Drug Safety Evaluation
The use of insulin detemir during pregnancy: a safety evaluation Ronit Koren, Yoel Toledano & Moshe Hod† Introduction
2.
Mechanism of detemir action
3.
Efficacy and safety of detemir during pregnancy
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†
1.
4.
Conclusion
5.
Expert opinion
Tel Aviv University, Helen Schneider Hospital for Women, Rabin Medical Center, Division of Maternal Fetal Medicine, Sackler Faculty of Medicine, Petah-Tiqva, Israel
Introduction: Diabetes during pregnancy causes both fetal and maternal complications. Insulin is the most effective pharmacological treatment for controlling hyperglycemia during gestation and can limit adverse outcomes. Insulin detemir (IDet), a novel basal insulin, has already been used for this indication for several years. It was reclassified in 2012 by the FDA from category C to category B for the treatment of pregnant women with diabetes. Areas covered: This article reviews published data regarding the use of IDet during pregnancy. We discuss pharmacokinetic and pharmacodynamic qualities of IDet and potential advantages for its use during pregnancy. Expert opinion: IDet is a viable option for the management of diabetes during pregnancy. Though data is limited, its safety and efficacy is probably comparable to human insulin, and in some aspects superior to it. More data, specifically for IDet in pregnancies complicated by gestational diabetes (GDM) or type 2 diabetes, is needed. Keywords: detemir, diabetes mellitus, gestational, pregnancy, safety Expert Opin. Drug Saf. (2015) 14(4):593-599
1.
Introduction
Gestational diabetes (GDM) is defined as a condition associated with maternal hyperglycemia, which is less severe than in overt diabetes. Nevertheless, it is associated with an increased risk of adverse pregnancy outcomes [1]. It accounts for > 90% of diabetes during pregnancy [2]. Pregestational diabetes, type 1 (T1DM) or type 2 (T2DM), accounts for 1.8% of all diabetes among pregnant women [3]. The prevalence of GDM is estimated to be 7% in the United States and between 1 -- 25% around the world, depending on the diagnostic criteria and patient’s demographics [4,5]. The rising prevalence of diabetes during pregnancy in the last years is attributed to the increased obesity rate and maternal age. Moreover, it contributes to the worldwide diabetes epidemic [3,6]. Adopting the diagnostic criteria based on the Hyperglycemia and Adverse Pregnancy Outcomes study will increase this prevalence even more [1]. Pregestational diabetes causes maternal, fetal and neonatal complications, including congenital malformations, spontaneous abortions, macrosomia [7,8], spontaneous preterm delivery [9], perinatal mortality [10], pre-eclampsia, cesarean section, postpartum hemorrhage and maternal mortality [11,12]. Strict glycemic control has shown to decrease the rate of these complications although not to the level achieved in the general population [11,13]. In addition to these complications, GDM as well as pregestational diabetes is associated with an increased risk of shoulder dystocia, neonatal hypoglycemia, hyperbilirubinemia and extended maternal and neonatal hospitalizations [14-17]. Similar to pregestational diabetes, treating GDM is associated with a decrease in the incidence of these complications [18]. In women who could not achieve glycemic control with lifestyle modification and medical nutrition therapy, pharmacologic treatment is indicated. Insulin is the main therapy for pregestational diabetes. However, in women with GDM oral 10.1517/14740338.2015.1013533 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name (generic) Phase Indication Mechanism of action Route of administration Chemical structure
Insulin detemir Launched, Category B for pregnancy Indicated to improve glycemic control in adults and children with diabetes mellitus Long-acting human insulin analog Subcutaneous C14 fatty acid chain (myristic acid)
Pro
Thr
Tyr
Phe Phe Gly
Arg Glu
Lys
Gly
B29
Thr
Cys
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A21 Asn Cys
Val
Tyr
Leu
Asn A1
Gly Ile
Glu
Tyr
Leu
Leu
Gln
Val
Ala
Tyr
Glu
Glu
Leu
Gln Cys Cys Thr
Ser
Ile
Cys
Val
Ser
Leu His Ser Gly
B1 Phe Val
Pivotal trials
Cys His Leu
[37,58]
glyburide and metformin were also suggested as therapeutic options [19-21], although their use is still controversial and further research is needed [22]. Traditionally, only human insulin was used during pregnancy. Compared to human insulin, insulin analogs have been shown to result with a similar or a better glycemic control as well as a lower risk of hypoglycemia and weight gain in non-pregnant subjects with T1DM or T2DM [23-25]. Use of the short-acting insulin analogs lispro and aspart during pregnancy is considered safe [26,27]. They may also convey advantages for maternal glycemic control over human insulin, for example, a diminished rate of hypoglycemic episodes [28-31]. The long-acting insulin analogs detemir and glargine are also administered during pregnancy. However, the data on insulin glargine during gestation is limited to retrospective studies [32-34]. These reports show no significant difference in safety and efficacy compared to NPH insulin. Instead, insulin detemir (IDet) (Box 1) treatment in women with T1DM had a better control of fasting plasma glucose, without an increase in hypoglycemia rate, compared to NPH [35]. IDet was reclassified from class C to class B (i.e., does not increase the risk of harm to the fetus) in 2012 [36]. This new classification was based on animal data [36] and on a prospective clinical study in women with T1DM [37]; the aim of this review is to evaluate the efficacy and safety of IDet administration in women with pregestational diabetes and GDM. 594
Asn Gln
2.
Mechanism of detemir action
IDet (LysB29-tetradecanoyl des-(B30)) is a long-acting soluble insulin analog, in which the threonine residue at the position B30 has been removed and a 14-carbon fatty acid side chain has been attached to position B29 [38]. It has a protracted action attributed to the strong self-association of IDet hexameric molecules at the injection site and a strong binding to albumin in the bloodstream [39]. It is supplied as a clear solution. Its absorption is not dependent on resuspension before injection, or on formation and dissolution of microprecipitates in contrast to insulins NPH and glargine, respectively [40]. It has a slower onset and a less pronounced peak of action compared with NPH insulin [41]. The activity profile of IDet was flatter than insulin NPH in clamp studies in patients with T1DM as well as T2DM [42,43]. A review summarizing glucose clamp studies reported that the mean duration of action of IDet is close to 24 h in patients with T1DM and probably longer in patients with T2DM. However, this does not necessarily represent the actual duration of action in each individual. The standard deviation is considerable, and the exact dosing can vary between individuals [44]. The diminished within-subject variability and reduced risk of hypoglycemia may be related to the protracted absorption and flat activity profile of IDet vs NPH [42,45]. Concerns about the metabolic and mitogenic properties of insulin analogs have been raised. The mitogenic potential of
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Insulin detemir
insulin is mediated in part by its affinity to the IGF-1 receptor. Insulin glargine has a six to eightfold increased IGF-1 receptor affinity compared with human insulin, whereas IDet has 15 times lower affinity [46,47]. In vivo, insulin glargine is converted into two active metabolites (M1 and M2) that have lower affinity to the IGF-1 receptor [48,49]. In experimental cell culture models both insulin glargine and IDet had an increased mitogenic activity in comparison to short-acting analogs and human insulin [50]. These in vitro results might not have major clinical relevance as in vivo IDet is bound to albumin at concentrations higher than those used in this study. In contrast, Varewijck et al. found that IGF-1 receptor is not activated at all by IDet [51]. Together, the mitogenic activity of different insulin formulations and the possible effect on embryonic development remain to be explored. It is assumed that insulin cannot cross the placenta because of its large molecular weight [52]. Still, transfer of insulin-antiinsulin-antibody complexes has been detected in women with T1DM administered non-human insulin. It was associated with anti-insulin antibodies in the mother at the time of delivery [53]. Currently, there is no data regarding transplacental transfer of IDet. Rates of insulin absorption, onset and action duration may be affected by injection site, exercise, obesity, age, renal dysfunction, and dose [54,55]. During pregnancy, insulin requirements tend to fall during the first trimester and rise during the second and third trimesters [56]. In addition, peak postprandial plasma insulin concentrations rise slower during late pregnancy. This, in turn, can impact the timing of prandial insulin administration [57]. There is insufficient data regarding pharmacokinetics and pharmacodynamics of insulin analogs during pregnancy.
Efficacy and safety of detemir during pregnancy
3.
IDet treatment in patients with T1DM Few studies have examined the efficacy and safety of IDet during pregnancy despite its increasing use in this population. The clinical trials are summarized in (Table 1). A randomized, open-label, multinational parallel-group trial compared the safety and efficacy of IDet vs NPH insulin in pregnant women with T1DM [37,58]. Three hundred and ten women with T1DM were randomized before or during early pregnancy to receive IDet or NPH, both in combination with insulin aspart in a basal-bolus regimen. The efficacy of IDet was found to be non-inferior to NPH. Target glycated hemoglobin (A1C) levels of < 6% at both 24 and 36 gestational weeks were comparable in the IDet and NPH groups (41 vs 32%, respectively, p = 0.28). Furthermore, women in the IDet group had a significantly lower fasting plasma glucose levels and pregnancies tended to reach closer to term. In addition, minor hypoglycemic episodes occurred in > 90% of subjects in both groups and nocturnal hypoglycemia in roughly 80%. Severe hypoglycemic episodes were 3.1
documented in 16 vs 21% of the IDet and NPH groups, respectively (p = 0.615). A similar proportion of patients had deterioration of retinopathy during the study: 7.9 vs 8.9% in the IDet and NPH groups, respectively. Notably, there was no difference in weight gain between the two groups and no maternal deaths were reported. As far as fetal and neonatal complications are concerned, there were no differences in the frequency of malformations, in the overall number of adverse events and in mortality between the two study groups. Severe hypoglycemia can be a limiting factor due to the strict glycemic control recommended for pregnant women with diabetes. Remarkably, present evidence suggests that hypoglycemia has no adverse effects on the fetus in humans [59,60]. In women with T1DM, the risk of severe hypoglycemia is much higher during the first trimester than in the year preceding the pregnancy [61]. Risk factors include hypoglycemia unawareness, severe hypoglycemia in the year preceding the pregnancy, long duration of diabetes and low A1C levels at conception [62]. Severe hypoglycemia has not been well studied in pregnant women with T2DM. In a post hoc analysis of a trial involving continuous glucose monitoring in insulin-treated pregnant women with T1DM and T2DM [63,64], the rates of severe hypoglycemia in women with both T1DM and T2DM were comparable (16 vs 17% respectively). The rate of severe hypoglycemia in pregnant women with T2DM is elevated in the third trimester and is higher than the rate prior to conception [64]. Recently, a retrospective study compared women with T1DM treated with continuous subcutaneous insulin infusion vs multiple daily injections, with IDet as the long-acting insulin [65]. In accordance with the previous prospective study [37,58], the glycemic control, maternal--neonatal outcomes and fetal fat body mass growth were not significantly different. There was a trend towards less hypoglycemic episodes in the IDet group. Likewise, another retrospective study compared pregnancy outcomes and glycemic control between 46 and 67 women with T1DM using insulin glargine and IDet, respectively [66]. No major differences were detected, apart from a lower rate of large for gestational age (LGA) in the glargine group. Several confounders including higher prevalences of smoking, pre-eclampsia or diabetic nephropathy in the glargine group were alluded to this observation. Two additional small case series reported on the use of IDet during pregnancy [67,68]. First, no congenital malformations were identified in a series including 10 women with T1DM. Furthermore, rates of macrosomia or LGA in this report and in studies using other insulin formulations were comparable [67]. Second, several adverse events were reported in a follow-up of 14 women with T1DM and four with T2DM [68]. The complications included severe hypoglycemia, poorly controlled diabetes, fetal anomalies and neonatal death on day 20, all documented in one woman. Half of the offspring were LGA. Most of them experienced neonatal hypoglycemias. In addition, six of eighteen had neonatal
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Table 1. Clinical trials using IDet during pregnancy. Ref.
Study design
[37,58]
RCT
[65]
Retrospective
[66]
Retrospective
[67]
Case series
[68]
Case series
[69]
Case report
Patient no
152 (IDet) vs 158 (NPH) 35(CSII) vs 18 (MDI) (IDet as basal) 67 (IDet) vs 47 (glargine) 10 (IDet) 14 T1DM, 4 T2DM (IDet) 1 (IDet)
Diabetes type
Efficacy
Safety
Neonatal adverse outcomes
T1DM
# FPG in IDet group
No difference
No difference
T1DM
No difference
No difference
T1DM
No difference
# hypoglycemia with IDet No difference
T1DM
N/A
N/A
T1DM T2DM
Poorly controlled diabetes N/A
Severe hypoglycemia N/A
No congenital malformations LGA, NJ, NH and other outcomes* NJ, apnea, ICU admission
T1DM
# LGA with glargine
*Fetal anomalies and neonatal death, respiratory distress syndrome and admission to ICU. CSII: Continuous subcutaneous insulin infusion; DM: Diabetes mellitus; ICU: Intensive care unit; IDet: Insulin detemir; N/A: Not applicable; NJ: Neonatal jaundice; NH: Neonatal hypoglycemia; RCT: Randomized controlled trial.
jaundice requiring phototherapy, three developed respiratory distress syndrome and three were admitted to the intensive care unit. Indeed, this small cohort included subjects with poorly controlled diabetes before and during early pregnancy. Only 5 of 18 women received pre-conception counseling, and the mean pre-conception A1C level was 8.6%. During pregnancy, glycemic control improved but was still unsatisfactory (7.1 and 7% during the second and third trimesters, respectively). Hence, the high level of neonatal complications reported in this study could be related to uncontrolled hyperglycemia. Finally, Sciacca et al. reported on a 25-year old woman with T1DM treated with IDet as the basal insulin [69]. This woman had a preconception A1C level of 8.8%, which reduced slowly during pregnancy to 5.1% at delivery. Adverse neonatal events included jaundice and admission to the intensive care unit due to repeated apneas. In a control visit 16 months after delivery, the baby was healthy with normal growth. In agreement with the previous study, the complications cannot be attributed to IDet use. Rather, possible causes are poorly controlled diabetes and lack of preconception counseling. IDet treatment in patients with T2DM and GDM To the best of our knowledge, the only published data on the use of IDet in pregnant women with T2DM derives from a very small case series mentioned above [68]. Moreover, in patients with GDM we have not found any published data. 3.2
IDet in laboratory animals Female rats exposed to supra-physiological doses of IDet before and during pregnancy produced litters with visceral anomalies. Pregnant rabbits, administered even higher doses during organogenesis, had fetuses with increased incidence of gallbladder abnormalities. These animal studies included concurrent human insulin control groups. They determined 3.3
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that IDet and human insulin had similar embryotoxicity and teratogenicity. This suggests that the effects observed could be attributed to insulin-induced hypoglycemia in normal animals [36]. 4.
Conclusion
Evidence for the use of IDet during pregnancy is scarce. Only one prospective randomized multicenter trial has evaluated the safety and efficacy of IDet in a population of pregnant women with T1DM. However, information on IDet treatment in pregnant women with either T2DM or GDM is lacking. Altogether, it is probable that IDet is not inferior to human insulin in terms of safety and efficacy. 5.
Expert opinion
The use of IDet in pregnancy is expanding, especially after its reclassification by the FDA to category B in 2012. It has several advantages for pregnant women with diabetes. In the sole multicenter trial in T1DM, the IDet group had a significantly lower fasting plasma glucose levels. Overall, IDet was noninferior to NPH insulin in this large study [58]. Women with T1DM in this study used IDet in two very fragile periods, prior to conception and during the first trimester. This trial was only powered to show non-inferiority for A1C at term for IDet compared with NPH, and not to detect a difference with regard to the other safety end points. Still, no elevation in the risk for congenital malformations was detected. Hence, it is reasonable to determine that IDet is similarly safe in other diabetes types treated with insulin, T2DM and GDM. Insulin treatment use during gestation in GDM or T2DM is usually shorter or the same as in T1DM. Studies evaluating the safety and efficacy of IDet for these diabetes types during pregnancy are lacking.
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Insulin detemir
IDet was non-inferior to NPH insulin during pregnancy regarding severe hypoglycemic episodes [37,70]. Actually, IDet administration leads to a reduced number of severe hypoglycemic episodes in non-pregnant patients with DM as compared with insulins NPH and glargine [71]. Weight gain during pregnancy using IDet or insulin NPH treatments was comparable [37]. Obesity is a major risk factor in the etiology of T2DM and GDM [72]. Also, gestational weight gain during the first trimester is associated with an increased risk for developing GDM [16]. IDet is not associated with weight gain in non-pregnant patients, especially in the morbidly obese subgroup. The mechanism for this weight sparing effect is not fully understood. Several hypotheses supporting this include a reduced rate of hypoglycemic episodes, suppression of hepatic glucose output and elevated satiety signaling within the central nervous system [73,74]. As weight gain generally plays an important role in the pathophysiology of diabetes, and particularly during pregnancy, this quality of IDet becomes an advantage. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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In summary, the use of IDet during pregnancies complicated by T2DM and GDM should be the subject of further investigation. Possibly, it will establish the role of IDet as the preferable basal insulin during every stage of pregnancy from conception to delivery.
Acknowledgment R Koren and Y Toledano equally contributed to this manuscript.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. a nationwide, population-based study. Diabet care 2004;27(12):2819-23
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intensive insulin therapy for pregnant women with insulin-dependent diabetes mellitus. Obstet Gynecol 1995;85(3):417-22 60.
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Mello G, Biagioni S, Ottanelli S, et al. Continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI) of rapid-acting insulin analogues and detemir in type 1 diabetic (T1D) pregnant women. J Matern Fetal Neonatal Med 2014;1-6 Callesen NF, Damm J, Mathiesen JM, et al. Treatment with the long-acting insulin analogues detemir or glargine during pregnancy in women with type 1 diabetes: comparison of glycaemic control and pregnancy outcome. J Matern Fetal Neonatal Med 2013;26(6):588-92
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Lapolla A, Di Cianni G, Bruttomesso D, et al. Use of insulin detemir in pregnancy: a report on 10 type 1 diabetic women. Diabet Med 2009;26(11):1181-2
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Shenoy VV, Cook SJ, Parry AF, et al. Audit of insulin detemir in pregnancy: a retrospective case series. Diabet Med 2012;29(7):958-9
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Pedersen-Bjergaard U, Kristensen PL, Beck-Nielsen H, et al. Effect of insulin analogues on risk of severe hypoglycaemia in patients with type 1 diabetes prone to recurrent severe hypoglycaemia (HypoAna trial): a prospective, randomised, open-label, blinded-endpoint crossover trial. Lancet Diabetes Endocrinol 2014;2(7):553-61
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Haukka J, Hoti F, Erasto P, et al. Evaluation of the incidence and risk of hypoglycemic coma associated with selection of basal insulin in the treatment of diabetes: a Finnish register linkage study. Pharmacoepidemiol Drug Saf 2013;22(12):1326-35
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Cavicchia PP, Liu J, Adams SA, et al. Proportion of gestational diabetes mellitus attributable to overweight and obesity among non-hispanic black, non-hispanic white, and hispanic women in South Carolina. Matern Child Health J 2014;18(8):1919-26
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Haak T, Tiengo A, Draeger E, et al. Lower within-subject variability of fasting blood glucose and reduced weight gain with insulin detemir compared to NPH insulin in patients with type 2 diabetes. Diabetes Obes Metab 2005;7(1):56-64
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Affiliation Ronit Koren1,2 MD, Yoel Toledano3 MD & Moshe Hod†2,3 MD † Author for correspondence 1 Institute of Endocrinology, Beilinson Hospital, Rabin Medical Center, 49100 Petah Tikva, Israel 2 Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Tel: +972528888899; Fax: +97299503516; E-mail: [email protected] 3 Division of Maternal Fetal Medicine, Helen Schneider Women’s Hospital, Rabin Medical Center, Beilinson Hospital, 49100 Petah Tikva, Israel
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The use of insulin detemir during pregnancy: a safety evaluation Ronit Koren, Yoel Toledano & Moshe Hod† Introduction
2.
Mechanism of detemir action
3.
Efficacy and safety of detemir during pregnancy
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†
1.
4.
Conclusion
5.
Expert opinion
Tel Aviv University, Helen Schneider Hospital for Women, Rabin Medical Center, Division of Maternal Fetal Medicine, Sackler Faculty of Medicine, Petah-Tiqva, Israel
Introduction: Diabetes during pregnancy causes both fetal and maternal complications. Insulin is the most effective pharmacological treatment for controlling hyperglycemia during gestation and can limit adverse outcomes. Insulin detemir (IDet), a novel basal insulin, has already been used for this indication for several years. It was reclassified in 2012 by the FDA from category C to category B for the treatment of pregnant women with diabetes. Areas covered: This article reviews published data regarding the use of IDet during pregnancy. We discuss pharmacokinetic and pharmacodynamic qualities of IDet and potential advantages for its use during pregnancy. Expert opinion: IDet is a viable option for the management of diabetes during pregnancy. Though data is limited, its safety and efficacy is probably comparable to human insulin, and in some aspects superior to it. More data, specifically for IDet in pregnancies complicated by gestational diabetes (GDM) or type 2 diabetes, is needed. Keywords: detemir, diabetes mellitus, gestational, pregnancy, safety Expert Opin. Drug Saf. (2015) 14(4):593-599
1.
Introduction
Gestational diabetes (GDM) is defined as a condition associated with maternal hyperglycemia, which is less severe than in overt diabetes. Nevertheless, it is associated with an increased risk of adverse pregnancy outcomes [1]. It accounts for > 90% of diabetes during pregnancy [2]. Pregestational diabetes, type 1 (T1DM) or type 2 (T2DM), accounts for 1.8% of all diabetes among pregnant women [3]. The prevalence of GDM is estimated to be 7% in the United States and between 1 -- 25% around the world, depending on the diagnostic criteria and patient’s demographics [4,5]. The rising prevalence of diabetes during pregnancy in the last years is attributed to the increased obesity rate and maternal age. Moreover, it contributes to the worldwide diabetes epidemic [3,6]. Adopting the diagnostic criteria based on the Hyperglycemia and Adverse Pregnancy Outcomes study will increase this prevalence even more [1]. Pregestational diabetes causes maternal, fetal and neonatal complications, including congenital malformations, spontaneous abortions, macrosomia [7,8], spontaneous preterm delivery [9], perinatal mortality [10], pre-eclampsia, cesarean section, postpartum hemorrhage and maternal mortality [11,12]. Strict glycemic control has shown to decrease the rate of these complications although not to the level achieved in the general population [11,13]. In addition to these complications, GDM as well as pregestational diabetes is associated with an increased risk of shoulder dystocia, neonatal hypoglycemia, hyperbilirubinemia and extended maternal and neonatal hospitalizations [14-17]. Similar to pregestational diabetes, treating GDM is associated with a decrease in the incidence of these complications [18]. In women who could not achieve glycemic control with lifestyle modification and medical nutrition therapy, pharmacologic treatment is indicated. Insulin is the main therapy for pregestational diabetes. However, in women with GDM oral 10.1517/14740338.2015.1013533 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name (generic) Phase Indication Mechanism of action Route of administration Chemical structure
Insulin detemir Launched, Category B for pregnancy Indicated to improve glycemic control in adults and children with diabetes mellitus Long-acting human insulin analog Subcutaneous C14 fatty acid chain (myristic acid)
Pro
Thr
Tyr
Phe Phe Gly
Arg Glu
Lys
Gly
B29
Thr
Cys
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A21 Asn Cys
Val
Tyr
Leu
Asn A1
Gly Ile
Glu
Tyr
Leu
Leu
Gln
Val
Ala
Tyr
Glu
Glu
Leu
Gln Cys Cys Thr
Ser
Ile
Cys
Val
Ser
Leu His Ser Gly
B1 Phe Val
Pivotal trials
Cys His Leu
[37,58]
glyburide and metformin were also suggested as therapeutic options [19-21], although their use is still controversial and further research is needed [22]. Traditionally, only human insulin was used during pregnancy. Compared to human insulin, insulin analogs have been shown to result with a similar or a better glycemic control as well as a lower risk of hypoglycemia and weight gain in non-pregnant subjects with T1DM or T2DM [23-25]. Use of the short-acting insulin analogs lispro and aspart during pregnancy is considered safe [26,27]. They may also convey advantages for maternal glycemic control over human insulin, for example, a diminished rate of hypoglycemic episodes [28-31]. The long-acting insulin analogs detemir and glargine are also administered during pregnancy. However, the data on insulin glargine during gestation is limited to retrospective studies [32-34]. These reports show no significant difference in safety and efficacy compared to NPH insulin. Instead, insulin detemir (IDet) (Box 1) treatment in women with T1DM had a better control of fasting plasma glucose, without an increase in hypoglycemia rate, compared to NPH [35]. IDet was reclassified from class C to class B (i.e., does not increase the risk of harm to the fetus) in 2012 [36]. This new classification was based on animal data [36] and on a prospective clinical study in women with T1DM [37]; the aim of this review is to evaluate the efficacy and safety of IDet administration in women with pregestational diabetes and GDM. 594
Asn Gln
2.
Mechanism of detemir action
IDet (LysB29-tetradecanoyl des-(B30)) is a long-acting soluble insulin analog, in which the threonine residue at the position B30 has been removed and a 14-carbon fatty acid side chain has been attached to position B29 [38]. It has a protracted action attributed to the strong self-association of IDet hexameric molecules at the injection site and a strong binding to albumin in the bloodstream [39]. It is supplied as a clear solution. Its absorption is not dependent on resuspension before injection, or on formation and dissolution of microprecipitates in contrast to insulins NPH and glargine, respectively [40]. It has a slower onset and a less pronounced peak of action compared with NPH insulin [41]. The activity profile of IDet was flatter than insulin NPH in clamp studies in patients with T1DM as well as T2DM [42,43]. A review summarizing glucose clamp studies reported that the mean duration of action of IDet is close to 24 h in patients with T1DM and probably longer in patients with T2DM. However, this does not necessarily represent the actual duration of action in each individual. The standard deviation is considerable, and the exact dosing can vary between individuals [44]. The diminished within-subject variability and reduced risk of hypoglycemia may be related to the protracted absorption and flat activity profile of IDet vs NPH [42,45]. Concerns about the metabolic and mitogenic properties of insulin analogs have been raised. The mitogenic potential of
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Insulin detemir
insulin is mediated in part by its affinity to the IGF-1 receptor. Insulin glargine has a six to eightfold increased IGF-1 receptor affinity compared with human insulin, whereas IDet has 15 times lower affinity [46,47]. In vivo, insulin glargine is converted into two active metabolites (M1 and M2) that have lower affinity to the IGF-1 receptor [48,49]. In experimental cell culture models both insulin glargine and IDet had an increased mitogenic activity in comparison to short-acting analogs and human insulin [50]. These in vitro results might not have major clinical relevance as in vivo IDet is bound to albumin at concentrations higher than those used in this study. In contrast, Varewijck et al. found that IGF-1 receptor is not activated at all by IDet [51]. Together, the mitogenic activity of different insulin formulations and the possible effect on embryonic development remain to be explored. It is assumed that insulin cannot cross the placenta because of its large molecular weight [52]. Still, transfer of insulin-antiinsulin-antibody complexes has been detected in women with T1DM administered non-human insulin. It was associated with anti-insulin antibodies in the mother at the time of delivery [53]. Currently, there is no data regarding transplacental transfer of IDet. Rates of insulin absorption, onset and action duration may be affected by injection site, exercise, obesity, age, renal dysfunction, and dose [54,55]. During pregnancy, insulin requirements tend to fall during the first trimester and rise during the second and third trimesters [56]. In addition, peak postprandial plasma insulin concentrations rise slower during late pregnancy. This, in turn, can impact the timing of prandial insulin administration [57]. There is insufficient data regarding pharmacokinetics and pharmacodynamics of insulin analogs during pregnancy.
Efficacy and safety of detemir during pregnancy
3.
IDet treatment in patients with T1DM Few studies have examined the efficacy and safety of IDet during pregnancy despite its increasing use in this population. The clinical trials are summarized in (Table 1). A randomized, open-label, multinational parallel-group trial compared the safety and efficacy of IDet vs NPH insulin in pregnant women with T1DM [37,58]. Three hundred and ten women with T1DM were randomized before or during early pregnancy to receive IDet or NPH, both in combination with insulin aspart in a basal-bolus regimen. The efficacy of IDet was found to be non-inferior to NPH. Target glycated hemoglobin (A1C) levels of < 6% at both 24 and 36 gestational weeks were comparable in the IDet and NPH groups (41 vs 32%, respectively, p = 0.28). Furthermore, women in the IDet group had a significantly lower fasting plasma glucose levels and pregnancies tended to reach closer to term. In addition, minor hypoglycemic episodes occurred in > 90% of subjects in both groups and nocturnal hypoglycemia in roughly 80%. Severe hypoglycemic episodes were 3.1
documented in 16 vs 21% of the IDet and NPH groups, respectively (p = 0.615). A similar proportion of patients had deterioration of retinopathy during the study: 7.9 vs 8.9% in the IDet and NPH groups, respectively. Notably, there was no difference in weight gain between the two groups and no maternal deaths were reported. As far as fetal and neonatal complications are concerned, there were no differences in the frequency of malformations, in the overall number of adverse events and in mortality between the two study groups. Severe hypoglycemia can be a limiting factor due to the strict glycemic control recommended for pregnant women with diabetes. Remarkably, present evidence suggests that hypoglycemia has no adverse effects on the fetus in humans [59,60]. In women with T1DM, the risk of severe hypoglycemia is much higher during the first trimester than in the year preceding the pregnancy [61]. Risk factors include hypoglycemia unawareness, severe hypoglycemia in the year preceding the pregnancy, long duration of diabetes and low A1C levels at conception [62]. Severe hypoglycemia has not been well studied in pregnant women with T2DM. In a post hoc analysis of a trial involving continuous glucose monitoring in insulin-treated pregnant women with T1DM and T2DM [63,64], the rates of severe hypoglycemia in women with both T1DM and T2DM were comparable (16 vs 17% respectively). The rate of severe hypoglycemia in pregnant women with T2DM is elevated in the third trimester and is higher than the rate prior to conception [64]. Recently, a retrospective study compared women with T1DM treated with continuous subcutaneous insulin infusion vs multiple daily injections, with IDet as the long-acting insulin [65]. In accordance with the previous prospective study [37,58], the glycemic control, maternal--neonatal outcomes and fetal fat body mass growth were not significantly different. There was a trend towards less hypoglycemic episodes in the IDet group. Likewise, another retrospective study compared pregnancy outcomes and glycemic control between 46 and 67 women with T1DM using insulin glargine and IDet, respectively [66]. No major differences were detected, apart from a lower rate of large for gestational age (LGA) in the glargine group. Several confounders including higher prevalences of smoking, pre-eclampsia or diabetic nephropathy in the glargine group were alluded to this observation. Two additional small case series reported on the use of IDet during pregnancy [67,68]. First, no congenital malformations were identified in a series including 10 women with T1DM. Furthermore, rates of macrosomia or LGA in this report and in studies using other insulin formulations were comparable [67]. Second, several adverse events were reported in a follow-up of 14 women with T1DM and four with T2DM [68]. The complications included severe hypoglycemia, poorly controlled diabetes, fetal anomalies and neonatal death on day 20, all documented in one woman. Half of the offspring were LGA. Most of them experienced neonatal hypoglycemias. In addition, six of eighteen had neonatal
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Table 1. Clinical trials using IDet during pregnancy. Ref.
Study design
[37,58]
RCT
[65]
Retrospective
[66]
Retrospective
[67]
Case series
[68]
Case series
[69]
Case report
Patient no
152 (IDet) vs 158 (NPH) 35(CSII) vs 18 (MDI) (IDet as basal) 67 (IDet) vs 47 (glargine) 10 (IDet) 14 T1DM, 4 T2DM (IDet) 1 (IDet)
Diabetes type
Efficacy
Safety
Neonatal adverse outcomes
T1DM
# FPG in IDet group
No difference
No difference
T1DM
No difference
No difference
T1DM
No difference
# hypoglycemia with IDet No difference
T1DM
N/A
N/A
T1DM T2DM
Poorly controlled diabetes N/A
Severe hypoglycemia N/A
No congenital malformations LGA, NJ, NH and other outcomes* NJ, apnea, ICU admission
T1DM
# LGA with glargine
*Fetal anomalies and neonatal death, respiratory distress syndrome and admission to ICU. CSII: Continuous subcutaneous insulin infusion; DM: Diabetes mellitus; ICU: Intensive care unit; IDet: Insulin detemir; N/A: Not applicable; NJ: Neonatal jaundice; NH: Neonatal hypoglycemia; RCT: Randomized controlled trial.
jaundice requiring phototherapy, three developed respiratory distress syndrome and three were admitted to the intensive care unit. Indeed, this small cohort included subjects with poorly controlled diabetes before and during early pregnancy. Only 5 of 18 women received pre-conception counseling, and the mean pre-conception A1C level was 8.6%. During pregnancy, glycemic control improved but was still unsatisfactory (7.1 and 7% during the second and third trimesters, respectively). Hence, the high level of neonatal complications reported in this study could be related to uncontrolled hyperglycemia. Finally, Sciacca et al. reported on a 25-year old woman with T1DM treated with IDet as the basal insulin [69]. This woman had a preconception A1C level of 8.8%, which reduced slowly during pregnancy to 5.1% at delivery. Adverse neonatal events included jaundice and admission to the intensive care unit due to repeated apneas. In a control visit 16 months after delivery, the baby was healthy with normal growth. In agreement with the previous study, the complications cannot be attributed to IDet use. Rather, possible causes are poorly controlled diabetes and lack of preconception counseling. IDet treatment in patients with T2DM and GDM To the best of our knowledge, the only published data on the use of IDet in pregnant women with T2DM derives from a very small case series mentioned above [68]. Moreover, in patients with GDM we have not found any published data. 3.2
IDet in laboratory animals Female rats exposed to supra-physiological doses of IDet before and during pregnancy produced litters with visceral anomalies. Pregnant rabbits, administered even higher doses during organogenesis, had fetuses with increased incidence of gallbladder abnormalities. These animal studies included concurrent human insulin control groups. They determined 3.3
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that IDet and human insulin had similar embryotoxicity and teratogenicity. This suggests that the effects observed could be attributed to insulin-induced hypoglycemia in normal animals [36]. 4.
Conclusion
Evidence for the use of IDet during pregnancy is scarce. Only one prospective randomized multicenter trial has evaluated the safety and efficacy of IDet in a population of pregnant women with T1DM. However, information on IDet treatment in pregnant women with either T2DM or GDM is lacking. Altogether, it is probable that IDet is not inferior to human insulin in terms of safety and efficacy. 5.
Expert opinion
The use of IDet in pregnancy is expanding, especially after its reclassification by the FDA to category B in 2012. It has several advantages for pregnant women with diabetes. In the sole multicenter trial in T1DM, the IDet group had a significantly lower fasting plasma glucose levels. Overall, IDet was noninferior to NPH insulin in this large study [58]. Women with T1DM in this study used IDet in two very fragile periods, prior to conception and during the first trimester. This trial was only powered to show non-inferiority for A1C at term for IDet compared with NPH, and not to detect a difference with regard to the other safety end points. Still, no elevation in the risk for congenital malformations was detected. Hence, it is reasonable to determine that IDet is similarly safe in other diabetes types treated with insulin, T2DM and GDM. Insulin treatment use during gestation in GDM or T2DM is usually shorter or the same as in T1DM. Studies evaluating the safety and efficacy of IDet for these diabetes types during pregnancy are lacking.
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Insulin detemir
IDet was non-inferior to NPH insulin during pregnancy regarding severe hypoglycemic episodes [37,70]. Actually, IDet administration leads to a reduced number of severe hypoglycemic episodes in non-pregnant patients with DM as compared with insulins NPH and glargine [71]. Weight gain during pregnancy using IDet or insulin NPH treatments was comparable [37]. Obesity is a major risk factor in the etiology of T2DM and GDM [72]. Also, gestational weight gain during the first trimester is associated with an increased risk for developing GDM [16]. IDet is not associated with weight gain in non-pregnant patients, especially in the morbidly obese subgroup. The mechanism for this weight sparing effect is not fully understood. Several hypotheses supporting this include a reduced rate of hypoglycemic episodes, suppression of hepatic glucose output and elevated satiety signaling within the central nervous system [73,74]. As weight gain generally plays an important role in the pathophysiology of diabetes, and particularly during pregnancy, this quality of IDet becomes an advantage. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Acknowledgment R Koren and Y Toledano equally contributed to this manuscript.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. a nationwide, population-based study. Diabet care 2004;27(12):2819-23
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Affiliation Ronit Koren1,2 MD, Yoel Toledano3 MD & Moshe Hod†2,3 MD † Author for correspondence 1 Institute of Endocrinology, Beilinson Hospital, Rabin Medical Center, 49100 Petah Tikva, Israel 2 Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Tel: +972528888899; Fax: +97299503516; E-mail: [email protected] 3 Division of Maternal Fetal Medicine, Helen Schneider Women’s Hospital, Rabin Medical Center, Beilinson Hospital, 49100 Petah Tikva, Israel
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