Transportability Methods for Time-to-Event Outcomes: Application in Adjuvant Colon Cancer Trials.

PURPOSE: Differences in the benefits of treatment on 5-year overall survival have been observed in 12 randomized phase III colon cancer adjuvant clinical trials from the ACCENT group. We investigated the reasons for these differences by incorporating the distribution of the observed covariates from each trial. MATERIALS AND METHODS: We applied state-of-the-art transportability methods on the basis of causal inference, and compared them with a conventional meta-analysis approach to predict the treatment effect for the target population. Prediction errors were defined to evaluate whether the identifiability conditions necessary for causal inference were satisfied among the 12 trials, and to measure the performance of each method. RESULTS: In the one-trial-at-a-time transportability analysis, the ranks of prediction errors for the target population were mostly consistent with the discrepancy in treatment effects among the 12 trials across the three models. The overall prediction errors between the leave-one-trial-out transportability method and the conventional individual participant data meta-analysis approach were very similar, and more than 40% lower than the overall prediction errors from the one-trial-at-a-time transportability method. CONCLUSION: The discrepancy in treatment effects among the 12 trials is unlikely to arise from the choice of model specification or distribution of observed covariates but from the distribution of unobserved covariates or study-level features. The ability to quantify heterogeneity among the 12 trials was greatly reduced in both the leave-one-trial-out transportability method and the conventional meta-analysis approach compared with the one-trial-at-a-time transportability method.

A Diabetes Genetic Risk Score Is Associated With All-Cause Dementia and Clinically Diagnosed Vascular Dementia in the Million Veteran Program.

OBJECTIVE: Diabetes and dementia are diseases of high health care burden worldwide, and studies have shown that diabetes is associated with an increased relative risk of dementia. We set out to examine whether type 2 diabetes-associated genetic variants were associated with dementia and whether they differed by race/ethnicity or clinical dementia diagnosis. RESEARCH DESIGN AND METHODS: We evaluated associations of two type 2 diabetes genetic risk scores (GRS and GRS-nonAPOE: a score without rs429358, a variant associated with Alzheimer disease [AD]) with three classifications of clinical dementia diagnoses in the Million Veteran Program (MVP): all-cause dementia, vascular dementia (VaD), and AD. We conducted our analysis stratified by European (EUR), African (AFR), and Hispanic (HIS) races/ethnicities. RESULTS: In EUR, we found associations of the GRS with all-cause dementia (odds ratio [OR] 1.06, P = 1.60e-07) and clinically diagnosed VaD (OR 1.12, P = 5.2e-05) but not with clinically diagnosed AD (OR 1.02, P = 0.43). The GRS was not associated with any dementia outcome in AFR or HIS. When testing with GRS-nonAPOE, we found that effect size estimates in EUR increased and P values decreased for all-cause dementia (OR 1.08, P = 2.6e-12), for VaD (OR 1.14, P = 7.2e-07), and for AD (OR 1.06, P = 0.018). For AFR, the association of GRS-nonAPOE and clinically diagnosed VaD (OR 1.15, P = 0.016) was statistically significant. There were no significant findings for HIS. CONCLUSIONS: We found evidence suggesting shared genetic pathogenesis of diabetes with all-cause dementia and clinically diagnosed VaD.

Trends in Timing of and Glycemia at Initiation of Second-line Type 2 Diabetes Treatment in U.S. Adults.

OBJECTIVE: Therapeutic inertia threatens the potential long-term benefits of achieving early glycemic control after type 2 diabetes diagnosis. We evaluated temporal trends in second-line diabetes medication initiation among individuals initially treated with metformin. RESEARCH DESIGN AND METHODS: We included data from 199,042 adults with type 2 diabetes in the U.S. Department of Veterans Affairs health care system initially treated with metformin monotherapy from 2005 to 2013. We used multivariable Cox proportional hazards and linear regression to estimate associations of year of metformin monotherapy initiation with time to second-line diabetes treatment over 5 years of follow-up (primary outcome) and with hemoglobin A1c (HbA1c) at the time of second-line diabetes treatment initiation (secondary outcome). RESULTS: The cumulative 5-year incidence of second-line medication initiation declined from 47% among metformin initiators in 2005 to 36% in 2013 counterparts (P < 0.0001) despite a gradual increase in mean HbA1c at the end of follow-up (from 6.94 ± 1.28% to 7.09 ± 1.42%, Ptrend < 0.0001). In comparisons with metformin monotherapy initiators in 2005, adjusted hazard ratios for 5-year initiation of second-line diabetes treatment ranged from 0.90 (95% CI 0.87, 0.92) for 2006 metformin initiators to 0.68 (0.66, 0.70) for 2013 counterparts. Among those receiving second-line treatment within 5 years of metformin initiation, HbA1c at second-line medication initiation increased from 7.74 ± 1.66% in 2005 metformin initiators to 8.55 ± 1.92% in 2013 counterparts (Ptrend < 0.0001). CONCLUSIONS: We observed progressive delays in diabetes treatment intensification consistent with therapeutic inertia. Process-of-care interventions early in the diabetes disease course may be needed to reverse adverse temporal trends in diabetes care.

Genetic Risk Score for Type 2 Diabetes and Traits Related to Glucose-Insulin Homeostasis in Youth: The Exploring Perinatal Outcomes Among Children (EPOCH) Study.

OBJECTIVE: The metabolic phenotype of youth-onset type 2 diabetes (T2D) differs from that of adult-onset T2D, but little is known about genetic contributions. We aimed to evaluate the association between a T2D genetic risk score (GRS) and traits related to glucose-insulin homeostasis among healthy youth. RESEARCH DESIGN AND METHODS: We used data from 356 youth (mean age 16.7 years; 50% female) in the Exploring Perinatal Outcomes Among Children (EPOCH) cohort to calculate a standardized weighted GRS based on 271 single nucleotide polymorphisms associated with T2D in adults. We used linear regression to assess associations of the GRS with log-transformed fasting glucose, 2-h glucose, HOMA of insulin resistance (HOMA-IR), oral disposition index, and insulinogenic index adjusted for age, sex, BMI z score, in utero exposure to maternal diabetes, and genetic principal components. We also evaluated effect modification by BMI z score, in utero exposure to maternal diabetes, and ethnicity. RESULTS: Higher weighted GRS was associated with lower oral disposition index (ß = -0.11; 95% CI -0.19, -0.02) and insulinogenic index (ß = -0.08; 95% CI -0.17, -0.001), but not with fasting glucose (ß = 0.01; 95% CI -0.01, 0.02), 2-h glucose (ß = 0.03; 95% CI -0.0004, 0.06), or HOMA-IR (ß = 0.02; 95% CI -0.04, 0.07). BMI z score and in utero exposure to maternal diabetes increased the effect of the GRS on glucose levels. CONCLUSIONS: Our results suggest that T2D genetic risk factors established in adults are relevant to glucose-insulin homeostasis in youth and that maintaining a healthy weight may be particularly important for youth with high genetic risk of T2D.

Association Between Early Hypertension Control and Cardiovascular Disease Incidence in Veterans With Diabetes.

OBJECTIVE: Guidelines for hypertension treatment in patients with diabetes diverge regarding the systolic blood pressure (SBP) threshold at which treatment should be initiated and treatment goal. We examined associations of early SBP treatment with atherosclerotic cardiovascular disease (ASCVD) events in U.S. adults with diabetes. RESEARCH DESIGN AND METHODS: We studied 43,986 patients with diabetes who newly initiated antihypertensive therapy between 2002 and 2007. Patients were classified into categories based on SBP at treatment initiation (130-139 or ≥140 mmHg) and after 2 years of treatment (100-119, 120-129, 130-139, 140-159, and ≥160 mmHg). The primary outcome was composite ASCVD events (fatal and nonfatal myocardial infarction and stroke), estimated using inverse probability of treatment-weighted Poisson regression and multivariable Cox proportional hazards regression. RESULTS: Relative to individuals who initiated treatment when SBP was 130-139 mmHg, those with pretreatment SBP ≥140 mmHg had higher ASCVD risk (hazard ratio 1.10 [95% CI 1.02, 1.19]). Relative to those with pretreatment SBP of 130-139 mmHg and on-treatment SBP of 120-129 mmHg (reference group), ASCVD incidence was higher in those with pretreatment SBP ≥140 mmHg and on-treatment SBP 120-129 mmHg (adjusted incidence rate difference [IRD] 1.0 [-0.2 to 2.1] events/1,000 person-years) and in those who achieved on-treatment SBP 130-139 mmHg (IRD 1.9 [0.6, 3.2] and 1.1 [0.04, 2.2] events/1,000 person-years for those with pretreatment SBP 130-139 mmHg and ≥140 mmHg, respectively). CONCLUSIONS: In this observational study, patients with diabetes initiating antihypertensive therapy when SBP was 130-139 mmHg and those achieving on-treatment SBP <130 mmHg had better outcomes than those with higher SBP levels when initiating or after 2 years on treatment.