Long-term metformin adherence in the Diabetes Prevention Program Outcomes Study

Abstract

Introduction: To investigate long-term metformin adherence in the Diabetes Prevention Program Outcomes Study (DPPOS) by examining: (1) predictors of long-term adherence to study metformin and (2) whether metformin adherence was associated with incident type 2 diabetes.

Research design and methods: DPPOS was an open-label continuation of the randomized clinical trial (Diabetes Prevention Program (DPP)) in which eligible participants randomized to the metformin group were offered study metformin and followed over 11 years. A brief structured adherence interview was administered semiannually. Metformin adherence was assessed by pill counts. Predictors of metformin adherence were examined in multivariate regression models. Incident diabetes associated with metformin adherence and other variables was assessed in Cox proportional hazards models.

Results: Of 868 participants eligible to continue taking study metformin, 664 (76%) took at least some metformin over 11 years, with 478 of them reporting problems with adherence. DPPOS cumulative adherence showed significant associations of higher adherence (≥80%) with early adherence at 3 months in DPP (p<0.001) and lower depression scores during DPPOS (p<0.001); significant differences were also seen by race/ethnicity (p<0.004). Predicting adherence by multivariate modeling showed odds of adherence significantly lower for Black participants and for participants reporting more than one barrier. Odds for adherence were significantly higher for those adherent early in DPP and those reporting at least one planned strategy to improve adherence. Higher metformin adherence was significantly associated with a lower diabetes risk (p=0.04), even after adjustment for demographic variables, depression, and anxiety scores.

Conclusions: In this long-term diabetes prevention study, early metformin adherence and planned strategies to promote adherence improved long-term adherence over 11 years; higher adherence to metformin was related to lower diabetes incidence. Incorporating strategies to promote adherence when initially prescribing metformin and counseling to support adherence over time are warranted.

Keywords: diabetes mellitus; medication adherence; metformin; preventive medicine; type 2.

Figure 1

Participant study flow diagram for metformin group. *Permanently discontinued from metformin during the DPP either because fasting plasma glucose ≥140 mg/dL or other protocol deviations and thus ineligible to take study metformin. †This includes 216 participants diagnosed with diabetes during the DPP, but with fasting plasma glucose <140 mg/dL. ‡For those eligible to take study metformin at DPPOS baseline (n=868), 216 (24.9%) were diagnosed with diabetes during DPP and a further 235 (27.1%) were diagnosed during DPPOS follow-up. In those who never took any study metformin during DPPOS (n=204), 59 (28.9%) were diagnosed during DPP while a further 48 (23.5%) were diagnosed during DPPOS. In those who took study metformin at one or more DPPOS visits (n=664), 157 (23.6%) were diagnosed during DPP while a further 187 (28.2%) were diagnosed during DPPOS. DPP, Diabetes Prevention Program; DPPOS, DPP Outcomes Study.

Figure 2

Barrier and strategy reporting during DPPOS follow-up (n=478). Panel A: Per cent of participants who reported specific barriers to adherence to study metformin. Panel B: Per cent of participants who reported specific strategies to improve adherence to study metformin. Dots in the figures represent observed percentages while lines indicate the modeled percentages of participants from a multinomial GEE model with barrier categories and strategy categories as the outcomes. Barrier categories with significant changes over time: no barriers (p<0.001; not shown); forgets to take pills (p<0.01); multiple barriers (p<0.001); gastrointestinal symptoms (p<0.05); disruption of activities (p<0.01). Strategy categories with significant changes over time: reminder device (p<0.001); multiple strategies (p<0.001); activity strategy (p<0.001). DPP, Diabetes Prevention Program; DPPOS, DPP Outcomes Study; GEE, generalized estimating equation.

Figure 3

ORs for adherence among participants who took study metformin during DPPOS and reported adherence problems at one or more visits (n=478*). Panel A: includes assessing number of barriers metformin adherence (1 vs >1) and number of strategies to promote metformin adherence (1, >1 vs 0). Panel B: includes assessing types of barriers to adherence and types of strategies to improve adherence. ORs and CIs were calculated from a GEE model with metformin adherence as the outcome and variables listed in the figure as covariates in a multivariate model. Age, marital status, educational level, employment status, and income level were all measured at DPP baseline. The follow-up SF-36 and concomitant medications variables are averaged over follow-up visits. In these models, barriers and strategies (both number and category) were included as time-varying covariates (ie, the reported values at each participant-visit). Depression scores, anxiety scores, and number of concomitant medications were included in the models as logged values, so estimates of OR for these covariates are expressed per 1-unit log increase. *Only participants who reported problems taking their study metformin at one or more visits were included in this analysis, as only those participants had interview data collected on barriers and strategies to study metformin use. DPP, Diabetes Prevention Program; DPPOS, DPP Outcomes Study; GEE, generalized estimating equation; SF-36, Short Form-36.

Figure 4

HR for developing diabetes in those who took at least some study metformin during DPPOS (n=652)*. HRs and their 95% CIs from a Cox Proportional Hazards model for time to diabetes measured from DPPOS baseline. All variables listed in the figure are covariates included in a multivariate model. Age, marital status, educational level, employment status, and income level were all measured at DPP baseline. The follow-up SF-36 and number of concomitant medications variables are averages during follow-up. Cumulative metformin adherence is calculated as the cumulative per cent of visits (up to and including each collection time point) at which a participant took 80% or more of their prescribed study metformin. *Includes only participants whose diagnosis of diabetes, or censoring, occurred on or after August 1, 2002 (the official start date of DPPOS) were included in this analysis. There was a total of 216 participants from this study who developed diabetes prior to the start of DPPOS. Depression scores, anxiety scores, and number of concomitant medications were included in the models as logged values, so estimates of OR for these covariates are expressed per 1-unit log increase. DPP, Diabetes Prevention Program; DPPOS, DPP Outcomes Study; SF-36, Short Form-36.