria more than tripled.
Risk in relation to age and sex
T1DM patients who were older when first registered had increased risk for any complication with each five years delay; the risk of severity increased with the length of delay. The risk of kidney damage, but not retinopathy, was higher for females (1.3 to 1.5 times).
What do we learn?
Overall, the study indicates that it is not worthwhile to stress out patients over keeping the HbA1C below 6.5% in the absence of any meaningful risk reduction at this level compared to a target of 7%. On the other hand, it does increase the risk of severe hypoglycemic episodes, which could cause significant fluctuations in the blood glucose levels. This in turn might underlie the borderline increase in risk of microvascular complications at such low (near-normal) levels.
Another study has shown no risk reduction for cardiovascular disease with this level of HbA1C compared with below 6.5%, with data ranging back for 9 years. This does not take into account the still earlier control of blood glucose or the lack of it, which is known to exert a metabolic memory, leaving a metabolic legacy in terms of diabetic complications.
Therefore, the take home is that patients with T2DM should be reminded to avoid hypoglycemia. Secondly, the intensity of treatment should be related to improved quality of life and not only biochemical parameters. If an HbA1C of <6.5% is linked to improved health and performance, and reasonably easy to achieve without undue stress, it should be aimed at, but otherwise, a level between 6.5% and 6.9% should be the target.
Future promising treatments include continuous glucose monitoring with insulin pump where required, as well as initiation of cotreatment with drugs that inhibit sodium-glucose cotransporter 2, which increase HbA1C control without inducing hypoglycemia.
HbA1c level as a risk factor for retinopathy and nephropathy in children and adults with type 1 diabetes: Swedish population based cohort study. Marcus Lind, Aldina Pivodic, Ann-Marie Svensson, Arndis F Ólafsdóttir, Hans Wedel, & Johnny Ludvigsson. British Medical Journal 2019; 366 https://doi.org/10.1136/bmj.l4894. https://www.bmj.com/content/366/bmj.l4894