Insulin glargine 300 U/ <scp>mL</scp> safety data in pregnancy

The rise in the prevalence of hyperglycaemia in pregnancy (HIP) is alarming globally. The global prevalence of HIP in 2021 was 16.7% (21.1 million live births affected).1 According to the World Health Organization (WHO) and the International Federation of Gynaecology and Obstetrics (FIGO), HIP can be classified as either pre-gestational diabetes, gestational diabetes mellitus (GDM) or diabetes in pregnancy (DIP). It has been estimated that most cases of HIP (80.3%) were caused by GDM, while 10.6% were the result of diabetes detected prior to pregnancy, and 9.1% due to diabetes (type 1 and type 2) first detected in pregnancy.1 Notably, the majority of the cases of HIP (87.5%) were reported from low- and middle-income countries, where access to antenatal care is often limited.1 HIP is a risk factor for adverse maternal, foetal and neonatal outcomes such as spontaneous abortion, foetal anomalies, pre-eclampsia, preterm labour, stillbirth, macrosomia, congenital malformations, neonatal hypoglycaemia, neonatal hyperbilirubinemia and neonatal respiratory distress syndrome.2 Therefore, optimal glycaemic control during pregnancy is crucial for women with diabetes to prevent adverse events associated with hyperglycaemia. International guidelines such as the American Diabetes Association (ADA)2 and the American College of Obstetricians and Gynecologists (ACOG),3 and the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE)4 are in agreement on glycaemic targets during pregnancy in people with type 1 diabetes(T1D) or type 2 diabetes (T2D) which are as follows: a fasting plasma glucose (FPG) level ≤95 mg/dL (≤5.3 mmol/L), a 1-hour post-prandial glucose (PPG) level ≤140 mg/dL (≤7.8 mmol/L) or a 2-hour PPG level ≤120 mg/dL (≤6.7 mmol/L), whereas for glycated haemoglobin (HbA1c), the target is <6–6.5% (42–48 mmol/mol) without significant hypoglycaemia. Moreover, the ADA and AACE/ACE guidelines2, 4 recommend continuous glucose monitoring (CGM) metrics for assessing and managing glycaemic control in pregnant women with T1D, such as time in range 63–140 mg/dL (3.5–7.8 mmol/L), with a goal >70%. The current evidence does not strongly support the use of CGM in pregnant women with T2D and GDM for maternal or neonatal benefits. However, it may be considered for pregnant women who are at risk for hypoglycaemia, especially those on insulin therapy.4 Several international guidelines recommend that insulin therapy should remain the gold standard treatment for women with GDM who have failed to achieve glycaemic targets with lifestyle interventions or recommended oral anti-diabetic therapies.2, 3, 5 Metformin and glyburide, individually or in combinations, are not recommended as the first-line treatment for GDM in many current guidelines because they cross the placenta to the foetus, raising concerns about long-term safety for the offspring. Notably, offspring exposed to metformin for GDM treatment showed higher body mass index (BMI), greater waist-to-height ratios and an increased risk of obesity.2-4 Other oral and non-insulin injectable glucose-lowering agents lack long-term safety data.2, 6 Insulin is the preferred first-line treatment for GDM because its large molecular size prevents it from crossing the placenta.2, 5 Several insulin formulations are available in the market for the management of diabetes; however, the choice of an appropriate insulin analogue for the treatment of the HIP population is totally governed by its safety profile.7 Rapid-acting bolus insulin analogues (e.g., lispro and aspart) have shown improvement in the PPG level and a reduced risk of maternal hypoglycaemia compared with human insulin.8-11 In clinical practice, long-acting basal insulin (BI) analogues such as insulin detemir and insulin glargine 100 U/mL (Gla-100) are often used if meal-time insulin is not indicated. They are characterised by a more stable and longer-acting pharmacokinetics–pharmacodynamics profile and have a lower risk of hypoglycaemia than human BI.12, 13 The results of two randomised controlled trials (RCTs) in pregnant women with diabetes demonstrated that insulin detemir, a first-generation BI analogue, lowered FPG levels with a comparable HbA1c and lesser incidences of hypoglycaemia with similar maternal and foetal outcomes compared with Neutral Protamine Hagedorn (NPH) insulin.12, 14 Moreover, real-world data from the EVOLVE study in pregnant women with pre-existing diabetes demonstrated that insulin detemir was associated with a similar risk to other BIs for major congenital malformations, neonatal death, maternal hypoglycaemia, pre-eclampsia and stillbirth.15 A meta-analysis of eight observational clinical studies has shown that Gla-100, another first-generation BI analogue, caused no significant differences in safety-related maternal or neonatal outcomes in pregnancy compared with NPH insulin.16, 17 Moreover, post-marketing pharmacovigilance (PV) data (more than 1000 pregnancy outcomes) showed that the use of Gla-100 during pregnancy indicates no specific AEs on pregnancy or on the health of the foetus and newborn child.18, 19 Although, Gla-100 is widely used, it has not been evaluated in RCTs involving pregnant women with diabetes.13 Longer-acting second-generation BI analogues, insulin degludec 100 U/mL (IDeg-100) and insulin glargine 300 U/mL (Gla-300), have a more stable and longer over 24-hour duration of action profile and less variability than the first-generation BI analogues, translating to less hypoglycaemia in clinical trials.20 Previously reported observational studies suggest that IDeg-100 has shown good glycaemic control without causing any maternal/neonatal complications in pregnant women with diabetes.21-23 Recently, the results from the EXPECT RCT provided evidence regarding the efficacy and safety of IDeg-100 in women with T1D who were pregnant or planning a pregnancy. The findings of this study suggest that IDeg-100 could be used for glycaemic control in pregnancy, with no additional safety concerns.24 Gla-300 had a similar structure to Gla-100 and was approved in 2015 (marketing authorisation: US, February 25, 2015; EU, April 24, 2015). It is produced in Escherichia coli.13, 25 Gla-300 has a more stable, prolonged duration of action (up to 36 hours) with a similar glycaemic control and a lower risk of hypoglycaemia compared with Gla-100.25, 26 It is administered once daily. Previously, the effectiveness and safety of Gla-300 have been demonstrated in RCTs25, 27 and real-world evidence studies.28-30 Moreover, the InRange study showed that Gla-300 is non-inferior to IDeg-100 for glycaemic control and glycaemic variability as measured by CGM-derived metrics, with comparable occurrences of hypoglycaemia and safety profiles in adults with T1D.31 These findings highlight that Gla-300 can be a potential alternative to the existing BI analogues. However, the efficacy and safety of Gla-300 in pregnant women with diabetes are yet to be investigated in an RCT setting. The reproductive and embryo-toxicity of Gla-100 were assessed in female rats and Himalayan rabbits. Gla-100, at doses approximately 50 times and 10 times the recommended human doses, did not show any direct harmful effects on pregnancy in female rats and rabbits, respectively.32, 33 Although there are no clinical studies on the use of Gla-300 in pregnant women, the findings from previous global PV data suggest that the use of Gla-300 during pregnancy (246 cases of exposures) was not associated with specific adverse events or congenital abnormalities.19 We examined the real-life safety of Gla-300 use in pregnancy, using a more recent post-marketing PV data from database initiation to January 25, 2024 (Table 1). The Medical Dictionary for Regulatory Activities (MedDRA) version 26.1 search terms were used for this analysis, and a cumulative search of Sanofi's global PV database was performed to identify pregnancy outcomes during Gla-300 use. A total of 546 cases of exposures to Gla-300 during pregnancy were identified, and these cases originated from 49 countries across the globe. In this analysis, the cumulative exposure of. Gla-300 was 17.34 million person-years, and the reporting rate for pregnancy/lactation-related cases was 30.95 per million person-years. Congenital, familial and genetic anomalies were reported rarely (five cases, 0.92% of cases for Gla-300; one each of cardiac, genito-urinary, musculoskeletal and connective tissues and respiratory and gastrointestinal tract disorders) and did not reveal any trend in the localisation of the anomaly. Spontaneous abortion rates were low, occurring in 14 cases (2.6% of cases for Gla-300; Table 1). Overall, in line with previous findings, the rates of congenital anomalies and spontaneous abortions were low and consistent with rates in the general population (3%–5%34, 35 and 10%,36, 37 respectively). Thus, our PV data analysis showed that the use of Gla-300 during pregnancy was not associated with specific adverse events or congenital abnormalities. Additionally, several points should be considered when interpreting the global PV data mentioned earlier. Given the constraints in data collection in the post-marketing setup, this analysis is subject to certain limitations, such as the lack of information on diabetes type, the duration of insulin therapy and the absence of a control group for comparison. Furthermore, we cannot assess the overall safety of Gla-300 in pregnant populations based solely on this analysis. This is a fundamental limitation of the current analysis. In contrast to clinical trials, database mining is limited in its ability to extract data due to minimal data reporting/missing information during the post-marketing phase. Additionally, retrospective data review is not feasible, and the results rely on the accuracy of the entered data. However, reporting these data is of importance for informing clinicians. The prevalence of HIP is increasing globally, and insulin is the first-line anti-diabetic agent recommended for optimal management in this population. Tight glycaemic control before conception and during pregnancy is essential to reduce maternal and foetal complications. The results of our recent analysis of global PV data suggest that Gla-300 could be used for glycaemic control in pregnant women with diabetes. However, future RCTs and real-world studies with a larger sample sizes are warranted to provide further evidence for the efficacy and safety of Gla-300 use in pregnancy. All the authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article and had full access to all the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. All the authors participated in the interpretation of the data and the writing, reviewing and editing of the manuscript and had the final responsibility for approving the published version. This analysis was done by Sanofi, Paris, France. Manuscript writing assistance was provided by Umakant Bahirat, PhD, an employee of Sanofi. JW, NG, ST and ZD are employees of Sanofi and may hold shares and/or stock options in the company. MD was an employee of Sanofi at the time of study conduct and may hold stocks/shares in the company. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.16295. Original data from our own analyses are included in the article. The data that support the table in this study are available from the corresponding author, NG, upon reasonable request.