Metformin Prescription for Insured Adults With Prediabetes From 2010 to 2012

Editors' Notes Context Randomized trial evidence shows that lifestyle changes or metformin can delay the progression of prediabetes to overt diabetes. Efforts to modify lifestyle interventions to include diabetes prevention have had various levels of uptake, but little is known about the uptake of metformin for this purpose. Contribution This study examined metformin use in a large sample of insured U.S. adults with prediabetes and found that only 3.7% were prescribed metformin over a 3-year period. Implication Metformin seems to be used infrequently to prevent the development of overt diabetes in patients with prediabetes. Diabetes prevention is an important national health goal. The number of persons with prediabetes, which has increased to more than 1 in 3 U.S. adults (1, 2), shows the urgent need for effective action leading to prevention. However, the means through which diabetes prevention can best be achieved on an individual as well as population level remains unclear. For more than 10 years, the literature has provided strong evidence to support the use of both intensive lifestyle intervention and metformin to help prevent diabetes among persons at increased risk because of prediabetes. In 2002, the DPP (Diabetes Prevention Program) showed that lifestyle intervention and metformin reduced the incidence of diabetes by 58% and 31%, respectively, compared with placebo over 2.8 years (3). These findings were supported by several other randomized studies and were shown to persist for up to 10 years in longitudinal observational studies (38). The 16-week intensive lifestyle intervention in the DPP was associated with the largest cumulative risk reduction, which prompted many translational studies (911). However, efforts to translate DPP-based lifestyle interventions have been associated with various levels of uptake and reach (912). In contrast, little is known about the translation of the evidence supporting metformin use to prevent diabetes. Such evidence is strongest for those at increased risk for progression to diabetes, including persons younger than 60 years, those with a body mass index (BMI) of 35 kg/m2 or greater, or those with a history of gestational diabetes (3, 6, 8, 13). Beginning in 2008, the annual Standards in Medical Care in Diabetes guidelines from the American Diabetes Association recommended metformin use for diabetes prevention in patients at very high risk who meet the aforementioned criteria and added that metformin use may be considered in those with impaired glucose tolerance, impaired fasting glucose level, or a hemoglobin A1c level of 5.7% to 6.4% (13). Despite inclusion in national guidelines for more than 6 years (13) and proven long-term tolerability, safety, and cost-effectiveness (14), the prescription of metformin in the real-world clinical approach to diabetes prevention remains unclear. The only published study to include incidence of metformin use among patients with prediabetes found that fewer than 0.1% were prescribed metformin (15). However, these data were collected from an integrated health delivery system that may not accurately reflect wider practice patterns and were reported for only 1 time point within 6 months of prediabetes identification. Further, this study began in 2006, which was 2 years before metformin use was first emphasized in national guideline recommendations for diabetes prevention (13, 16). The goal of our analysis was to characterize metformin prescriptions in a sample of insured, working-age adults with prediabetes from all 50 states. We also explored the association between specific patient characteristics and the receipt of metformin. We hypothesized that despite the existence of practice guidelines supporting its use, metformin is rarely prescribed for diabetes prevention. Methods We examined data from 2010 to 2012 from UnitedHealthcare (UHC), the nation's largest private insurer (17), using a retrospective cohort analysis of metformin prescription among adults with prediabetes over a 3-year period. Setting and Participants Participants were employees and covered dependents aged 19 to 58 years at baseline and enrolled in UHC benefit plans for 3 continuous years. The study window was from 2010 to 2012. Data from year 1 (2010) were used to define the sample with prediabetes and exclude persons with diabetes. All participants had diagnoses of prediabetes at year 1, defined as any of the following: 2 or more International Classification of Diseases, Ninth Revision (ICD-9), diagnostic codes of 790.2x from an inpatient or outpatient claim; last hemoglobin A1c level of 5.7% to 6.4%; last fasting plasma glucose level of 5.55 to 6.94 mmol/L (100 to 125 mg/dL); or last 2-hour plasma glucose level of 7.77 to 11.04 mmol/L (140 to 199 mg/dL) on an oral glucose tolerance test. Patients with a diagnosis of diabetes in year 1 were excluded from the sample. Diabetes was defined as any of the following: 1 or more ICD-9 diagnostic codes of 250.xx from an inpatient or outpatient claim; hemoglobin A1c level of 6.5% or greater; fasting plasma glucose level greater than 6.94 mmol/L (>125 mg/dL); 2-hour plasma glucose level of 11.1 mmol/L (200 mg/dL) or greater on an oral glucose tolerance test; or 1 or more prescription claims for insulin or an antiglycemic medication other than metformin. Data from 183 UHC employer groups with sufficient administrative and laboratory data to identify employees with prediabetes and pharmacy claims over the 3-year study window were available as part of a larger design study on health benefits (Appendix) (18) (Moin T, Steers WN, Ettner SL, Duru OK, Turk N, Neugebauer R, et al. The association of a diabetes-specific health plan with ER and inpatient hospital utilization: a natural experiment for translation in diabetes [NEXT-D]. In preparation.). These 183 groups were identified from a larger set of 1357 employer groups that purchased benefit plans from UHC between 2009 and 2010. Compared with the larger pool of 1174 groups, these 183 groups tended to be larger, had slightly higher proportions of patients with chronic conditions, and had slightly more Hispanic employees but were similar in terms of other racial/ethnic distributions, mean employee income, proportion of female employees, and proprietary estimates of benefit generosity provided by the health plan. Among the 183 employer groups, there were 35910 employees or covered dependents who were continuously enrolled with UHC for 3 years and had prediabetes in year 1. We excluded patients with a history of diabetes in year 1 (n= 9606), those who were not aged 19 to 58 years in year 1 (n= 8006) because national guidelines highlight evidence for metformin use in patients younger than 60 years, and women with a history of the polycystic ovary syndrome (n= 258) because metformin can be prescribed for reasons other than diabetes prevention in this group (for example, oligomenorrhea and infertility) (1921). We also excluded those who were pregnant (n= 426) because metformin is classified under U.S. Food and Drug Administration pregnancy category B, as well as those with an elevated creatinine level (defined as 132.6 mol/L [1.5 mg/dL] for men and 123.8 mol/L [1.4 mg/dL] for women [n= 262]) because renal insufficiency is a contraindication to metformin use. The final analytic sample comprised 17352 patients with prediabetes (Figure ). We then identified a dominant provider for each patient by using the most frequent National Provider Identifier number in inpatient or outpatient claims during the 3-year study window. Figure. Study flow diagram. The study window was 3 y (2010 to 2012). Prediabetes was defined as any of the following: 2 ICD-9 diagnostic codes of 790.2x from an inpatient or outpatient claim, last hemoglobin A1c level of 5.7% to 6.4%, last fasting plasma glucose level of 5.55 to 6.94 mmol/L (100 to 125 mg/dL), or last 2-h plasma glucose level of 7.77 to 11.04 mmol/L (140 to 199 mg/dL) on an oral glucose tolerance test. Pregnancy was defined as 1 pregnancies during the study. Elevated creatinine level was defined as 132.6 mol/L (1.5 mg/dL) for men and 123.8 mol/L (1.4 mg/dL) for women. ICD-9 = International Classification of Diseases, Ninth Revision; PCOS = the polycystic ovary syndrome. Primary Outcome The primary outcome was a dichotomous indicator for metformin prescription among adult employees and covered dependents with prediabetes based on UHC prescription claims data. Metformin prescription was defined as any prescription claim for metformin in the 3-year study window. For patients who developed diabetes during years 2 and 3 (2011 and 2012), only metformin prescriptions before diabetes identification were included. Covariates The age and sex of patients were obtained from UHC eligibility files. Education, income, and race/ethnicity were estimated by UHC using a proprietary algorithm that incorporated geographic locators (that is, ZIP codes of record); consumer survey information; census income distribution data; and first, middle, and last names. Comorbid conditions, including history of the polycystic ovary syndrome, pregnancy, gestational diabetes, and obesity (BMI 30 kg/m2), were defined as 1 or more ICD-9related diagnoses from inpatient or outpatient claims. Statistical Analysis We used a multivariate logistic regression model to test the association between specific patient characteristics and metformin prescription during the 3-year study window. We adjusted the model for age, sex, race, income, education, diagnosis of obesity, and number of comorbid conditions at baseline. Age and obesity were included in the model because the evidence for metformin use is greatest in those younger than 60 years or with a BMI greater than 35 kg/m2. We included race because certain groups (such as African Americans) have a higher risk for diabetes, and this may affect willingness or motivation to prescribe metformin for prevention. Sex was included because women are more likely