Insulin degludec, type 1 diabetes and exercise
While physical exercise is good for people with type 1 diabetes, it does carry a risk of hypoglycaemia, which is why it may be necessary to reduce insulin doses afterwards. However, the ADREM (Adjustment of insulin Degludec to Reduce post-Exercise (nocturnal) hypoglycaeMia in people with diabetes) study, reported in a recent issue of Diabetologia, finds that no adjustment in the dose of insulin degludec is needed following a bout of aerobic exercise. Dr Susan Aldridge reports.
Regular physical exercise is recommended for people with type 1 diabetes because it has beneficial effects on general wellbeing and cardiometabolic health. However, there is an increased risk of hypoglycaemia with aerobic exercise because it reduces insulin requirements. This occurs because muscle glycogen storage needs to be replenished after exercise, which leads to increased insulin sensitivity and glucose disposal. These effects usually peak seven to 11 hours after exercise, but they can last for up to 24 hours. A hypo is therefore more likely to occur, particularly at night and especially after afternoon or evening activity. The risk can be even more pronounced among those with impaired awareness of hypoglycaemia.
The prospect of nocturnal hypoglycaemia may deter people with type 1 diabetes from engaging in sporting activity, thereby missing out on the benefits. Reducing the dose of first-generation, long-acting insulins after exercise, whether delivered by injection or pump, can prevent exercise-induced nocturnal hypoglycaemia, as can reducing the basal rates of insulin pumps. A reduction of 20% is often recommended post-exercise.
Insulin degludec is a second-generation, long-acting insulin analogue that has a much longer half-life than other long-acting insulins, resulting in a more stable glucose-lowering profile and longer duration of action. Its use has been associated with reduced risk of hypoglycaemia, particularly nocturnal hypoglycaemia. Its longer insulin half-life must be taken into account when looking at dosing adjustments around exercise. One study found that a 25% dose reduction in insulin degludec did not reduce hypoglycaemia risk during five days of consecutive exercise in people with type 1 diabetes, but there were only seven participants. We therefore don’t yet know what recommendation to make for dose reduction of insulin degludec in people with type 1 diabetes who want to do aerobic exercise.
That’s why Linda Drenthan of Radboud University Medical Centre, Nijmegen, The Netherlands, and colleagues carried out a new study comparing the effects of two different degludec doses with no dose adjustment on the incidence of nocturnal hypoglycaemia and glucose profiles after aerobic exercise among people with type 1 diabetes who were at elevated risk of hypoglycaemia.
The ADREM study
The ADREM study was an open-label, randomised controlled study. There were 18 participants who had a history of at least one severe hypo in the last year or who had been diagnosed with hypoglycaemia unawareness. After a screening visit, a cycling exercise test of 45 minutes was planned that would take them to 70% of their heart rate reserve, thereby serving as a measure of the impact of aerobic exercise on their glucose profile. They were then assigned to one of three insulin regimens post-exercise: no adjustment of insulin degludec (CON), reduction of 40% (D40) and reduction of 20% (D20-P).
For the first two, the dose was to be taken at 23:00 on the exercise day, with the exercise itself being carried out at 18:00, while for the 20% reduction group, the dose was to be taken with an eight-hour postponement at 07:00 the next day. For D40, the usual 20% dose reduction of a long-acting insulin was doubled to take account of the longer half-life of degludec. Meanwhile, the postponement in the D20-P regimen accounts for the fall in insulin levels of around 16% overnight.
This was a crossover trial with six potential treatment sequences and these were distributed among the participants. Continuous glucose monitoring (CGM) was started between 15:30 and 16:30 on an exercise day and continued for six days after the exercise day, and various other blood tests were also carried out. Day one was the first exercise day and exercise was repeated on day 15 and day 29.
On the exercise day, participants had lunch at home, with a 50% decrease in their usual short-acting insulin dose to prevent hypoglycaemia before and during their exercise test. After the test and before going home, they ate a standardised meal with a 25% reduction in their short-acting insulin dose. Thereafter, they did not eat until the next day unless they needed to because of hypoglycaemia.
The primary outcome was time below range (TBR) in the night after the exercise test. Time above range(TAR), time in range (TIR), mean glucose and the number of hypos were also measured, both during the first and second days after the exercise test and for the six days afterwards. Participants not already on degludec were transferred to it for the purposes of the trial.
Glucose profiles after exercise
TBR was generally low during the night following the exercise session and did not differ significantly between the three treatment regimens. During the day following the exercise test, TBR was lower for D40 than for CON, but the number of hypoglycaemic events was similar. During the second whole day, D20-P was associated with more TBR and more hypoglycaemic events than the D40 regime, but neither differed significantly from the CON regime.
No differences in TBR and hypoglycaemic events were found between the three treatment regimens during the total six days after the exercise test. Finally, no severe hypos occurred during the entire study period.
When it came to TAR, there were no differences between the three regimens during the night after the exercise test, but the D20-P regimen led to significantly more TAR during the day after the test compared with the two other regimens. These differences were ironed out later, though, because there were no TAR differences between the three regimens during the second day after exercise, nor for the total six-day period.
Finally, TIR is, of course, always of interest to those using CGM. During the night after the exercise test, D20-P was associated with less TIR compared with D40, but neither differed significantly from CON. And the day after the exercise test, D20-P was associated with significantly less TIR than D40 and CON. There were no differences in TIR between treatment regimens during the second day, nor for the whole six-day study period.
Insulin degludec and exercise
To summarise the above findings, it seems that adjustment of insulin degludec dosing after aerobic exercise performed in the afternoon had no impact on the incidence of nocturnal hypoglycaemia in people with type 1 diabetes.
Reducing it by 40% does slightly reduce TBR the next day, but this did not translate into fewer hypoglycaemic events. Meanwhile, postponement of degludec to the next morning at a 20% lower dose led to more TAR and less TIR the next day and slightly more TBR on the second day. The authors conclude that these results do not support dose adjustments of insulin degludec in people with type 1 diabetes following exercise.
Two recent studies have reported a relatively low incidence of nocturnal hypoglycaemia after aerobic exercise in people with type 1 diabetes who were using insulin degludec. This new study adds to the evidence showing that this also applies to those who are at higher risk of hypoglycaemia. The authors believe that strict adherence to the need to reduce short-acting insulin at the post-exercise meal was a crucial factor in their results. Although this wouldn’t be sufficient for people on first-generation, long-acting insulins, it may be that reducing meal-related, short-acting insulin after evening exercise could reduce the risk of nocturnal hypoglycaemia in people with type 1 diabetes on insulin degludec.
An earlier study did report that insulin glargine and insulin degludec have a similar nocturnal hypoglycaemic risk profile in people with type 1 diabetes after performing moderate-intensity aerobic exercise without needing to reduce the insulin dose. In that study, those with a high risk of hypoglycaemia were excluded and the participants injected their long-acting insulin in the morning. Since insulin glargine has its strongest glucose-lowering effect during the first 12 hours after injection, it is plausible that a higher number of nocturnal hypoglycaemic events might occur for those injecting this type of insulin in the evening, as is still common practice.
The strengths of this study lie in its randomised crossover design, the robust exercise protocol, the use of CGM and the everyday life setting. However, the findings might not be generalised to people performing morning exercise or injecting their insulin degludec in the morning. However, research has shown that morning exercise leads to a lower risk of nocturnal hypoglycaemia compared with afternoon exercise, at least for people on pump therapy. Therefore, it’s likely that morning exercise can also be performed safely without adjusting the dose of insulin degludec.
In conclusion, reducing the dose of insulin degludec after afternoon exercise has no effect on the risk of subsequent nocturnal hypoglycaemia in people with type 1 diabetes. Adjustments in meal-related, short-acting insulin before and after exercise may be a good idea for people using insulin degludec, but this study does not support adjusting the dose of insulin degludec after exercise. This is good news for people with type 1 diabetes because it’s one less thing to think about when undertaking physical activity.
To read this paper, go to: Drenthen LCA, Ajie M, Abbink EJ, Rodwell L, Thijssen DHJ, Tack CJ, de Galan BE. No insulin degludec dose adjustment required after aerobic exercise for people with type 1 diabetes: the ADREM study. Diabetologia online 7 March 2023. https://doi.org/10.1007/s00125-023-05893-9
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Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.