The prevalence of gestational diabetes mellitus (GDM) in the United States more than doubled from 1.5% in 1989–1990 to 4.2% 2001–2004. Between 7% and 35% of diagnosed women will require pharmacologic treatment during pregnancy.1 The only U.S. Food and Drug Administration approved medication for the treatment of GDM is insulin,2 although glyburide (an oral agent) is also used.3
Glyburide is a second-generation sulfonylurea thought to be effective for the treatment of GDM.4 Glyburide is believed to be safe based on results from animal and in vitro placental studies showing minimal transfer,5,6 although recent studies in humans have shown fetal transfer.7 Its ease of use and low cost are advantages compared with insulin, which is administered by injection and entails higher costs.8
In 2000, Langer et al9 conducted the first randomized controlled trial comparing glyburide with insulin in 404 women with GDM. Since then, two more randomized controlled trials,10,11 three observational studies,12–14 and two meta-analyses15,16 have compared the efficacy or effectiveness of the two drugs. It is unknown how evidence from these studies has affected choice of medication in routine practice and which factors influence the prescription of glyburide compared with insulin. There are no current estimates of the dissemination of glyburide use during pregnancy in the U.S. population.
Our objective was to characterize pharmacologic treatment of women with GDM by describing trends in the use of glyburide compared with insulin over the past decade and identifying predictors of initial choice of pharmacotherapy.
MATERIALS AND METHODS
We conducted a retrospective cohort study of women with gestational diabetes identified in Truven Health's MarketScan Commercial Claims and Encounters database from 2000 to 2011. This database is the largest collection of claims from patients with employer-sponsored health insurance in the United States.17 Data from individual patients are integrated from all providers of care over time for as long as the patient is enrolled in the employer's health plan. Truven Health Analytics reviews all claims and enrollment data to ensure completeness, accuracy, and reliability.
The database has information from more than 100 payers of private health insurance for employees and their dependents, covering more than 25 million lives annually. It contains details of enrollment, demographics (age, sex, geographic region), inpatient and outpatient services, and outpatient pharmacy data. These data include information about diagnoses (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] diagnosis codes) and procedures (Current Procedural Terminology 4 [CPT-4] and ICD-9-CM procedure codes) in the outpatient and inpatient settings reported on administrative claims. Data on prescription medications (National Drug Codes) filled through outpatient pharmacies are also reported using insurance claims. Each enrolled individual is assigned a unique, encrypted identification number making it possible to link records and obtain nearly comprehensive record of encounters with the health care system.
We identified women who had claims for delivery of a liveborn neonate through the use of ICD-9 diagnosis, procedure, and CPT-4 codes (see the Appendix online at http://links.lww.com/AOG/A500). Because multiple claims can be generated during delivery care, we grouped those occurring consecutively and defined delivery date as the date of the earliest claim. Women were required to be continuously enrolled during the year before and at least 3 months after the delivery date (Fig. 1A).
For each delivery, we identified women who had a claim with a diagnosis code for GDM (ICD-9-CM 648.8–648.83) in the year before delivery date. If two deliveries occurred within a 12-month period, GDM diagnosis codes for the second pregnancy were assessed in the period beginning 6 weeks after the delivery date of the first pregnancy. The 6-week period was used to avoid capturing GDM diagnosis codes that might occur postpartum from the first pregnancy (Fig. 1B). We excluded women 1) with diagnosis codes for insulin-dependent diabetes mellitus or noninsulin-dependent diabetes mellitus; 2) younger than 15 years or older than 50 years; and 3) with diagnosis or procedure codes for pregnancy with multiple gestations. Our cohort was restricted to the first eligible GDM pregnancy for a given woman.
We identified women in our cohort with a pharmacy claim for insulin or glyburide using National Drug Codes. Women were classified as insulin or glyburide initiators based on the drug class of their first claim; the date on this claim was defined as initiation of pharmacotherapy (index date). We excluded those initiating pharmacologic treatment after delivery or who had an index date occurring earlier than 150 days before delivery (suggestive of management for prepregnancy noninsulin-dependent diabetes mellitus). We also identified treatment changes occurring after the index date but before delivery. Change in pharmacotherapy was defined as any claim occurring after the index date for a drug class different to that prescribed at initiation. We also identified a group of women with GDM who were not treated pharmacologically within 150 days of delivery. We excluded from this analysis women whose index prescription was for thiazolidinediones (n=181) or acarbose (n=27).
We identified characteristics that might influence the choice of initial therapy (insulin or glyburide) for GDM. All characteristics were defined through the use of ICD-9-CM diagnosis or CPT-4 codes and assessed before the index date. Comorbidities of interest were: infertility diagnosis (ICD-9-CM V26.8, V26.81 CPT-4 89252, 89268, 89281, 58310, 58311, 58321–23, 58970–76, 89250–57, 89268, 89272, 89280–81, 89290–91, 89352–54) or treatment (at least one claim for clomiphene, urofollitropin, follitropin, menotropin, ganirelix, cetrorelix); obesity (ICD-9-CM 278.0X, 649.1X, V77.8, V85.3x, V85.4); hypothyroidism (ICD-9-CM 244.X); hyperandrogenism (defind as an ICD-9-CM code for alopecia [704.0X], hirsutism [704.1] or acne [706.0, 706.1]); metabolic syndrome (ICD-9-CM 277.7); and polycystic ovarian syndrome (ICD-9-CM 256.4). Because metformin is used off label for infertility or to reduce risk of miscarriage, we identified use of metformin early in pregnancy (greater than 150 days before delivery) and used this as a covariate in the analyses.
Trends in the use of glyburide compared with insulin between years 2000 and 2010 were estimated by calculating the proportion of women who initiated glyburide using as a denominator the total number of women treated with medication in a given year. Multivariable log-linear regression was used to estimate average annual percent change and 95% confidence intervals (CIs) in the use of glyburide for the overall period and within intervals of interest.18 Binomial regression was used to adjust for covariates of interest using fractional polynomials to flexibly model the association between age and choice of initial therapy.19 We estimated prevalence ratios and 95% CI for the association between baseline characteristics (age, region, comorbidities, calendar time) and treatment with glyburide compared with insulin. To estimate the association between drug class at initiation and risk of change, we calculated risk ratios and 95% CI.
All analyses were conducted using SAS 9.3. This study using existing, deidentified data was determined to be exempt from further review by the Public Health–Nursing institutional review board, Office of Human Research Ethics at the University of North Carolina at Chapel Hill.
Among women with a delivery code and who met our enrollment criteria (N=1,108,383), 122,064 had an eligible pregnancy complicated by GDM. Of these women, 10,778 (8.1%) had a pharmacy claim for insulin (n=4,905) or glyburide (n=5,873) during the 150 days before delivery. Among women treated pharmacologically, the use of glyburide increased monotonically from 7.4% in 2001 to 64.5% in 2011 becoming the more common treatment since 2007 (Table 1). Comparing glyburide with insulin, the adjusted annual percent change was higher between 2000 and 2007 (34.0%, 95% CI 20.4–49.1) and reached a plateau after 2008 with an annual increase of 3.7% (95% CI 0.8–6.7). The increase was observed across all age groups (Fig. 2).
Among women treated with glyburide or insulin, the mean age at baseline was 33 years (standard deviation [SD] 4.9) compared with 32 (SD 5.2) years in those not treated pharmacologically. Among the pharmacologically treated group, approximately half were prescribed glyburide (54.5%, n=5,873). In bivariate analysis, glyburide use was less common than insulin use in the Northeast (45.8% compared with 54.2%) and more common in the South (56.4% compared with 43.7%) and Midwest (54.9% compared with 45.1%) regions of the United States (Table 1). There was a small variation between regions in the proportion of women not treated pharmacologically, ranging from 88.1% to 93.8%. The proportion of women with comorbidities was generally similar between treatment groups, whereas those who were not treated pharmacologically had fewer comorbid conditions (Table 2).
In multivariate analyses comparing glyburide with insulin, those in the Northeast and Midwest were less likely to be prescribed glyburide by 19% and 4%, respectively (prevalence ratio 0.81 95% CI 0.76–0.87, P<.001; prevalence ratio 0.96, 95% CI 0.93–1.00, P<.001). Women with metabolic syndrome (prevalence ratio 0.71, 95% CI 0.50–0.99), hyperandrogenism (prevalence ratio 0.77, 95% CI 0.62–0.97), polycystic ovarian syndrome (prevalence ratio 0.88, 95% CI 0.78–0.99), hypothyroidism (prevalence ratio 0.89, 95% CI 0.83–0.96), or a history of infertility treatment (prevalence ratio 0.93, 95% CI 0.86–1.02) were less likely to be treated with glyburide (Table 3). Among women with an ICD-9 diagnosis code for obesity, there was no preference for one treatment over the other (prevalence ratio 1.04, 95% CI 0.98–1.10). Prior metformin use was not associated with initiation of glyburide (prevalence ratio 1.01, 95% CI 0.94–1.09). The adjusted probability of being prescribed glyburide varied by age with a 5% decrease for every 10 years increase in age (prevalence ratio 0.95, 95% CI 0.91–0.99) (Fig. 2). When compared with bivariate analysis, we did not observe important changes in the point estimates or CIs after adjusting for covariates, except for obesity.
Among women initially treated with glyburide, 7.8% (n=461) received an additional medication or switched to a different drug class. The most common drug classes were insulin (n=387 [6.6%]) or metformin (n=74 [1.3%]). Among those initiating insulin, 1.1% (n=54) had a change in treatment before delivery. In this group, 0.8% (n=37) subsequently started glyburide and 0.3% (n=16) metformin. Women initiating glyburide were 8.1 times more likely to have a change in treatment before delivery (risk ratio 8.1, 95% CI 6.0–10.8).
We found a marked increase in the use of glyburide for the treatment of GDM in a commercially insured United States cohort from 2000 to 2011 with a corresponding decrease in insulin use. This trend was coincident with the publication of results from randomized clinical trials9–11 and observational studies.12–14,20 Our results support findings from recent studies showing widespread use of glyburide despite lack of conclusive clinical evidence being available.3,21 This trend needs to be interpreted in the light of changes in GDM diagnosis and initiation of pharmacotherapy in this population over time.
Among the comorbidities of interest for which we had data, we did not find strong predictors of glyburide initiation. Women with infertility, polycystic ovarian syndrome, and hyperandrogenism were more likely to be treated with insulin as were those with hypothyroidism or metabolic syndrome. Women with an obesity ICD-9-CM code were equally likely to be prescribed with glyburide or insulin. Because insulin resistance is increased in all these conditions, the degree of perceived insulin resistance could be an additional driver of initial choice of treatment for GDM.
Few studies have reported on changes in treatment (switching or augmenting) after initiation of medication. The majority focused on failure of glyburide.22–25 Less is known about failure after initiation on insulin therapy, where only one trial (Langer,9 n=24/203) and one observational study (Gilson,15,26 n=3/11) have reported frequencies between 12% and 27%. Although treatment failure could explain changes in treatment, tolerance or preference could also have a role. Our findings are consistent with previous literature in which changes in treatment are more common in women initiating glyburide.
Little is known about the role of age on the preference to initiate treatment with oral agents among women with GDM. Our results provide evidence that age is one of the factors associated with choice of therapy. This was most evident in recent years after the dissemination of glyburide use (Fig. 2). This may reflect more severe glucose intolerance in older women because there is some evidence that GDM severity increases with age. These findings are also consistent with studies showing that maternal age is a risk factor for failing to achieve glucose control with glyburide.23
As a result of the nature of health care claims data, we could not consider the influence of glucose tolerance test results, gestational age, biometrics (weight or height), or race or ethnicity on the choice of therapy. We believe our definition of GDM in combination with the exclusion of women who had early pharmacy claims for the drugs of interest yields a cohort of “true” gestational diabetics. This approach was validated by Andrade et al27 who reported a positive predictive value of 85% (95% CI 71–94%). Also, we were limited to the ascertainment of obesity through the use of ICD-9-CM diagnosis codes. This was also validated by Andrade et al27 who reported a high positive predictive value (92%, 95% CI 90–94) but low sensitivity (33%). Although this suggests that there is considerable underreporting of obesity, women with the code are likely obese. Although misclassification is likely not differential between the drug classes of interest, it could bias results toward the null and we therefore cannot rule out the possibility of an effect of obesity on choice of treatment. Because our population has employer-provided insurance, results from this study may not be generalizable to those covered by Medicaid or the uninsured. In a recent study by Albrecht et al,28 it was estimated that 61.4% of women with GDM would be privately insured. Therefore, our results are reflective of patterns of care among a large, nationwide population.
Strengths of the study include sample size, ascertainment, and timing of medication use based on dispensed prescriptions. Our study likely includes women with different degrees of severity and is reflective of the full spectrum of patients treated in a variety of clinical settings. By restricting our cohort to women who were continuously enrolled in the year before delivery, we assured that use of health care and pharmacy services would be observable throughout pregnancy. Therefore, medication use in our study is based on pharmacy claims of dispensed drugs, which allowed us to identify the earliest prescription in pregnancy. By using pharmacy claims, we likely have better ascertainment of initiation of treatment during pregnancy compared with self-report.
Dissemination of glyburide for the pharmacologic treatment of GDM has been rapid and our findings indicate that since 2007, it has become the more common choice, particularly among younger, noninsulin-resistant women. As a result of its uptake, robust evaluation of glyburide's relative effectiveness is warranted to inform treatment decisions for women with gestational diabetes.
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