Use of antidiabetic agents in the treatment of gestational diabetes mellitus in Germany,

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1 bs_bs_banner doi: /jog J. Obstet. Gynaecol. Res. Vol. 40, No. 6: , June 2014 Use of antidiabetic agents in the treatment of gestational diabetes mellitus in Germany, Christina Heilmaier 1, Christian Thielscher 1, May Ziller 2, Verena Altmann 3 and Karel Kostev 3 1 FOM University of Applied Sciences, Essen, 2 Department of Gynecological Endocrinology, Reproductive Medicine and Osteoporosis, Philipps-University of Marburg, Marburg, and 3 IMS Health, Frankfurt, Germany Abstract Aim: Adequate blood glucose control during pregnancy is important because gestational diabetes mellitus (GDM) is known to have adverse effects on the mother and child. Due to an increasing prevalence of GDM in recent years, more information on the use of different antidiabetic agents is required, which was the aim of the present study. Material and Methods: Data from 32 diabetic practices in Germany were collected from January 2008 to December 2012 and analyzed using the Disease Analyzer Database. All women with International Classification of Diseases diagnosis O24 (that is, GDM) participated, except for patients with known type I or II diabetes mellitus, who were excluded. Analysis focused on the proportion of women requiring drug treatment in general. Thereafter, subanalysis was performed with a focus on the administration of different antidiabetic agents, namely insulin, metformin, and sulfonylurea. Results: Within the given timeframe, medication-based treatment for GDM significantly rose to reach 30.8% of all women with GDM. Both the administration of insulin and metformin grew considerably within the 5-year period with metformin being increasingly used without supplemental insulin and at lower dosages. Within the insulin treatment arm, insulin analogues became increasingly important. The proportion of sulfonylurea remained stable (0.2%). Conclusions: GDM is more often treated with antidiabetic agents and, due to the fact that metformin is more frequently prescribed, it can be assumed that it is increasingly regarded as a safe and effective alternative to insulin. Key words: disease analyzer, gestational diabetes mellitus, insulin, metformin, treatment. Introduction The prevalence of type II diabetes mellitus (DM2), and its numerous comorbidities, such as cardiovascular or kidney disease, is spiraling and already affected around 5.75% of the German population in At the same time, the frequency of gestational diabetes mellitus (GDM) also increased and is now reported in 2 6% of all pregnancies in Europe 2 and up to 7% of all pregnancies in the USA. 3 In general, GDM constitutes carbohydrate intolerance with respect to an impaired glucose tolerance with an initial onset or recognition during pregnancy. 4 As demonstrated in several studies, GDM leads to adverse outcomes for both the mother and child, such as macrosomia, primary cesarean delivery, neonatal Received: July Accepted: December Reprint request to: Dr Karel Kostev, IMS Health, Epidemiology, Darmstädter Landstrasse 108, Frankfurt, Germany. kkostev@de.imshealth.com The Authors

2 Antidiabetic agents in GDM hypoglycemia, pre-eclampsia, shoulder dystocia, or an increased risk of adiposity and type II diabetes in later life. 5 9 As a result of the large-scaled Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study that showed a continuous and graded correlation between maternal glucose concentrations already below those currently diagnostically indicative of diabetes and the risk for an adverse perinatal outcome, 6 the International Association for Diabetes in Pregnancy Study Group (IADPSG) has reviewed and revised the criteria to diagnose GDM. According to the modified IADPSG criteria, GDM should now be diagnosed in the presence of a positive 75-g oral glucose tolerance test (OGTT) with a fasting glucose 5.1 mmol/l, a 1-h glucose 10.0 mmol/l, and/or a 2-h glucose 8.5 mmol/l. 10 GDM is usually caused by a reduced insulin sensitivity in human cells, which is a common phenomenon in pregnant women and which is due to the progressively rising levels of fetoplacental hormones, such as progesterone, cortisol, growth hormone, prolactin, and human placental lactogen. 11 Normally, pancreatic insulin secretion increases, which compensates; but, if this countermeasure fails or insulin secretion declines for other reasons, such as β-cell dysfunction, GDM occurs. 12,13 As in DM2, the primary intervention recommended to women diagnosed with GDM is dietary counseling in combination with an adjustment to the amount and type of physical activity ( lifestyle advice ). 12,14 If these measures do not succeed in terms of achieving optimal glycemic control, subcutaneous insulin therapy thus far has been the standard of treatment given that data were missing on the possible teratogenicity associated with the transplacental transfer of oral hypoglycemic agents and any potential maternal and neonatal adverse events. However, in light of recent studies, especially the Metformin in Gestational Diabetes (MIG) trial 15 that showed no differences in neonatal outcomes when metformin and subcutaneous insulin therapy were compared, both metformin and sulfonylurea have been increasingly effectively and safely used in the treatment of GDM Despite these results, which have been favorable for metformin, it has not yet been formally approved for GDM therapy 18 and remains offlabel for use with very little known on the actual number of pregnant women treated with metformin. The aim of our study, therefore, was to learn more about the distribution of different therapeutic regimens in GDM in a large patient cohort (>6500 women with newly diagnosed GDM) with a special focus on the percentage of women receiving insulin, metformin or sulfonylurea, respectively. We analyzed data from a 5-year period (January 2008 to December 2012) and also assessed whether changes in prescription manner were noticeable as a response to the increasing availability of data dealing with metformin or sulfonylurea use compared to insulin during pregnancy. Methods The Disease Analyzer Database (IMS HEALTH) collects drug prescriptions, diagnoses, and basic medical and demographic data directly from the practice computer systems of registered doctors. 19 Diagnoses (International Classification of Diseases [ICD]-10), prescriptions (Anatomical Therapeutic Chemical [ATC] Classification System), and the quality of the reported data were monitored by IMS based on a number of criteria (completeness of documentation, linkage between diagnoses and prescriptions, etc.). The sampling methods for the selection of physicians practices were appropriate to obtain a representative database of primary care practices. 20 Prescription statistics for several drugs were very similar to the available data from pharmaceutical prescription reports. 20 The period of database analysis was 2 separate years, namely, from January 2008 to December 2008 and from January 2012 to December An initial diagnosis of GDM (ICD: O24) was defined as the index date. All subjects with a first-time prescription of insulin (ATC: A10C) or metformin (ATC: A10J) were selected, while an earlier confirmed diagnosis of type I or type II diabetes (ICD: E10, E11, E14) led to exclusion from the study sample. The main outcome measures were the proportion of women requiring drug therapy for the treatment of GDM. Three treatment arms were defined and separately analyzed: (i) insulin; (ii) metformin; and (iii) sulfonylurea. The remaining patients who achieved blood sugar control by lifestyle modifications alone were assigned to the no treatment group, and did not undergo further analysis. Within the insulin arm, it was also determined whether human insulin or insulin analogues were used; in the metformin group, the supplemental administration of insulin was assessed. Results were given as means ± standard deviations and proportions. Demographic data available included patient age and health insurance (private vs statutory health insurance). Differences in the characteristics of patients with incident 2014 The Authors 1593

3 C. Heilmaier et al. insulin and metformin therapy were assessed using χ 2 -tests. All analyses were carried out using sas 9.2. Results A total of 6516 women from 32 diabetic practices in Germany with a diagnosis of GDM were included in the study. There were 1273 women in 2008 and 1323 women in 2012 for comparisons between 2008 and The mean age of patients was 32.3 ± 5.4 years with no significant differences found between the different treatment arms (P = 0.520) or within a particular treatment arm (P = 0.649) when data from 2008 and 2012 were compared. Moreover, insurance status distribution was similar (P = 0.552), meaning that insurance status did not influence the prescription of specific agents. The average recorded body mass index was high in all samples (about 31 kg/m 2 ); again, no significant differences were found between nor within a treatment arm (P > 0.05). As can be seen from Figure 1, the proportion of women requiring drug therapy to achieve adequate glycemic control significantly rose between 2008 (22.5%) and 2012 (30.8%, P < 0.001). Within the antidiabetic agents, the proportion of women receiving metformin prescriptions increased from 1.6% in 2008 to 5.3% in 2012 (P < 0.001). At the same time, the proportion of insulin-treated women grew from 20.4% in 2008 to 26.4% in 2012 (P < 0.001) (Fig. 2). The prescription of sulfonylurea remained stable during this period of time and made up only 0.2% of the sample. Within the metformin treatment arm, it was noted that 48.7% of patients required additional insulin in 2008 to achieve adequate blood sugar control, while in 2012 only 27.2% of women needed supplemental agents for metformin (P < 0.001). Interestingly, the mean metformin dosages considerably decreased within the given timeframe, namely from 1857 ± 326 mg in 2008 to 1067 ± 484 mg in 2012 (P = 0.02). There were more women using insulin analogues in 2012 compared with 2008 (35.8% vs 21.4% of insulin users, P < 0.001). Contrary to this, the proportion of patients with human insulin therapy decreased from 78.6% in 2008 to 64.2% in 2012 (P < 0.001) (Fig. 3). Discussion The prevalence of GDM has considerably increased in recent years. 21,22 At the same time, the number of patients for whom lifestyle modifications alone failed in achieving adequate postprandial glucose targets Figure 2 Both the proportion of ( ) insulin-treated women as well as the proportion of ( ) women receiving metformin considerably increased from 2008 to GD, gestational diabetes. 35% 30% 25% 22.5% 23.7% 26.3% 28.4% 30.8% Women (%) 20% 15% 10% 5% 0% Figure 1 From 2008 to 2012, an increase in the proportion of women who needed antidiabetic agents for gestational diabetes mellitus treatment was found. Figure 3 While ( ) insulin analogues are increasingly used, the proportion of ( ) human insulin has decreased from 2008 to The Authors

4 Antidiabetic agents in GDM and, therefore, requiring drug therapy for GDM, also rose, 23 which was also seen in our study, with a significant increase between 2008 and This development awakens interest in gaining more information on antidiabetic drug therapy in pregnancy, which was the focus of the present study. Glucose levels directly influence maternal and neonatal outcomes and even glucose values lower than normally diagnostic for diabetes seem to have an adverse effect, such that strict glycemic control is necessary. Several studies have been conducted comparing the efficiency and tolerability of different antidiabetic agents, such as insulin, sulfonylurea, and metformin. Historically, insulin was used for GDM as it does not cross the placenta (from maternal to fetal circulation) 18 and due to the fact that only limited data on oral antidiabetics were available. 24 Insulin was the most often prescribed agent in our study, too, and correspondingly, as the number of women needing medication-based treatment increased, so too did the proportion of insulin prescriptions. The trend towards a preference for the administration of insulin analogues instead of human insulin, as detected in our study, might be due to the fact that insulin analogues are known to cause less hypoglycemia when compared with human insulin. Thus, new German guidelines recommend the use of insulin analogues as short-acting agents. However, insulin holds several disadvantages, such as the requirement of intensive educational instruction at the beginning of therapy, its subcutaneous application, the necessity of ideal storage conditions, stringent blood glucose monitoring as well as the fact that it is much costlier than oral antidiabetics. Therefore, patients prefer metformin to insulin 15 and treatment compliance is probably improved. 25 Moreover, oral antidiabetics have a good compatibility with pregnancy. For example, in various studies, 15,25,26 the metformin discontinuation rate was found to range between just 2 and 6% and this was mainly due to intolerable gastrointestinal side-effects. While sulfonylureas are the most commonly applied oral antidiabetics in GDM in the USA, 23 these medications are rarely used in Germany for this indication, and this is also reflected in our study with a proportion of only 0.2%. Contrary to that, the use of metformin grew considerably in Germany in recent years (also detected in our study) due to its additional advantages when compared to both insulin and sulfonylurea: it does not lead to maternal hypoglycemia, ameliorates insulin sensitivity, and is not accompanied by weight gain. 27 The latter is especially beneficial because of the obesity often encountered in women suffering from GDM. 15 Rowan et al. showed that patients on metformin had gained less weight between the time of study enrolment and 36 weeks of gestation than had women treated with insulin and those women who received a combination of metformin and supplemental insulin (between 18 and 46% across studies 15,28,29 ) required fewer insulin doses. 15,25 Interestingly, in our study, almost half (48.7%) of all women treated with metformin required additional insulin in 2008, which is a comparable proportion to that found in the MIG trial, 15 while just 27.2% needed supplemental insulin in 2012, constituting a significant decrease (P < 0.001). Thus, not only did the number of patients treated with metformin considerably increase within a 5-year period, but so did the proportion of women achieving sufficient blood sugar control with metformin administration alone. This is especially of interest as, at the same time, mean metformin dosages significantly decreased. Perhaps more effort was spent in lifestyle modifications, such as dietary changes, in 2012, leading to an improved insulin sensitivity, so that less metformin was required. Although metformin crosses the placenta leading to concentrations similar to those present in maternal circulation, 30 it neither increases the rate of congenital malformations 31,32 nor harms fetal or neonatal growth. 25,33 35 However, it has advantages, such as a significantly lower incidence of neonatal hypoglycemia, 15,36 maternal hypertonia, 37 and pre-eclampsia, 15,28,38 and fewer neonatal admissions to the intensive care unit 38 than in the insulin group. Other benefits appear to include a reduced rate of macrosomia, 25 which is probably responsible for a reduction in the number of cesarean deliveries. 38 In addition to favorable primary outcomes, the first long-term follow-up results from 1.5- to 2-year-old children did not reveal any differences regarding diet and motor and social development when compared to children of mothers not exposed to any antidiabetic agent. 39,40 Instead, the Offspring Follow-Up (TOFU) study showed that children of the metformin treatment arm had a metabolically healthier pattern of fat distribution, namely, less ectopic or visceral fat and more subcutaneous fat stores, 41,42 which is regarded as an important predictor of insulin resistance and an adverse metabolic consequence of adiposity. 41,43 On the contrary, some studies found a significantly higher rate (up to 12.1%) of preterm birth in metformin-treated pregnancies, 15,26,29,37,44 but this was not detected throughout. 28 Due to the fact that 2014 The Authors 1595

5 C. Heilmaier et al. birthweight did not significantly differ between the insulin only and the metformin groups, 16,28,36,45 its significance remains unclear. We are aware of the following study limitations: retrospective primary care database analyses are in general limited by the validity and completeness of the data. In particular, no valid information on the onset of GDM, change in diagnostic procedures (screening), prescribed daily insulin doses, and important outcome measures (e.g., hypoglycemia) were available in the database. In particular, the onset of GDM might have been of interest as one may hypothesize that, the earlier GDM was diagnosed, the more frequent patients would have consulted their doctors possibly leading to improved GDM treatment. Data on socioeconomic status and lifestyle-related risk factors (e.g., smoking, alcohol, physical activity) were also lacking. Moreover, no information about ethnicity is available. An additional important variable that cannot be estimated from the database is birthweight. However, the aim of our study was to assess the general trend for the prescription manner in GDM, which could be sufficiently answered by the data available. In summary, our study was the first that confirmed in a large study cohort that GDM is increasingly treated with antidiabetic agents and that metformin is increasingly seen as an effective and safe agent for this purpose. Although the initial long-term results are encouraging regarding the use of metformin in pregnancy, it will be the task of future follow-up studies to assess the possible differences in childhood between children exposed to metformin and those exposed to insulin in utero, which might lead to further changes in prescription manner in GDM. Disclosure None declared. References 1. Wilke T, Ahrendt P, Schwartz D, Linder R, Ahrens S, Verheyen F. 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