Impact of Parental or First-Degree Family History of Diabetes on Diabetes Incidence and Progression During Long-term Follow-up in the Diabetes Prevention Program Outcomes Study

Abstract

Objective: To determine the effects of first-degree family history of diabetes on diabetes incidence in Diabetes Prevention Program (DPP) and Diabetes Prevention Program Outcomes Study (DPPOS) participants.

Research design and methods: In the DPP, adults with prediabetes were randomized to an intensive lifestyle intervention, metformin, or placebo and followed for incident diabetes. On study completion 88% of eligible DPP participants reenrolled in DPPOS for long-term follow-up. The present analysis includes all 3,072 participants with family history information through DPPOS, with a median follow-up of 21 years (1,975 had parental history of diabetes [PH] [312 biparental, 947 maternal, 716 paternal], 226 had only sibling history [SH], and 871 denied any family history). The primary outcome is incident diabetes based on American Diabetes Association criteria, with adjustment for demographic and clinical variables, DPP randomization arm, and polygenic risk score (PRS).

Results: Adjusted hazard ratio (HR) was 1.21 (95% CI 1.06, 1.38) for any family history, 1.19 (1.04, 1.35) for PH, and 1.15 (0.91, 1.44) for SH. Biparental history conferred greater hazard (HR 1.44 [95% CI 1.22, 1.69]) than maternal (1.22 [1.08, 1.38]) or paternal (1.22 [1.08, 1.39]) diabetes history alone. PRS explained 32% of the association of any family history with diabetes risk.

Conclusions: PH increased type 2 diabetes risk after DPP treatment group was controlled for. That effect was only partially explained by PRS, suggesting that rare gene variants, familial, and environmental factors may contribute to type 2 diabetes risk in people with prediabetes.

Graphical abstract

Figure 1

Kaplan-Meier curves for the primary (progression of prediabetes to diabetes) and secondary (progression of diabetes to HbA_1c ≥7%) outcomes with nominal log-rank test P values comparing family history groups (No-FH, PH, and SH only).

Figure 2

Degrees of family history risks of outcomes progression from prediabetes to diabetes and progression of diabetes to HbA_1c ≥7%. HRs and 95% CIs for family history effects on both outcomes. Results are compiled from separate models, described in Tables 1 and 2 and Supplementary Tables 2 and 3. Models include adjustment for demographic variables (age, sex, race and ethnicity, and education), PRS, clinical baseline variables (BMI, triglycerides, systolic blood pressure [systolic blood pressure], FPG), and treatment arm.