The Effectiveness of Superbolus on Postprandial Blood Glucose Management of Pregnant Women With Type 1 Diabetes

Abstract

Aim:

Pregnancies of women with pregestational diabetes are at risk of after-meal glucose peaks and late after-meal hypoglycemia, particularly at breakfast. We aimed to explore the effectiveness of a specific feature of insulin pump therapy called superbolus in preventing these glucose swings.

Methods:

In this retrospective observational study, we analyzed continuous glucose monitoring data of patients with type 1 diabetes in pregnancy who were advised to use superbolus to manage their breakfast. Some of the postprandial basal insulin delivery was partially reduced and delivered instead as additional insulin bolus on top of a normal bolus. Outcomes of interest were one hour after breakfast glucose levels, the time in glucose range for after breakfast period, the number of late hypoglycemic episodes.

Results:

Overall, 21 consecutive pregnant women with type 1 diabetes (mean age 34.3 ± 5.5 years, mean pregestational body mass index 23.7 ± 4.7 kg/m², HbA1c levels during pregnancy 6.1 ± 0.6%) were studied. Superbolus reduced after breakfast glucose peaks (one hour after breakfast glucose levels 130 ± 17 mg/dL vs 123 ± 10 mg/dL before and after superbolus use, respectively, P = .01), improved the time in glucose range for after breakfast period (70.4% vs 50.8%, P = .001), and reduced the number of late hypoglycemic episodes (3 [1-5] vs 1 [0-2], P< .0001).

Conclusion:

Superbolus was effective in avoiding after-meal glucose peaks, increased postprandial glucose time in target, without late hypoglycemia occurrence. It represents a valid option for the treatment of pregnant women with type 1 diabetes using insulin pump.

Introduction

Pregnancies complicated by pregestational diabetes have a challenging clinical management both for healthcare professionals and for women with diabetes. Glucose swings in pregnancy are associated with adverse maternal and neonatal outcomes such as neonatal hypoglycemia, babies small or large for gestational age, neonatal jaundice, fetal malformations, oligo- or polidramnios, respiratory distress, birth trauma, and neonatal intensive care unit request.^1,2 Therefore, a careful monitoring of blood glucose levels and their maintenance in adequate pregnancy-specific glucose range is essential for the care of patients with diabetes in pregnancy. However, too tight glucose control is accompanied by increased frequency of hypoglycemic events, which may also compromise the well-being of both mother and fetus. In particular, postprandial glucose excursions ¹ affect the daily glucose pattern of women with diabetes in pregnancy. Typically, after an early glucose peak, a late after-meal hypoglycemia occurs, particularly after breakfast.

The use of technological devices such as insulin pump, real-time continuous glucose monitoring (rt-CGM) systems, intermittent glucose monitoring systems, and sensor-augmented pump systems represents a valid support for the treatment of diabetes in pregnancy. ³ Data from the international CONCEPTT trial documented that the use of rt-CGM during pregnancy in patients with type 1 diabetes (T1D) was associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycemia. ⁴ Specifically, neonatal health outcomes were significantly improved, with lower incidence of large for gestational age, fewer neonatal intensive care admissions, and fewer incidences of neonatal hypoglycemia. The authors concluded that CGM should be offered to all pregnant women with T1D using intensive insulin therapy. The very recent availability of advanced hybrid closed-loop systems is a major step forward in the care of T1D.^5,6 These systems provide an automatic basal insulin infusion and an automatic bolus delivery in the case of hyperglycemia. However, their use during pregnancy is not definitely approved because the lowest glucose target they could reach in automatic mode is higher than that required for pregnancy.

The superbolus is a particular feature of basic insulin pump therapy that could be useful in preventing glucose swings. ⁷ It consists in stopping or partially reducing some of the basal insulin delivery, and delivering it instead as additional insulin bolus on top of a normal bolus. Although it is quite well known, there are few scientific evidences supporting this practical procedure. No evidence about the effects of superbolus on glycemic control in patients affected by T1D during pregnancy exists.

Materials and Methods

This was a retrospective observational study approved by our Institutional Review Board. All included women signed a written informed consent. We aimed to report the effectiveness of superbolus on after-meal glucose swings in pregnancies of women with T1D. Our Interdisciplinary Diabetes and Pregnancy Center at the Niguarda Hospital, Milan, Italy, is a referred center for the management of women with diabetes in pregnancy using technology. In most of the cases, women start an insulin pump therapy before the pregnancy, when they are planning it. ⁸ During scheduled visits, glucose data were discussed and therapeutic actions were taken. We retrospectively collected data of 21 consecutive pregnant women affected by T1D wearing an rt-CGM system integrated with insulin pumps in which a transient hyperglycemia (blood glucose level >130 mg/dL) one hour after breakfast with subsequent late hypoglycemia (blood glucose level <70 mg/dL between two hours after breakfast and lunch) was observed. For the management of these glycemic excursions, the basal insulin delivery was reduced of 70% to 80% at the moment of the meal bolus for two hours, delivering this amount of reduced insulin as additional insulin bolus on top of the normal meal bolus. This was the superbolus. Therefore, women used superbolus as outpatient and the rt-CGM data were then used for analysis during the visit. Women were advised to maintain the same breakfast in terms of type of food and carbohydrates (CHO) grams; no changes in physical activity nor in insulin/CHO ratio and insulin correction factor were recorded before and after the use of superbolus. According to healthcare professionals’ advice, patients took their insulin through a suggested bolus 25 to 30 minutes before breakfast. The pump placement site was inspected for the presence of lipodystrophies. Pump infusion set was changed every three days. Before breakfast no hypoglycemic episodes, no predictive low-glucose suspension nor hyperglycemia requiring insulin bolus had happened. Furthermore, patients did not do physical activity. Basal rates were unchanged for the morning. Other basal rates during the afternoon or the night were modified according to the glucose trends. All this information was recorded in a patient’s logbook that was analyzed during the visit. The CGM data of the week before and the week after superbolus introduction were analyzed. All the enrolled women were at the same period of pregnancy (ie, second trimester of gestation). Outcomes of interest were one hour after breakfast glucose levels, the time in glucose range (70-120 mg/dL) for after breakfast period (ie, within two hours after breakfast), the number of late hypoglycemic episodes (<70 mg/dL) between two hours after breakfast and lunch.

Statistical Analysis

Data were expressed as means ± standard deviation for continuous variables and percentages for categorical variables. The Kolmogorov-Smirnov test was used to test the normality of distribution of continuous variables. Outcomes of interest before and after superbolus use were compared using the Wilcoxon signed-rank test. As this was a feasibility study, no prior power calculation was performed. A P value <.05 was considered for statistical significance. Analyses were performed using SPSS version 21.0 (SPSS Inc., Chicago, Illinois).

Results

Overall, 21 consecutive pregnant women with T1D (mean age 34.3 ± 5.5 years, mean pregestational body mass index 23.7 ± 4.7 kg/m², HbA1c levels during pregnancy 6.1 ± 0.6%) were involved in the study. Twelve women wore a Medtronic insulin pump system with its associated glucose sensor. Six women wore an Omnipod insulin pump with a Dexcom glucose sensor. Three women wore an Animas insulin pump with a Dexcom glucose sensor. Insulin Aspart and insulin Lispro were used by 13 and 8 women, respectively. Before-pregnancy HbA1c levels were in target (<6.5% or 48 mmol/mol) for pregnancy planning in 67% of the cases. Only 14.3% of women had diabetes-related complications. Before using superbolus, when we analyzed the CGM weekly reports, we noticed the presence of a systematic glucose peak one hour after breakfast and a subsequent (almost two hours and half/three hours after meal) symptomatic hypoglycemia. Sometimes, after this hypoglycemia, even if the before low-suspend function was active, there was a fast glucose rise. Superbolus reduced after breakfast glucose peaks (one hour after breakfast mean glucose levels 130 ± 17 mg/dL vs 123 ± 10 mg/dL before and after superbolus use, respectively, P = .01) as reported in Figure 1, improved the time in glucose range for after breakfast period (70.4% vs 50.8%, P = .001), and reduced the number of late hypoglycemic episodes (3 [1-5] vs 1 [0-2], P< .0001). No hypoglycemic episode was recorded within the first two hours after delivering superbolus. When comparing glucose data at lunchtime, we did not find any statistically difference between the period without and with superbolus use. Mean prelunch glucose levels were 90.4 ± 13.2 mg/dL vs 93.3 ± 7.3 mg/dL for the period without and with superbolus use, respectively, P = .18. Mean postlunch glucose levels were 108.7 ± 18.8 mg/dL vs 110.8 ± 14.9 mg/dL for the period without and with superbolus use, respectively, P = .69. The average body weights for the period before and after the superbolus use were 64.0 ± 8.5 and 64.5 ± 8.4 kg, respectively. The weight difference was of 0.4 kg and was statistically significant (P< .0001). The total insulin daily doses were different between the period without and the period with superbolus use (mean insulin unit difference of 7.5, P = .001) in the two weeks because basal rates were unchanged for the morning but other basal rates during the afternoon or the night were modified according to the glucose trends. Furthermore, insulin boluses of meals were different according to the amount of carbohydrates taken.

Figure 1.

One hour after breakfast mean glucose levels and standard deviation before and after superbolus use.

Discussion

Superbolus may help manage postmeal glucose peaks in pregnancies of women with T1D using insulin pumps. It allows to reach more often after-meal glucose levels on pregnancy-specific target, avoiding subsequent hypoglycemia. This increases after-meal time spent in glucose range. The calculation of the best basal-bolus combination for postprandial glucose control in insulin pump therapy still represents a problem. To calculate the exact dose of insulin to be given at the time of a meal, people with T1D need to estimate the exact amount of carbohydrates they eat. To do this, the carbohydrate counting technique is used. It takes into account the individual insulin-carbohydrate ratio estimating the number of insulin units for the grams of carbohydrates. This is one of the most challenging actions in daily blood sugar management for a person with T1D. Some situations (eg, covering high glycemic index foods or large intakes of carbohydrates) require that insulin is needed quickly. Another condition of potential advantage of quick insulin action is pregnancy. Pregnancy involves an additional challenge represented by the effect of pregnancy-specific hormones on blood sugar levels. The effect of these hormones on glucose levels is particularly marked in the morning. Breakfast is the meal that requires the largest increase of insulin dose with advancing gestation^9,10 with hard management of glucose swings. Insulin absorption is delayed with advancing gestation so the premeal bolus should be even earlier in late pregnancy. If a high insulin dose is taken at breakfast, there is the probability of having after-breakfast glucose levels on target. Nevertheless, a subsequent hypoglycemia due to the late effect of insulin analogue occurs. The use of the ultrarapid insulin analogue faster aspart, might improve postmeal glucose excursions, however, there are no data, yet. Insulin pumps allow to split the basal into different time segments, thus potentially limiting glucose swings. However, at the top of therapy management, the tendency to hyperglycemia after breakfast and subsequent hypoglycemia in pregnancies complicated by pregestational diabetes remains. This is not a marginal aspect because high postprandial glucose levels are associated with high risk of babies large for gestational age and others adverse neonatal outcomes. ²

Pregnant women out of fear of the effects of blood sugar on their babies try to correct the hyperglycemia sometimes by giving too much extra insulin. This typically follows late hypoglycemia. Hypoglycemia is itself a dangerous event for the health and well-being of the mother and can put the fetus in a stressful situation. Despite the possibility of using advanced technological systems and proper training of women with pregestational diabetes, hypoglycemia is still unfortunately very frequent.

Superbolus could help clinical management of postprandial glucose swings. It was described for the first time by Walsh. ¹¹ Its clinical relevance is high; however, a complete diffusion in different categories of patients was not reached. Very recently, a randomized crossover clinical trial has been promoted to test a superbolus-based strategy for high glycemic index meal management in children with T1D. ¹² The study participants eat a high glycemic index breakfast receiving insulin bolus in the form of superbolus and normal bolus on alternate days. The evaluations of the outcome measures (ie, glucose levels after the prandial bolus and indices of glycemic excursion) will allow to test the real efficacy of superbolus in clinical contest. Biomedical engineering studies aiming to find the right basal-bolus ratio for postprandial glucose control demonstrated that an algorithm for bolus administration mode could be useful. ¹³ They performed an in silico validation of the algorithm considering some groups of subjects (ie, adults, adolescents, and children) but pregnant women were never included. A recent paper proposed an automated superbolus feature for commercial insulin pumps. ¹⁴ The authors tested an algorithm that automatically shapes a superbolus without the need of manual intervention. This could avoid the risk of a glucose rebound once the superbolus is gone because an a priori amount (a specific percentage of basal rate and for a specific time) of basal insulin has been removed which may not always be correctly guessed. We use superbolus in almost all our patients reducing basal insulin rate for two hours with a basal reduction of 70% to 80%, depending on personal glucose profiles. Compared with a standard bolus, a superbolus more closely matches normal physiology where there is a rapid release of insulin after meals and followed shortly by increased insulin production.

Our study has relevant implications for clinical practice. To the best of our knowledge, we have documented for the first time the use of this special feature of insulin pump in the context of the care of women with pregestational diabetes in pregnancy. Lowering the percentage of glucose levels spent in high pregnancy-specific range using a superbolus could reduce the risk of neonatal complications. Healthcare professionals should be advised of the possibility of using the superbolus.

It is necessary to obtain methodologically more robust data in this category of women from randomized controlled clinical trials. The limitations of our study are certainly those typical of observational studies which do not allow to test the effectiveness of the intervention without being able to eliminate all confounding factors. Particularly, the regression toward the mean, the Hawthorne effect, and the effect of unmeasured confounding variables could have influenced our results. This does not allow us to highlight the association of the intervention with the clinical benefits obtained from it. Unfortunately, we do not have CGM data of the single days because during every visit we systematically record mean before- and after-meal glucose levels, time in glucose range for after-meal period, the number and the time of hypoglycemic events, and weekly standard deviation. However, our study documented a clear benefit on postprandial blood glucose trend by avoiding hyperglycemia and reducing the risk of late hypoglycemic episodes.

Conclusions

The current standard therapy consisting of an insulin bolus on top of basal for controlling glucose after a meal is not enough. Superbolus could be an effective and safe insulin delivery mode for women with diabetes in pregnancy using insulin pump. The use of advanced hybrid closed-loop systems is not allowed in pregnancy. Delivering skills on superbolus in the context of an education program to support advanced boluses was recently reported to be feasible but a low superbolus use between participants was recorded. ¹⁵ Further studies with a randomized controlled design and with adequate sample size are needed to test the efficacy of superbolus in clinical practice. Further research on superbolus algorithm is recommended to test pregnancy-specific features of advanced hybrid closed-loop systems and, hopefully, to integrate others biometrics variables (eg, temperature, heart rate, sweating) in the algorithm.