Publications

OBJECTIVE

There is suggestive evidence linking hypoglycemia with cardiovascular disease, but few data have been collected in a community-based setting. Information is lacking on individual cardiovascular outcomes and cause-specific mortality.

RESEARCH DESIGN AND METHODS

We conducted a prospective cohort analysis of 1,209 participants with diagnosed diabetes from the Atherosclerosis Risk in Communities (ARIC) study (analytic baseline, 1996-1998). Severe hypoglycemic episodes were identified using first position ICD-9 codes from hospitalizations, emergency department visits, and ambulance calls through 2013. Cardiovascular events and deaths were captured through 2013. We used adjusted Cox regression models with hypoglycemia as a time-varying exposure.

RESULTS

There were 195 participants with at least one severe hypoglycemic episode during a median fellow-up of 15.3 years. After severe hypoglycemia, the 3-year cumulative incidence of coronary heart disease was 10.8% and of mortality was 28.3%. After adjustment, severe hypoglycemia was associated with coronary heart disease (hazard ratio [HR] 2.02, 95% CI 1.27-3.20), all-cause mortality (HR 1.73, 95% CI 1.38-2.17), cardiovascular mortality (HR 1.64, 95% CI 1.15-2.34), and cancer mortality (HR 2.49, 95% CI 1.46-4.24). Hypoglycemia was not associated with stroke, heart failure, atrial fibrillation, or noncardiovascular and noncancer death. Results were robust within subgroups defined by age, sex, race, diabetes duration, and baseline cardiovascular risk.

CONCLUSIONS

Severe hypoglycemia is clearly indicative of declining health and is a potent marker of high absolute risk of cardiovascular events and mortality.

OBJECTIVE

To characterize long-term kidney disease trajectories in persons with and without diabetes in a general population.

RESEARCH DESIGN AND METHODS

We classified 15,517 participants in the community-based Atherosclerosis Risk in Communities (ARIC) study by diabetes status at baseline (1987-1989; no diabetes, undiagnosed diabetes, and diagnosed diabetes). We used linear mixed models with random intercepts and slopes to quantify estimated glomerular filtration rate (eGFR) trajectories at four visits over 26 years.

RESULTS

Adjusted mean eGFR decline over the full study period among participants without diabetes was -1.4 mL/min/1.73 m/year (95% CI -1.5 to -1.4), with undiagnosed diabetes was -1.8 mL/min/1.73 m/year (95% CI -2.0 to -1.7) (difference vs. no diabetes, < 0.001), and with diagnosed diabetes was -2.5 mL/min/1.73 m/year (95% CI -2.6 to -2.4) (difference vs. no diabetes, < 0.001). Among participants with diagnosed diabetes, risk factors for steeper eGFR decline included African American race, high-risk genotype, systolic blood pressure ≥140 mmHg, insulin use, and higher HbA.

CONCLUSIONS

Diabetes is an important risk factor for kidney function decline. Those with diagnosed diabetes declined almost twice as rapidly as those without diabetes. Among people with diagnosed diabetes, steeper declines were seen in those with modifiable risk factors, including hypertension and glycemic control, suggesting areas for continued targeting in kidney disease prevention.

AIMS/HYPOTHESIS

We aimed to evaluate the link between severe hypoglycaemia and domain-specific cognitive decline, smaller brain volumes and dementia in adults with type 2 diabetes, which so far has been relatively poorly characterised.

METHODS

We included participants with diagnosed diabetes from the community-based Atherosclerosis Risk in Communities (ARIC) study. At the participants' fifth study visit (2011-2013), we examined the cross-sectional associations of severe hypoglycaemia with cognitive status, brain volumes and prior 15 year cognitive decline. We also conducted a prospective survival analysis of incident dementia from baseline, visit 4 (1996-1998), to 31 December 2013. Severe hypoglycaemia was identified, using ICD-9 codes, from hospitalisations, emergency department visits and ambulance records. Prior cognitive decline was defined as change in neuropsychological test scores from visit 4 (1996-1998) to visit 5 (2011-2013). At visit 5, a subset of participants underwent brain MRIs. Analyses were adjusted for demographics, APOE genotype, use of diabetes medication, duration of diabetes and glycaemic control.

RESULTS

Among 2001 participants with diabetes at visit 5 (mean age 76 years), a history of severe hypoglycaemia (3.1% of participants) was associated with dementia (vs normal cognitive status): OR 2.34 (95% CI 1.04, 5.27). In the subset of participants who had undergone brain MRI (n = 580), hypoglycaemia was associated with smaller total brain volume (-0.308 SD, 95% CI -0.612, -0.004). Hypoglycaemia was nominally associated with a 15 year cognitive change (-0.14 SD, 95% CI -0.34, 0.06). In prospective analysis (n = 1263), hypoglycaemia was strongly associated with incident dementia (HR 2.54, 95% CI 1.78, 3.63).

CONCLUSIONS/INTERPRETATION

Our results demonstrate a strong link between severe hypoglycaemia and poor cognitive outcomes, suggesting a need for discussion of appropriate diabetes treatments for high-risk older adults.

Importance

The incidence of epilepsy is higher in older age than at any other period of life. Stroke, dementia, and hypertension are associated with late-onset epilepsy; however, the role of other vascular and lifestyle factors remains unclear.

Objective

To identify midlife vascular and lifestyle risk factors for late-onset epilepsy.

Design, Setting, and Participants

The Atherosclerosis Risk in Communities (ARIC) study is a prospective cohort study of 15 792 participants followed up since 1987 to 1989 with in-person visits, telephone calls, and surveillance of hospitalizations (10 974 invited without completing enrollment). The ARIC is a multicenter study with participants selected from 4 US communities. This study included 10 420 black or white participants from ARIC with at least 2 years of Medicare fee-for-service coverage and without missing baseline data. Data were analyzed betweeen April 2017 and May 2018.

Exposures

Demographic, vascular, lifestyle, and other possible epilepsy risk factors measured at baseline (age 45-64 years) were evaluated in multivariable survival models including demographics, vascular risk factors, and lifestyle risk factors.

Main Outcomes and Measures

Time to development of late-onset epilepsy (2 or more International Classification of Diseases, Ninth Revision codes for epilepsy or seizures starting at 60 years or older in any claim [hospitalization or outpatient Medicare through 2013]), with first code for seizures after at least 2 years without code for seizures.

Results

Of the 10 420 total participants (5878 women [56.4%] and 2794 black participants [26.8%]; median age 55 years at first visit), 596 participants developed late-onset epilepsy (3.33 per 1000 person-years). The incidence was higher in black than in white participants (4.71; 95% CI, 4.12-5.40 vs 2.88; 95% CI, 2.60-3.18 per 1000 person-years). In multivariable analysis, baseline hypertension (hazard ratio [HR], 1.30; 95% CI, 1.09-1.55), diabetes (HR, 1.45; 95% CI, 1.17-1.80), smoking (HR, 1.09; 95% CI, 1.01-1.17), apolipoprotein E ε4 genotype (1 allele HR, 1.22; 95% CI, 1.02-1.45; 2 alleles HR, 1.95; 95% CI, 1.35-2.81), and incident stroke (HR, 3.38; 95% CI, 2.78-4.10) and dementia (HR, 2.56; 95% CI, 2.11-3.12) were associated with an increased risk of late-onset epilepsy, while higher levels of physical activity (HR, 0.90; 95% CI, 0.83-0.98) and moderate alcohol intake (HR, 0.72; 95% CI, 0.57-0.90) were associated with a lower risk. Results were similar after censoring individuals with stroke or dementia.

Conclusions and Relevance

Potentially modifiable risk factors in midlife and the APOE ε4 genotype were positively associated with risk of developing late-onset epilepsy. Although stroke and dementia were both associated with late-onset epilepsy, vascular and lifestyle risk factors were significant even in the absence of stroke or dementia.

OBJECTIVE

To identify the association between brain vascular changes and cortical volumes on MRI and late-onset epilepsy.

METHODS

In 1993-1995, 1,920 participants (median age 62.7, 59.9% female) in the community-based Atherosclerosis Risk in Communities (ARIC) Study underwent MRI, and white matter hyperintensities were measured. In addition, in 2011-2013, 1,964 ARIC participants (median age 72.4, 61.1% female) underwent MRI, and cortical volumes and white matter hyperintensities were measured. We identified cases of late-onset epilepsy (starting at age 60 or later) from ARIC hospitalization records and Medicare claims data. Using the 1993-1995 MRI, we evaluated the association between white matter hyperintensities and subsequent epilepsy using survival analysis. We used the 2011-2013 MRI to conduct cross-sectional logistic regression to examine the association of cortical volumes and white matter hyperintensities with late-onset epilepsy. All models were adjusted for demographics, hypertension, diabetes, smoking, and ε4 allele status.

RESULTS

Ninety-seven ARIC participants developed epilepsy after having an MRI in 1993-1995 (incidence 3.34 per 1,000 person-years). The degree of white matter hyperintensities measured at ages 49-72 years was associated with the risk of late-onset epilepsy (hazard ratio 1.27 per age-adjusted SD, 95% confidence interval [CI] 1.06-1.54). Lower cortical volume scores were associated cross-sectionally with higher odds of late-onset epilepsy (odds ratio 1.87, 95% CI 1.16-3.02) per age-adjusted SD.

CONCLUSIONS

This study demonstrates associations between earlier-life white matter hyperintensities on MRI and later-life incident epilepsy, and between cortical volumes measured later in life and late-onset epilepsy. These findings may help illuminate the causes of late-onset epilepsy.

Isolated systolic hypertension (ISH) and elevated pulse pressure (PP) are common blood pressure (BP) abnormalities in older adults, reflect poor vascular compliance, and can signify risk for cardiovascular outcomes. We sought to characterize the associations of ISH and widened PP with high-sensitivity Troponin-T (hs-cTnT; a marker of myocardial damage) and N-terminal pro-B-type natriuretic peptide (NT-proBNP; a marker of hemodynamic stress) levels in older adults. We performed a cross-sectional analysis of 5,251 Atherosclerosis Risk in Communities (ARIC) study participants without heart failure who attended visit 5 (2011 to 2013). We used logistic regression to evaluate the association of ISH (systolic BP ≥140 mm Hg and diastolic BP < 90 mm Hg) and quartiles of PP with detectable (≥5 ng/L) and elevated hs-cTnT (≥14 ng/L); as well as elevated NT-proBNP (≥100 pg/mL). The mean age was 75 years, 58% were women, and 78% were white. ISH was present in 24.7% and PP ≥ 70 mm Hg in 30.3% of this cohort. Compared to participants with nonhypertensive BP (<140/90 mm Hg), ISH was independently associated with hs-cTnT and NT-proBNP; adjusted odds ratio of 1.5 (95% confidence interval: 1.1 to 1.9) for detectable hs-cTnT; 1.3 (1.1 to 1.5) for elevated hs-cTnT; and 1.8 (1.6 to 2.1) for elevated NT-proBNP. Increasing quartiles of PP were also significantly associated with both elevated hs-cTnT (p-for-trend <0.0001) and NT-proBNP (p-for-trend <0.0001). These associations were not modified by BP treatment status. In conclusion, ISH and wide PP are relatively common in older adults despite contemporary BP treatment and are associated with abnormalities in hs-cTnT and NT-pro BNP, findings that could guide personalized treatment of older patients with these BP aberrations.