Type 1 Diabetes Genetic Risk in 109,954 Veterans With Adult-Onset Diabetes: The Million Veteran Program (MVP).

OBJECTIVE: To characterize high type 1 diabetes (T1D) genetic risk in a population where type 2 diabetes (T2D) predominates. RESEARCH DESIGN AND METHODS: Characteristics typically associated with T1D were assessed in 109,594 Million Veteran Program participants with adult-onset diabetes, 2011-2021, who had T1D genetic risk scores (GRS) defined as low (0 to <45%), medium (45 to <90%), high (90 to <95%), or highest (≥95%). RESULTS: T1D characteristics increased progressively with higher genetic risk (P < 0.001 for trend). A GRS ≥ 90% was more common with diabetes diagnoses before age 40 years, but 95% of those participants were diagnosed at age ≥40 years, and they resembled T2D in mean age (64.3 years) and BMI (32.3 kg/m2). Compared with the low risk group, the highest-risk group was more likely to have diabetic ketoacidosis (low 0.9% vs. highest GRS 3.7%), hypoglycemia prompting emergency visits (3.7% vs. 5.8%), outpatient plasma glucose <50 mg/dL (7.5% vs. 13.4%), a shorter median time to start insulin (3.5 vs. 1.4 years), use of a T1D diagnostic code (16.3% vs. 28.1%), low C-peptide levels if tested (1.8% vs. 32.4%), and glutamic acid decarboxylase antibodies (6.9% vs. 45.2%), all P < 0.001. CONCLUSIONS: Characteristics associated with T1D were increased with higher genetic risk, and especially with the top 10% of risk. However, the age and BMI of those participants resemble people with T2D, and a substantial proportion did not have diagnostic testing or use of T1D diagnostic codes. T1D genetic screening could be used to aid identification of adult-onset T1D in settings in which T2D predominates.

Mendelian randomization study of diabetes and dementia in the Million Veteran Program.

INTRODUCTION: Diabetes and dementia are diseases of high health-care burden worldwide. Individuals with diabetes have 1.4 to 2.2 times higher risk of dementia. Our objective was to evaluate evidence of causality between these two common diseases. METHODS: We conducted a one-sample Mendelian randomization (MR) analysis in the US Department of Veterans Affairs Million Veteran program. The study included 334,672 participants ≥65 years of age with type 2 diabetes and dementia case-control status and genotype data. RESULTS: For each standard deviation increase in genetically predicted diabetes, we found increased odds of three dementia diagnoses in non-Hispanic White participants (all-cause: odds ratio [OR] = 1.07 [1.05-1.08], P = 3.40E-18; vascular: OR = 1.11 [1.07-1.15], P = 3.63E-09, Alzheimer's disease [AD]: OR = 1.06 [1.02-1.09], P = 6.84E-04) and non-Hispanic Black participants (all-cause: OR = 1.06 [1.02-1.10], P = 3.66E-03, vascular: OR = 1.11 [1.04-1.19], P = 2.20E-03, AD: OR = 1.12 [1.02-1.23], P = 1.60E-02) but not in Hispanic participants (all P > 0.05). DISCUSSION: We found evidence of causality between diabetes and dementia using a one-sample MR study, with access to individual level data, overcoming limitations of prior studies using two-sample MR techniques.

Mendelian randomization study of diabetes and dementia in the Million Veteran Program.

INTRODUCTION: Diabetes and dementia are diseases of high healthcare burden worldwide. Individuals with diabetes have 1.4 to 2.2 times higher risk of dementia. Our objective was to evaluate evidence of causality between these two common diseases. METHODS: We conducted a one-sample Mendelian randomization (MR) analysis in the U.S. Department of Veterans Affairs Million Veteran program. The study included 334,672 participants ≥65 years of age with type 2 diabetes and dementia case-control status and genotype data. RESULTS: For each standard deviation increase in genetically-predicted diabetes, we found increased odds of three dementia diagnoses in non-Hispanic White participants (all-cause: OR=1.07[1.05-1.08], P =3.40E-18; vascular: OR=1.11[1.07-1.15], P =3.63E-09, Alzheimer's: OR=1.06[1.02-1.09], P =6.84E-04) and non-Hispanic Black participants (all-cause: OR=1.06[1.02-1.10], P =3.66E-03, vascular: OR=1.11[1.04-1.19], P =2.20E-03, Alzheimer's: OR=1.12 [1.02-1.23], P =1.60E-02) but not in Hispanic participants (all P >.05). DISCUSSION: We found evidence of causality between diabetes and dementia using a one-sample MR study, with access to individual level data, overcoming limitations of prior studies utilizing two-sample MR techniques.

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.

Role of Frailty in Identifying Benefit From Transcatheter Versus Surgical Aortic Valve Replacement.

BACKGROUND: Frailty is associated with a higher risk for adverse outcomes after aortic valve replacement (AVR) for severe aortic valve stenosis, but whether or not frail patients derive differential benefit from transcatheter (TAVR) versus surgical (SAVR) AVR is uncertain. METHODS: We linked adults ≥65 years old in the US CoreValve HiR trial (High-Risk) or SURTAVI trial (Surgical or Transcatheter Aortic-Valve Replacement in Intermediate-Risk Patients) to Medicare claims, February 2, 2011, to September 30, 2015. Two frailty measures, a deficit-based and phenotype-based frailty index (FI), were generated. The treatment effect of TAVR versus SAVR was evaluated within FI tertiles for the primary end point of death and nondeath secondary outcomes, using multivariable Cox regression. RESULTS: Of 1442 (linkage rate =60.0%) individuals included, 741 (51.4%) individuals received TAVR and 701 (48.6%) received SAVR (mean age 81.8±6.1 years, 44.0% female). Although 1-year death rates in the highest FI tertiles (deficit-based FI 36.7% and phenotype-based FI 33.8%) were 2- to 3-fold higher than the lowest tertiles (deficit-based FI 13.4%; hazard ratio, 3.02 [95% CI, 2.26-4.02], P<0.001; phenotype-based FI 17.9%; hazard ratio, 2.05 [95% CI, 1.58-2.67], P<0.001), there were no significant differences in the relative or absolute treatment effect of SAVR versus TAVR across FI tertiles for all death, nondeath, and functional outcomes (all interaction P>0.05). Results remained consistent across individual trials, frailty definitions, and when considering the nonlinked trial data. CONCLUSIONS: Two different frailty indices based on Fried and Rockwood definitions identified individuals at higher risk of death and functional impairment but no differential benefit from TAVR versus SAVR.

Identification of Frailty Using a Claims-Based Frailty Index in the CoreValve Studies: Findings from the EXTEND-FRAILTY Study.

Background In aortic valve disease, the relationship between claims-based frailty indices (CFIs) and validated measures of frailty constructed from in-person assessments is unclear but may be relevant for retrospective ascertainment of frailty status when otherwise unmeasured. Methods and Results We linked adults aged ≥65 years in the US CoreValve Studies (linkage rate, 67%; mean age, 82.7±6.2 years, 43.1% women), to Medicare inpatient claims, 2011 to 2015. The Johns Hopkins CFI, validated on the basis of the Fried index, was generated for each study participant, and the association between CFI tertile and trial outcomes was evaluated as part of the EXTEND-FRAILTY substudy. Among 2357 participants (64.9% frail), higher CFI tertile was associated with greater impairments in nutrition, disability, cognition, and self-rated health. The primary outcome of all-cause mortality at 1 year occurred in 19.3%, 23.1%, and 31.3% of those in tertiles 1 to 3, respectively (tertile 2 versus 1: hazard ratio, 1.22; 95% CI, 0.98-1.51; P=0.07; tertile 3 versus 1: hazard ratio, 1.73; 95% CI, 1.41-2.12; P<0.001). Secondary outcomes (bleeding, major adverse cardiovascular and cerebrovascular events, and hospitalization) were more frequent with increasing CFI tertile and persisted despite adjustment for age, sex, New York Heart Association class, and Society of Thoracic Surgeons risk score. Conclusions In linked Medicare and CoreValve study data, a CFI based on the Fried index consistently identified individuals with worse impairments in frailty, disability, cognitive dysfunction, and nutrition and a higher risk of death, hospitalization, bleeding, and major adverse cardiovascular and cerebrovascular events, independent of age and risk category. While not a surrogate for validated metrics of frailty using in-person assessments, use of this CFI to ascertain frailty status among patients with aortic valve disease may be valid and prognostically relevant information when otherwise not measured.