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doi:10.1111/jog.12384
J. Obstet. Gynaecol. Res. Vol. 40, No. 6: 1592–1597, June 2014
Use of antidiabetic agents in the treatment of gestational diabetes mellitus in Germany, 2008–2012 Christina Heilmaier1, Christian Thielscher1, May Ziller2, Verena Altmann3 and Karel Kostev3 1 FOM University of Applied Sciences, Essen, 2Department of Gynecological Endocrinology, Reproductive Medicine and Osteoporosis, Philipps-University of Marburg, Marburg, and 3IMS 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 2009.1 At the same time, the frequency of gestational diabetes mellitus (GDM) also increased and is now reported in
2–6% of all pregnancies in Europe2 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 9 2013. Accepted: December 13 2013. Reprint request to: Dr Karel Kostev, IMS Health, Epidemiology, Darmstädter Landstrasse 108, 60598 Frankfurt, Germany. Email: [email protected]
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© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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) trial15 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.15–17 Despite these results, which have been favorable for metformin, it has not yet been formally approved for GDM therapy18 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 2012. 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
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insulin and metformin therapy were assessed using χ2-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 2012. 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/m2); 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 2012. GD, gestational diabetes.
35% 30.8% 30% 26.3%
Women (%)
25%
22.5%
28.4%
23.7%
20% 15% 10% 5% 0%
2008
2009
2010
2011
2012
Figure 1 From 2008 to 2012, an increase in the proportion of women who needed antidiabetic agents for gestational diabetes mellitus treatment was found.
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Figure 3 While (■) insulin analogues are increasingly used, the proportion of (□) human insulin has decreased from 2008 to 2012.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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 2012. 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 insulin15 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 studies15,28,29) 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 malformations31,32 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 unit38 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 Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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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. [Incidence and prevalence of type 2 diabetes mellitus in Germany: An analysis based on 5.43 million patients]. Dtsch Med Wochenschr 2013; 138: 69–75. 2. Buckley BS, Harreiter J, Damm P et al. Gestational diabetes mellitus in Europe: Prevalence, current screening practice and barriers to screening. A review. Diabet Med 2012; 29: 844–854. 3. Gestational diabetes mellitus. Diabetes Care 2004; 27 (Suppl 1): S88–S90.
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4. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15: 539–553. 5. Bellamy L, Casas J-P, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: A systematic review and meta-analysis. Lancet 2009; 373: 1773–1779. 6. Metzger BE, Lowe LP, Dyer AR et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008; 358: 1991– 2002. 7. Landon MB, Spong CY, Thom E et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med 2009; 361: 1339–1348. 8. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005; 352: 2477–2486. 9. Dabelea D, Hanson RL, Lindsay RS et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: A study of discordant sibships. Diabetes 2000; 49: 2208–2211. 10. Metzger BE, Gabbe SG, Persson B et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010; 33: 676–682. 11. Ryan EA, Enns L. Role of gestational hormones in the induction of insulin resistance. J Clin Endocrinol Metab 1988; 67: 341–347. 12. Lapolla A, Dalfrà MG, Fedele D. Management of gestational diabetes mellitus. Diabetes Metab Syndr Obes 2009; 2: 73– 82. 13. Lapolla A, Dalfrà MG, Mello G et al. Early detection of insulin sensitivity and beta-cell function with simple tests indicates future derangements in late pregnancy. J Clin Endocrinol Metab 2008; 93: 876–880. 14. Reader D, Splett P, Gunderson EP. Impact of gestational diabetes mellitus nutrition practice guidelines implemented by registered dietitians on pregnancy outcomes. J Am Diet Assoc 2006; 106: 1426–1433. 15. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP, MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008; 358: 2003– 2015. 16. Dhulkotia JS, Ola B, Fraser R, Farrell T. Oral hypoglycemic agents vs insulin in management of gestational diabetes: A systematic review and metaanalysis. Am J Obstet Gynecol 2010; 203: 457; e1–9. 17. Moore LE, Clokey D, Rappaport VJ, Curet LB. Metformin compared with glyburide in gestational diabetes: A randomized controlled trial. Obstet Gynecol 2010; 115: 55–59. 18. Homko CJ, Reece EA. Insulins and oral hypoglycemic agents in pregnancy. J Matern Fetal Neonatal Med 2006; 19: 679–686. 19. Kostev K. Datenbankbasierte epidemiologische Untersuchungen zur Behandlung von Patienten mit Diabetes mellitus in Deutschland. Goettingen, Optimus Verlag 2010. 20. Becher H, Kostev K, Schröder-Bernhardi D. Validity and representativeness of the ‘Disease Analyzer’ patient database for use in pharmacoepidemiological and pharmacoeconomic studies. Int J Clin Pharmacol Ther 2009; 47: 617–626. 21. Ferrara A. Increasing prevalence of gestational diabetes mellitus: A public health perspective. Diabetes Care 2007; 30 (Suppl 2): S141–S146.
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22. Dabelea D, Snell-Bergeon JK, Hartsfield CL et al. Increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth cohort: Kaiser Permanente of Colorado GDM Screening Program. Diabetes Care 2005; 28: 579–584. 23. Lawrence JM, Andrade SE, Avalos LA et al. Prevalence, trends, and patterns of use of antidiabetic medications among pregnant women, 2001–2007. Obstet Gynecol 2013; 121: 106– 114. 24. Nicholson W, Bolen S, Witkop CT, Neale D, Wilson L, Bass E. Benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes: A systematic review. Obstet Gynecol 2009; 113: 193–205. 25. Gandhi P, Bustani R, Madhuvrata P, Farrell T. Introduction of metformin for gestational diabetes mellitus in clinical practice: Has it had an impact? Eur J Obstet Gynecol Reprod Biol 2012; 160: 147–150. 26. Balani J, Hyer SL, Rodin DA, Shehata H. Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: A case-control study. Diabet Med 2009; 26: 798–802. 27. Langer O, Yogev Y, Xenakis EMJ, Rosenn B. Insulin and glyburide therapy: Dosage, severity level of gestational diabetes, and pregnancy outcome. Am J Obstet Gynecol 2005; 192: 134–139. 28. Tertti K, Ekblad U, Vahlberg T, Rönnemaa T. Comparison of metformin and insulin in the treatment of gestational diabetes: A retrospective, case-control study. Rev Diabet Stud 2008; 5: 95–101. 29. Ijäs H, Vääräsmäki M, Morin-Papunen L et al. Metformin should be considered in the treatment of gestational diabetes: A prospective randomised study. BJOG 2011; 118: 880–885. 30. Charles B, Norris R, Xiao X, Hague W. Population pharmacokinetics of metformin in late pregnancy. Ther Drug Monit 2006; 28: 67–72. 31. Gutzin SJ, Kozer E, Magee LA, Feig DS, Koren G. The safety of oral hypoglycemic agents in the first trimester of pregnancy: A meta-analysis. Can J Clin Pharmacol 2003; 10: 179–183. 32. Gilbert C, Valois M, Koren G. Pregnancy outcome after firsttrimester exposure to metformin: A meta-analysis. Fertil Steril 2006; 86: 658–663. 33. Kovo M, Haroutiunian S, Feldman N, Hoffman A, Glezerman M. Determination of metformin transfer across the human
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placenta using a dually perfused ex vivo placental cotyledon model. Eur J Obstet Gynecol Reprod Biol 2008; 136: 29– 33. Kovo M, Kogman N, Ovadia O, Nakash I, Golan A, Hoffman A. Carrier-mediated transport of metformin across the human placenta determined by using the ex vivo perfusion of the placental cotyledon model. Prenat Diagn 2008; 28: 544– 548. Nanovskaya TN, Nekhayeva IA, Patrikeeva SL, Hankins GDV, Ahmed MS. Transfer of metformin across the dually perfused human placental lobule. Am J Obstet Gynecol 2006; 195: 1081–1085. Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000; 343: 1134–1138. Gui J, Liu Q, Feng L. Metformin vs insulin in the management of gestational diabetes: A meta-analysis. PLoS ONE 2013; 8: e64585. Goh JEL, Sadler L, Rowan J. Metformin for gestational diabetes in routine clinical practice. Diabet Med 2011; 28: 1082– 1087. Buchanan TA, Xiang AH, Page KA. Gestational diabetes mellitus: Risks and management during and after pregnancy. Nat Rev Endocrinol 2012; 8: 639–649. Glueck CJ, Goldenberg N, Streicher P, Wang P. Metformin and gestational diabetes. Curr Diab Rep 2003; 3: 303–312. Ali AT, Ferris WF, Naran NH, Crowther NJ. Insulin resistance in the control of body fat distribution: A new hypothesis. Horm Metab Res 2011; 43: 77–80. Rowan JA, Rush EC, Obolonkin V, Battin M, Wouldes T, Hague WM. Metformin in gestational diabetes: The offspring follow-up (MiG TOFU): Body composition at 2 years of age. Diabetes Care 2011; 34: 2279–2284. Zhuang X-F, Zhao M-M, Weng C-L, Sun N-L. Adipocytokines: A bridge connecting obesity and insulin resistance. Med Hypotheses 2009; 73: 981–985. Rai L, Meenakshi D, Kamath A. Metformin: a convenient alternative to insulin for Indian women with diabetes in pregnancy. Indian J Med Sci 2009; 63: 491–497. Ogunyemi D, Jesse M, Davidson M. Comparison of glyburide versus insulin in management of gestational diabetes mellitus. Endocr Pract 2007; 13: 427–428.
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doi:10.1111/jog.12384
J. Obstet. Gynaecol. Res. Vol. 40, No. 6: 1592–1597, June 2014
Use of antidiabetic agents in the treatment of gestational diabetes mellitus in Germany, 2008–2012 Christina Heilmaier1, Christian Thielscher1, May Ziller2, Verena Altmann3 and Karel Kostev3 1 FOM University of Applied Sciences, Essen, 2Department of Gynecological Endocrinology, Reproductive Medicine and Osteoporosis, Philipps-University of Marburg, Marburg, and 3IMS 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 2009.1 At the same time, the frequency of gestational diabetes mellitus (GDM) also increased and is now reported in
2–6% of all pregnancies in Europe2 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 9 2013. Accepted: December 13 2013. Reprint request to: Dr Karel Kostev, IMS Health, Epidemiology, Darmstädter Landstrasse 108, 60598 Frankfurt, Germany. Email: [email protected]
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© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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) trial15 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.15–17 Despite these results, which have been favorable for metformin, it has not yet been formally approved for GDM therapy18 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 2012. 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 Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
1593
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insulin and metformin therapy were assessed using χ2-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 2012. 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/m2); 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 2012. GD, gestational diabetes.
35% 30.8% 30% 26.3%
Women (%)
25%
22.5%
28.4%
23.7%
20% 15% 10% 5% 0%
2008
2009
2010
2011
2012
Figure 1 From 2008 to 2012, an increase in the proportion of women who needed antidiabetic agents for gestational diabetes mellitus treatment was found.
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Figure 3 While (■) insulin analogues are increasingly used, the proportion of (□) human insulin has decreased from 2008 to 2012.
© 2014 The Authors Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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and, therefore, requiring drug therapy for GDM, also rose,23 which was also seen in our study, with a significant increase between 2008 and 2012. 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 insulin15 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 studies15,28,29) 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 malformations31,32 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 unit38 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 Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology
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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.
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