Comparison of Insulin Glargine 300 U/mL and Insulin Degludec 100 U/mL Around Spontaneous Exercise Sessions in Adults with Type 1 Diabetes: A Randomized Cross-Over Trial (ULTRAFLEXI-1 Study)

Abstract

Aims:

In the ULTRAFLEXI-1 study, we compared basal insulin Glargine 300 U/mL (IGlar U300) and insulin Degludec 100 U/mL (IDeg U100) for time below range <70 mg/dL (TBR^<70; 3.9 mmol/L) in two different doses (100% and 75% of the regular dose) when used around spontaneous exercise sessions in adults with type 1 diabetes.

Methods:

A randomized, single-center, four-period, cross-over trial was performed and in each of the four 2-weeks-periods, participants attended six spontaneous 60 min moderate-intensity evening cycle ergometer exercise sessions. The basal insulin administered on the exercise days were IGlar U300 100% or 75% of the regular dose or IDeg U100 100% or 75%, respectively (morning injection). The primary outcome was the TBR^<70 during the 24 h postexercise periods of the six spontaneous exercise sessions in the four trial arms and was analyzed in hierarchical order using the repeated measures linear mixed model.

Results:

Twenty-five people with type 1 diabetes were enrolled (14 males) with a mean age of 41.4 ± 11.9 years and an HbA_1c of 7.5% ± 0.8% (59 ± 9 mmol/mol). The mean ± standard error of mean TBR^<70 during the 24 h periods following the exercise sessions was 2.71% ± 0.51% for IGlar U300 (100%) and 4.37% ± 0.69% for IDeg U100 (100%) (P = 0.023) as well as 2.28% ± 0.53% for IGlar U300 and 2.55% ± 0.58% for IDeg U100 when using a 75% dose on exercise days (P = 0.720). Time in glucose range^70–180 was the highest in the IDeg U100 (100%) group.

Conclusions:

TBR^<70 within the first 24 h after spontaneous exercise sessions was significantly lower when receiving IGlar U300 compared to IDeg U100 when a regular basal dose was administered.

Introduction

Physical activity and regular exercise are cornerstones of modern diabetes management, contributing to improved glycemic control, less glycemic variability, and a reduced amount of exogenous insulin.^1
–3 Taking these positive aspects of being physically active into account, it is astonishing that people with type 1 diabetes are reluctant to regular physical activity and exercise.⁴ Barriers to physical activity are multifaceted, however, the major obstacle of being physically active is fear of hypoglycemia.⁵ Different therapy strategies have been identified to reduce the risk of hypoglycemia^1,2 and increase the time in glucose range 70–180 mg/dL (TIR^70–180; 3.9–10.0 mmol/L) around exercise.³ Strategies to lower the risk of hypoglycemia include reducing the prandial insulin dose⁶ and/or consuming exercise-carbohydrates.⁷

Besides these acute therapy manipulations for exercise, basal insulin dose reduction strategies were investigated by a few studies only.^8,9 For instance, in a study by Campbell et al., reducing insulin Glargine 100 U/mL (IGlar U100) by 20% yielded protection from hypoglycemia during and for 24 h following evening exercise sessions without negatively affecting TIR^70–180.⁸

Besides the potency of avoiding exercise-induced hypoglycemia by modifying insulin doses, 2nd generation basal insulins such as insulin Glargine 300 U/mL (IGlar U300) and insulin Degludec 100 U/mL (IDeg U100) might provide the opportunity to further reduce the risk of dysglycemia. In previous trials performed in people with type 1 diabetes, IGlar U300 demonstrated noninferiority versus IGlar U100 for glycemic control (HbA_1c).^10
–12 Also, a meta-analysis demonstrated a reduction in nocturnal hypoglycemic events with IGlar U300 compared to IGlar U100 in type 1 diabetes.¹³ Likewise, IDeg U100¹⁴ was demonstrated to lower the risk for nocturnal hypoglycemic events when compared to IGlar U100 due to its pharmacokinetic and pharmacodynamic properties.^15
–17 Even more interesting to health care professionals and people with diabetes was how IDeg U100 and IGlar U300 compare directly against each other.

In a first head-to-head study, the primary endpoint was defined as the day-to-day variability of the area under the glucose infusion rate curves over a treatment interval of 24 h in comparison of IGlar U300 and IDeg U100.¹⁸ This endpoint and the day-to-day variability in other pharmacodynamic parameters were lower for IDeg U100 than with IGlar U300. In a second study,¹⁹ it was found that IGlar U300 provided less fluctuating pharmacodynamic profiles compared with IDeg U100 in a once-daily morning dosing regimen. Two large head-to-head clinical trials, comparing both insulins for glucose lowering potential and risk of hypoglycemia, demonstrated no significant difference in the number of overall symptomatic hypoglycemic events.^20,21

As every physical activity and exercise session bears an additional hypoglycemic risk, a thorough exploration of this setting is warranted. Hence, in a study by Heise et al., changes in blood glucose and risk of hypoglycemia during and after moderate-intensity exercise were compared in adults with type 1 diabetes treated with IDeg U100 or IGlar U100.²² In this study, they found that people with type 1 diabetes treated with multiple daily injections (MDI), exercise-induced risk of hypoglycemia was low with IDeg U100 while similar to IGlar U100. In addition, we recently showed that a 25% reduction of the regular IDeg U100 dose around moderate-intensity exercise significantly improved TIR.^23,70–180, However, in this study a head-to-head comparison to another basal insulin was not performed and the exercise sessions were performed over five consecutive days.

Since often people are exercising in the evening²⁴ and these exercise sessions are often performed spontaneously due to work and/or weather conditions, there is a need to investigate which 2nd generation basal insulin can be best integrated in a flexible and physically active lifestyle accompanied with the lowest risk of hypoglycemia. This information is crucial for people living with type 1 diabetes and their health care providers striving to increase physical activity and regular exercise. In light of this, the aim of the present study was to compare time below range (TBR)^<70 among other glycemic outcomes around multiple spontaneous exercise sessions on either a regular (100%) or reduced (75%) dose of IGlar U300 or IDeg U100 in adults with type 1 diabetes.

Subjects

We enrolled people with type 1 diabetes, diagnosed for at least 1 year, aged 18–65 years, with an HbA_1c ≤ 10% (86 mmol/mol), a c-peptide level <0.3 nmol/L (0.91 ng/mL), treated with MDI for longer than 1 year, body mass index (BMI) 18.0–29.9 kg/m², and a VO_2peak >20 mL/kg/min. People on systemic corticosteroid, nonselective beta-blocker, or growth hormone treatment were excluded, as were the subjects with heart failure (NYHA III, IV), angina pectoris, recent myocardial infarction (within previous 12 months), advanced retinopathy, neuropathy, hypoglycemia unawareness, or an estimated glomerular filtration rate <50 mL/min/1.73 m² (key exclusion criteria).

Materials and Methods

The local Ethics Committee of the Medical University of Graz (Austria) approved the study protocol, which was registered at the German Clinical Trials Register (DRKS00018065; DRKS.de) and the EU Clinical Trials Register (EudraCT number 2019-003209-89). The study was conducted in conformity with the Declaration of Helsinki and Good Clinical Practice. Before any trial-related activities, potential participants were informed about the study protocol and participants gave their written informed consent.

This was a randomized, single-center, four-period, cross-over trial performed in adults with type 1 diabetes. Participants were allocated to four trial arms, each trial arm included six evening-exercise sessions within a period of 2 weeks. Three exercise sessions per week were randomly assigned from Monday to Friday. Participants received a phone call from the research team every morning at 8 AM that contained the information to inject a regular basal insulin dose (100%) or 75% of the regular basal insulin dose at 10 AM and whether there is an exercise session scheduled at 6 PM that day at the clinical research facility.

For the following exercise days within the same trial arm, which lasted for 14 days, the same basal insulin was used with the same basal insulin dose (100% or 75% of regular basal insulin dose); however, on nonexercise days within the 2 week-exercise period, participants remained on the same type of basal insulin, administering the regular basal insulin dose (100%) (Supplementary Fig. S1).

Screening visit

At the screening visit, participants were assessed for eligibility and performed a maximum incremental cardiopulmonary exercise test until exhaustion to determine the peak oxygen uptake (VO_2peak) and the first and the second lactate turn points (LTP₁ and LTP₂) to specify the exercise intensity for the upcoming exercise sessions.^6,25 Participants were equipped with a real-time continuous glucose monitoring device (rtCGM; Dexcom G6; Dexcom, Inc.), which was blinded during the nonexercise periods to the participants. They were allowed to use additional blood glucose measurement or an Abbott Freestyle Libre 1 device.

Basal insulin titration

After a sequential randomization to either IGlar U300 or IDeg U100, participants were titrated over a maximum period of 4 weeks with the aim to achieve a morning fasting blood glucose concentration of 80 − 130 mg/dL (4.4–7.2 mmol/L) over three consecutive days within the 4 weeks period. In addition, if during the day predefined premeal blood glucose level of <130 mg/dL (7.2 mmol/L) was not achieved, the bolus insulin dose was also adjusted. The same procedure was performed for the second titration to the remaining basal insulin (Supplementary Table S1).

Cycle ergometer exercise sessions

For each of the four 2 weeks trial arms, no additional strenuous exercise was permitted. Participants arrived at 05:30 PM at the clinical research facility to perform the 60 min moderate-intensity exercise session (midpoint between the LTP₁ and LPT₂; ∼60–65% of VO_2peak). At 05:45 PM, a cannula was inserted in the antecubital vein, participants completed the short International Physical Activity Questionnaire (IPAQ) once weekly and were equipped with an electrocardiogram (Faros 180; Bittium Corporation, Finland) and a heart rate monitor (Polar S810i; Polar Electro, Finland). Blood lactate and blood glucose were collected every 6 min during exercise from the earlobe for laboratory assessment (EKF S-Line; EKF Diagnostics, GER).

In addition, a glucometer was used for the immediate detection of the actual blood glucose level (Freestyle Libre; Abbott). During the exercise sessions, real-time continuous glucose monitoring (rtCGM; Dexcom G6; Dexcom, Inc.) was unblinded to avoid exercise-induced dysglycemia, and therapy adaptations were performed based on the recent European Association for the Study of Diabetes (EASD)/International Society for Pediatric and Adolescent Diabetes (ISPAD) position statement.³

The cycle ergometer exercise sessions were only started if blood glucose concentration was above 126 mg/dL (7.0 mmol/L) 15 min before the start of exercise testing.³ If blood glucose concentration was below this glycemic threshold, 15–30-gram carbohydrates (gel or juice) were given based on the trend arrow of the rtCGM. Blood glucose was measured again after 15 min and in case blood glucose was still below 126 mg/dL (7.0 mmol/L), this procedure was replicated as often as required. If blood glucose concentration was above 270 mg/dL (15.0 mmol/L) a ketone measurement was performed. If blood ketone levels were below 1.5 mmol/L, the exercise session was regularly started unless considered unsafe by the trial physician.

If ketones >1.5 mmol/L were detected, the exercise session was cancelled; in that case, this specific session was omitted, and the randomization schedule was followed for the next exercise session. During one exercise session per week, venous blood samples were drawn before, mid, and at the end of exercise to assess cortisol and IGF-1 levels by CLIA (CENTAUR; Siemens Healthcare Diagnostics).

Home phase during the exercise intervention periods

During the four 2 weeks exercise intervention periods, participants wore a blinded rtCGM. Dietary intake and insulin administration for both basal and bolus insulin were self-recorded. Furthermore, it was recommended that the participants consumed at least a lunch containing ∼1 g carbohydrate/kg bodyweight and a small snack with ∼15–30 g carbohydrates both with a regular prandial insulin dose during the exercise period. In the evening, after the exercise session, participants were told to consume again ∼1 g carbohydrate/kg bodyweight with a regular or 25% reduced prandial insulin dose based on their preference.

Endpoints

The primary outcome was TBR^<70 during the 24 h postexercise periods of six spontaneous exercise sessions in the four trial arms on either a regular (100%) or reduced (75%) IGlar U300 and IDeg U100 dose. Secondary outcomes included the TIR^70–180, time below range <54 mg/dL (TBR^<54; 3.0 mmol/L), time above range 181–250 mg/dL (TAR^181–250; 10.1–13.9 mmol/L), and TAR >250 mg/dL (TAR^>250; 13.9 mmol/L) for the 24 h postexercise periods, during exercise periods, and for the entire intervention period (overall). Adverse events, serious adverse events, and treatment emergent adverse events were recorded by the medical study team.

Statistics

Normal distribution of quantitative variables was assessed using Shapiro-Wilk tests. Qualitative variables were summarized as frequency with corresponding percentage (%), while quantitative variables are summarized as either mean ± standard deviation (SD) or mean ± standard error of mean or median and interquartile range as appropriate. Paired t-tests or their nonparametric equivalent Wilcoxon sign-rank tests were used to compare continuous primary and secondary endpoints with treatment. General or generalized linear mixed models were used to analyze treatment effects on both primary and secondary endpoints in hierarchical order.

First, 100% IGlar U300 was compared with 100% IDeg U100 for both primary and secondary endpoints. Second, 75% IGlar U300 was compared with 75% IDeg U100 for both primary and secondary endpoints. Third, 100% IGlar U300 was compared against 75% IGlar U300 and 100% IDeg U100 was compared against 75% IDeg U100 for both primary and secondary outcomes. Chi-square Fischer Exact tests were used to compare categorical secondary endpoints with treatment effects.

All data analyses were performed in Stata version 17.1 (StataCorp, TX) and R version 4.0.5 with a significance level set at P < 0.05.

In a similar trial, including nine people with type 1 diabetes,⁹ a median TBR^<70 during five consecutive days of moderate-intensity exercise for IDeg U100 of 240 min (range: 128–465 min) was observed. This corresponds to 48 min per day. In the present trial, a time spent in hypoglycemia of 50 min per day or 300 min for 6 days for the treatment IDeg U100 (100% dose) was assumed.

We further assumed a reduction of about 33% (corresponding to an absolute difference of 100 min) in time spent in hypoglycemia for IGlar U300 (100% dose). Using a paired t-test (5%, two-sided alpha), a sample size of 20 had 80% power to detect a difference in means of 100 ± 150 min between of IGlar U300 and IDeg U100. To achieve balance in the eight sequence groups, it was aimed to include 24 people with type 1 diabetes to yield a power of about 87%.

Results

In total, 25 people with type 1 diabetes (14 males) were enrolled with a mean ± SD age of 41.4 ± 11.9 years, BMI of 23.7 ± 3.1 kg/m², HbA_1c of 7.5% ± 0.8% (59 ± 9 mmol/mol), c-peptide level of 0.03 ± 0.06 nmol/L (0.09 ± 0.19 ng/mL), diabetes duration of 16.8 ± 10.4 years, and a prestudy total daily insulin dose of 41.5 ± 16.8 IU. No adverse events, serious adverse events, or treatment emergent adverse events occurred, except hypoglycemia, which was defined as the primary outcome.

At the study entry, participants had a mean basal insulin dose of 21.4 ± 9.9 IU, while four participants were using IGlar U100, seven insulin detemir, three IGlar U300, and 11 IDeg U100. Titration to IGlar U300 took 12.0 ± 5.5 days, resulting in a mean basal insulin dose of 26.5 ± 14.3 IU at the end of the titration phase, while switching the basal insulin therapy to IDeg U100 took 11.7 ± 5.8 days with a mean insulin dose of 22.3 ± 12.2 IU. Titration target was reached in a similar timespan (P = 0.882) and the amount of basal insulin dose was significantly higher with IGlar U300 (P < 0.0001).

Primary outcome

The primary outcome, the TBR^<70 within the cumulative 24 h postexercise periods for a regular basal insulin dose (100%), was significantly lower with IGlar U300 compared to IDeg 100 (2.71% ± 0.51% vs. 4.37% ± 0.69%, P = 0.023) (Fig. 1); however, no significant differences were found comparing both basal insulins when administering 75% of the regular dose (IGlar U300: 2.28% ± 0.53% vs. IDeg U100 2.55 ± 0.58, P = 0.751).

FIG. 1.

Comparison of IGlar U300 and IDeg U100 for a regular (100%) and 75% dose for the TBR <70 mg/dL (TBR^<70; <3.9 mmol/L) during the 24 h postexercise periods. IDeg U100, insulin Degludec 100 U/mL; IGlar U300, insulin Glargine 300 U/mL; TBR, time below range.

Secondary outcomes

In-exercise glycemia

During exercise, a regular dose of IGlar U300 resulted in less TBR^<70 when compared to IDeg U100 (2.17% ± 0.40% vs. 3.94% ± 0.71%, P = 0.012), while no significant differences were found when the basal insulin dose was reduced to 75% (P = 0.689). No significant differences were found for TBR^<54 between both basal insulins for neither a regular dose (P = 0.094) nor a 75% dose (P = 0.318). For a regular basal insulin dose, IDeg U100 was superior to IGlar U300 for TIR^70–180 (P = 0.035) and TAR^181–250 (P = 0.010), but not for TAR^>250 (P = 0.050) (Table 1).

Table 1.

Postexercise, in-Exercise, and 14 Days Glycemia in Comparison of Insulin Glargine 300 U/mL and Insulin Degludec 100 U/mL with a Regular Dose and 75% of the Regular dose

	IGlar U300 (100% dose)	IDeg U100 (100% dose)	IGlar U300 (75% dose)	IDeg U100 (75% dose)	P-value 1	P-value 2	P-value 3	P-value 4
Primary outcome
TBR^<70 (%) postexercise	2.71 ± 0.51	4.37 ± 0.69	2.28 ± 0.53	2.55 ± 0.58	0.023	0.751	0.558	0.012
TBR^<70 (%) postexercise; median (IQR)	2.34 (1.02–2.73)	3.48 (1.43–6.39)	1.59 (0.21–3.35)	1.43 (0.31–4.16)	0.042 ^a	0.977^a	0.206^a	0.011 ^a
Secondary outcomes
Postexercise
TBR^<54 (%)	0.54 ± 0.15	0.98 ± 0.23	0.33 ± 0.11	0.56 ± 0.20	0.072	0.350	0.378	0.086
TIR^70–180 (%)	60.96 ± 3.13	67.06 ± 2.59	61.22 ± 3.61	60.74 ± 3.27	0.012	0.952	0.913	0.015
TAR^181–250 (%)	36.33 ± 3.21	28.57 ± 2.83	36.49 ± 3.78	36.71 ± 3.57	0.003	0.973	0.951	0.003
TAR^>250 (%)	11.66 ± 2.22	7.81 ± 1.85	11.08 ± 2.89	11.19 ± 2.53	0.041	0.956	0.759	0.098
Mean glucose (mg/dL)	167.76 ± 4.98	153.78 ± 5.20	167.49 ± 6.56	166.98 ± 5.91	0.003	0.832	0.953	0.007
In-exercise
TBR^<54 (%)	0.37 ± 0.10	0.81 ± 0.28	0.27 ± 0.10	0.53 ± 0.22	0.094	0.318	0.702	0.299
TBR^<70 (%)	2.17 ± 0.40	3.94 ± 0.71	2.13 ± 0.53	2.40 ± 0.59	0.012	0.698	0.953	0.031
TIR^70–180 (%)	61.99 ± 3.04	67.23 ± 2.46	59.39 ± 3.76	62.74 ± 2.93	0.035	0.124	0.295	0.114
TAR^181–250 (%)	35.83 ± 3.17	28.83 ± 2.70	38.48 ± 4.00	34.85 ± 3.17	0.010	0.133	0.332	0.046
TAR^>250 (%)	11.11 ± 2.10	7.44 ± 1.92	12.08 ± 2.96	9.60 ± 1.96	0.050	0.150	0.604	0.315
Mean glucose (mg/dL)	167.4 ± 4.6	154.1 ± 4.9	170.5 ± 6.6	164.1 ± 5.0	0.004	0.124	0.498	0.045
14 days glycemia
TBR^<70 (%)	2.78 ± 0.40	3.71 ± 0.59	2.37 ± 0.42	3.04 ± 0.53	0.110	0.249	0.482	0.262
TBR^<54 (%)	0.52 ± 0.11	0.74 ± 0.12	0.43 ± 0.10	0.62 ± 0.17	0.204	0.277	0.606	0.497
TIR^70–180 (%)	60.94 ± 2.91	63.31 ± 2.81	59.61 ± 3.39	62.27 ± 2.64	0.271	0.151	0.539	0.797
TAR^181–250 (%)	36.29 ± 3.02	32.99 ± 3.09	38.02 ± 3.55	34.69 ± 2.96	0.175	0.122	0.476	0.620
TAR^>250 (%)	10.72 ± 1.95	9.72 ± 2.11	12.31 ± 2.79	9.88 ± 1.79	0.535	0.092	0.321	0.927
Mean glucose (mg/dL)	166.6 ± 4.8	160.7 ± 5.4	170.2 ± 6.3	162.8 ± 5.1	0.159	0.057	0.394	0.745

Statistically significant differences are highlighted in bold.

P-value 1 for IGlar U300 (100% dose) versus IDeg U100 (100% dose); P-value 2 for IGlar U300 (75% dose) versus IDeg U100 (75% dose); P-value 3 for IGlar U300 (75% dose) versus IGlar U300 (100% dose); P-value 4 for IDeg U100 (75% dose) versus IDeg U100 (100% dose). Data are given as mean ± SEM.

Analysis were done using sign-rank-tests.

IDeg U100, insulin Degludec 100 U/mL; IGlar U300, insulin Glargine 300 U/mL; IQR, interquartile range; SEM, standard error of mean; TAR, time above range; TBR, time below range; TIR, time in glucose range.

Cumulative carbohydrate administration to avoid hypoglycemia over the six exercise sessions per trial arm was numerically different, although not reaching statistical significance: with the regular basal insulin dose for IGlar U300 versus IDeg U100, the carbohydrate amount for all six exercise sessions together in each trial arm was 135.8 ± 93.1 versus 169.7 ± 114.1 g, P = 0.068; when a 75% dose was applied, the amount was 114.2 ± 98.8 versus 149.0 ± 105.7 g, P = 0.055. The median amounts of carbohydrate supplementation per exercise unit in each trial arm are detailed in Supplementary Table S2. When assessing the effect of insulin reduction within the same type of basal insulin, an insulin reduction resulted in a similar amount of carbohydrates needed to avoid hypoglycemia for IGlar U300 (P = 0.241) and for IDeg U100 (P = 0.281) during the exercise sessions.

Postexercise glycemia

Twenty-four hours postexercise periods TIR^70–180 was higher for IDeg U100 versus IGlar U300 when a regular basal insulin dose was applied (67.06% ± 2.59% vs. 60.96% ± 3.13%, P = 0.012), while no significant differences were found for TIR^70–180 when the basal insulin dose was reduced (P = 0.952). TAR^181–250 in the postexercise phase was higher for IGlar U300 versus IDeg U100 when a regular basal insulin dose was injected (36.33 ± 3.21 vs. 28.57 ± 2.83, P = 0.003), which was not detected when a 75% basal insulin dose was applied (P = 0.973). Similarly, TAR^>250 was higher for IGlar U300 versus IDeg U100 with a regular basal insulin dose injected (11.66 ± 2.22 vs. 7.81 ± 1.85, P = 0.041). When the basal insulin dose was reduced, no significant differences were found for TAR >250 (P = 0.956).

Overall, 14 days exercise period glycemia

Over the 14 days period during each of the four exercise phases, no significant differences were found for TBR^<54 (P = 0.204), TBR^<70 (P = 0.110), TIR^70–180 (P = 0.271), TAR^181–250 (P = 0.175), and TAR^>250 (P = 0.535) between both basal insulins when a regular basal insulin dose was administered (Table 1). This finding was confirmed when a 75% basal insulin dose was injected, detailing no significant differences for any of the predefined glycemic ranges.

Blood lactate, heart rate, and hormonal dynamics during exercise

The mean blood lactate response over all exercise sessions was 2.1 ± 0.5 mmol/L, detailing 63.6% of the LTP₂ and 24.7% of the maximal lactate concentration. Blood lactate responses during the four exercise periods were similar IGlar U300 (100%): 2.1 ± 0.5, IGlar U300 (75%): 2.1 ± 0.6, IDeg U100 (100%): 2.1 ± 0.5, IDeg U100 (75%): 2.1 ± 0.4; P = 0.733). Similarly, this finding was confirmed when assessed via the mean heart rate during the four exercise periods: IGlar U300 (100%), IGlar U300 (75%), IDeg U100 (100%), and IDeg U100 (75%); P = 0.308). Neither cortisol nor IGF-1 (Fig. 2).

FIG. 2.

Comparison of hormones IGF-1 and Cortisol for IGlar U300 and IDeg U100 with a regular (100%) and 75% dose at the beginning (ME1), in the middle (ME2) and at the end of the exercise sessions (ME3).

Physical activity, nutrition, and bolus insulin doses

Physical activity assessed by means of the short IPAQ was similar during the four exercise periods (IGlar U300 (100%), IGlar U300 (75%), IDeg U100 (100%), IDeg U100 (75%); P = 0.759). Nutrition with respect to the macronutrient and total kcal intake was also similar in between four trial arms (IGlar U300 (100%), IGlar U300 (75%), IDeg U100 (100%), and IDeg U100 (75%); P = 0.934). The total daily bolus insulin dose was not significantly different during each of the four 2 weeks exercise periods (P = 0.285).

Discussion

This was the first study assessing the TBR^<70 during postexercise conditions of IGlar U300 versus IDeg U100 in adults with type 1 diabetes performing spontaneous exercise on a cycle ergometer. Furthermore, we investigated different glycemic ranges around the exercise periods when 25% reduced basal insulin dose was injected.

Assessing the risk of hypoglycemia during the postexercise phase, including the nocturnal period, is of high clinical relevance since the sympathetic responses to hypoglycemia and hence awakening in response to nocturnal hypoglycemia is reduced.²⁶ However, with the prior knowledge that around 50% of people usually do exercise in the late afternoon/evening²⁴ and evening exercise sessions might be more suitable for improving HbA_1c levels than morning sessions,²⁷ specific therapy recommendations must be defined to lower the risk of hypoglycemia.

The urgent need to assess which basal insulin might be most suitable to be incorporated into physically active lifestyle is highlighted by evidence that exercise in combination with inappropriately high insulin levels can potentially lead to a fatal outcome. Our predefined primary outcome TBR^<70 showed that using IGlar U300 with a regular basal insulin dose provoked significantly less time spent in hypoglycemia when compared to IDeg U100 (100%) during postexercise conditions in adults with type 1 diabetes.

As exercise-induced hypoglycemia represents the major barrier to regular exercise,⁵ our data confirmed also for in-exercise conditions that IGlar U300 with a regular basal insulin dose provides a lower risk of hypoglycemia than IDeg U100 (100% dose). Taking these findings together, it can be concluded that people with type 1 diabetes, having an elevated risk and/or fear of exercise-induced hypoglycemia, might benefit from using IGlar U300 rather than IDeg U100 when performing spontaneous exercise without adjusting the basal insulin dose.

Intriguingly, although TBR^<54 was numerically lower when participants were using IGlar U300, no statistically significant difference to those using 100% of IDeg U100 was evident, probably due to the small total percentage observed in this specific glycemic range. Furthermore, when the basal insulin dose was reduced to 75% of the regular basal insulin dose, no significant differences were found in comparison of both basal insulins during and after exercise as well as during the entire 14 days exercise intervention period.

While for the overall 14 days exercise period, the TIR^70–180 was similar for IGlar U300 and IDeg U100 (100% dose), the IDeg U100 phase was shown to have a higher TIR when only the 24 h postexercise periods were analyzed. With respect to this, one could argue that IGlar U300 could be used in people facing an elevated risk of hypoglycemia around moderate intensity exercise sessions, while vice versa IDeg U100 might be used in those who are struggling with hyperglycemia around exercise sessions.

Interestingly, reducing IDeg U100 on the day of exercise decreased the risk of hypoglycemia within 24 h postexercise similar to that observed with the IGlar U300 regular (100%) dose, which disagrees with the recommendation by Riddell et al.,² in which it was postulated that reducing 2nd generation basal insulin would compromise overall glycemic control; however, reducing IDeg U100 also reduced the TIR^70–180 and TAR^181–250 when compared to a regular dose. This finding is also somewhat in contrast to a recent study from our research group, in which we showed that reducing IDeg U100 around exercise led to improved TIR,^70–180 with no statistically significant effect on TBR or TAR.⁹ However, in this previous research, the basal insulin dose was reduced 3 days before the start of the exercise period and the exercise sessions were performed over five consecutive days.

Interestingly, the effect of reducing the basal insulin dose on the 24 h postexercise glycemia as seen for IDeg U100 in our current study, was not observed for IGlar U300, which might be based on the in general low risk of hypoglycemia when a regular dose of IGlar U300 was used. Even though our study showed clear differences in comparison of both basal insulins for the in- and 24 h postexercise phases, the overall 14 days glycemia was unaffected by the type and dose of basal insulin.

Furthermore, in our study, the exercise intensity was well controlled, since the blood lactate, heart rate, and hormone responses were similar for the four trial arms. In conclusion, our study findings suggest that IGlar U300 when administered at the regular dose (100%) on days of moderate exercise sessions, yields a lower risk for hypoglycemia but lower TIR^70–180 and higher TAR 24 h postexercise when compared against IDeg U100 administered at the regular dose.

Conclusions

From our point of view, clinical recommendations when choosing the type of 2nd generation basal must be personalized, evaluating the current risk of hypoglycemia, glycemic control, and exercise experience³ to ensure that people with type 1 diabetes are moving forward to a physically active lifestyle with a low risk of glycemic disturbances. Both IGlar U300 and IDeg U100 can be safely used for spontaneous exercise sessions; however, our data suggest that to reduce the risk of exercise-induced hypoglycemia, IGlar U300 can be continued with the regular dose and IDeg U100 should be reduced by 25% on the day of exercise. Furthermore, lowering IGlar U300 around exercise is not needed if the person already has a low risk of hypoglycemia since it might aggravate TAR.

Footnotes

Acknowledgment

We thank Ulrike Leb-Stöger, Gerd Köhler, Barbara Weber, Max L. Eckstein, and Mathias Zanker for their support within the study.

Authors' Contributions

O.M. and H.S. have designed the study. O.M., H.S., A.M., F.Ab., H.K., C.S., A.O., F.Abb., P.B., J.L., I.M., C.S., L.H., P.N.P., and N.T. have performed the study. F.Az. and H.Z. performed the data analyses. O.M. has written the article and all authors contributed to the write-up and critical assessment.

Author Disclosure Statement

O.M. has received lecture fees from Medtronic, Sanofi, Novo Nordisk, TAD Pharma, and ADA; travel grants from Novo Nordisk A/S, Novo Nordisk AT, Novo Nordisk UK, Medtronic AT, Sanofi, and TAD Pharma and research grants from Cymru II COFUND fellowship/European Union, Novo Nordisk A/S, Novo Nordisk AT, Sanofi, Dexcom, Maisels, and DDG. F.Az. received speaker honoraria from AMGEN, Astra Zeneca, NovoNordisk, Boehringer Ingelheim, Eli Lilly, Sanofi Aventis, and research grants from Sanofi Aventis. H.S. received speaker's honoraria and is on the advisory board for Amgen, Astra Zeneca, Bayer, Böhringer Ingelheim, Eli Lilly, Kapsch, MSD, Novartis, NovoNordisk, and Sanofi-aventis. Remaining authors have no conflict of interest.

Funding Information

This study was funded by an investigator-initiated study grant to H.S. by Sanofi (DCV 2018-12349) and the Austrian Science Fund (FWF) (KLIF-851B to H.S.). Dexcom, Inc., supported the study with material funding.

Supplementary Material

Supplementary Figure S1

Supplementary Table S1

Supplementary Table S2

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Supplementary Material

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