Comparing Area-level Patient Density and Physician Prescribing Preference Instruments for the Effect of Antidiabetics...

Randomized trials of major adverse cardiovascular events found no effect of dipeptidyl-peptidase-4 inhibitors (DPP-4i) medications compared with second-generation sulfonylureas, while nonrandomized studies estimated a benefit of DPP-4i. Socioeconomic residual confounding was thought to be implicated. We compared area-level prescribing density and physician prescribing preference as candidate instrumental variables for the effect of DPP-4i medications on major adverse cardiovascular events.

Using Medicare claims data, we built two cohorts emulating randomized trials of sitagliptin or saxagliptin starters, each compared with sulfonylurea starters. The proportion of DPP-4i prescribing in a ZIP Code tabulation area defined the area-level prescribing density instrumental variable at various cutoffs (0% vs. 100% to <50% vs. ≥50%). Patients' physician prescribing history using the same proportion cutoffs was the physician prescribing preference candidate instrumental variable. An instantaneous physician preference instrumental variable used a physician's most recent prescription. We adjusted two-stage instrumental variable regression models for propensity score quintiles.

Unadjusted analyses for sitagliptin and saxagliptin, each compared with sulfonylurea, estimated a reduced risk of major adverse cardiovascular events [sitagliptin hazard ratio (HR) = 0.86; 95% confidence interval = 0.83, 0.88]; saxagliptin (HR = 0.68; 0.64, 0.73). All instrumental variables were strong and reduced covariate imbalance. Analyses of area-level prescribing density found no meaningful difference for sitagliptin (0% vs. 100% HR = 1.1; 0.79, 1.6). Analyses of physician prescribing preference estimated reduced risk for sitagliptin (<50% vs. ≥50% HR = 0.69; 0.48, 0.98). Instantaneous physician prescribing preference analyses showed little to no difference for sitagliptin (HR = 0.86; 0.60, 1.1) and saxagliptin (HR = 0.98; 0.56, 1.7).

Candidate instrumental variables focusing on short-term prescribing preference hold promise over area-based variables but remain inefficient.