Author + information
- Alexandra K. Lee, MSPH,
- John W. McEvoy, MBChB, BAO, MHS,
- Ron C. Hoogeveen, PhD,
- Christie M. Ballantyne, MD and
- Elizabeth Selvin, PhD, MPH∗ ()
- ↵∗Department of Epidemiology, Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, 2024 East Monument Street, Suite 2-600, Baltimore, Maryland 21287
Persons with diabetes mellitus who have a history of severe hypoglycemia are at increased risk of cardiovascular disease (CVD) (1). However, it remains unclear whether hypoglycemia is causally linked to cardiovascular risk or is merely a proxy of vulnerability. Cardiac troponin T measured with a high-sensitivity assay (hs-cTnT) is a blood-based biomarker of subclinical myocardial damage and is strongly associated with future cardiovascular events (2).
Our objective was to quantify the association of severe hypoglycemia with elevated hs-cTnT in older adults with diabetes before and after adjustment for potential confounding factors.
We examined hs-cTnT in adults, 67 to 89 years of age, with diagnosed diabetes during visit 5 (2011 to 2013) of the ARIC (Atherosclerosis Risk In Communities) study. Past severe hypoglycemia events from 1991 to 2013 were identified from primary position International Classification of Diseases-Ninth Revision codes in Medicare fee-for-service claims for ambulance services, emergency department visits, and hospitalizations (3). Hs-cTnT was measured with a pre-commercial assay (Elecsys Troponin T, Roche Diagnostics, Indianapolis, Indiana). Given the advanced age of participants, we used age- and sex-specific 99th percentile reference values for adults >65 years of age to define elevated hs-cTnT: >31 ng/l for men and >17 ng/l for women (4).
Because hs-cTnT is strongly associated with clinical CVD, we conducted analyses overall and stratified by prior coronary heart disease (CHD) or heart failure (HF) (adjudicated CHD event or HF hospitalization). We used Poisson regression with robust standard errors to generate prevalence ratios of elevated hs-cTnT, adjusted, first, for age, race-center, sex, and then additionally HbA1c and diabetes duration. We also tested for effect modification by prior CHD or HF. In a sensitivity analysis, we further adjusted for estimated glomerular filtration rate because troponin T is filtered by the kidney and poor kidney function increases risk of hypoglycemia.
After exclusions for missing data (n = 50), 2,148 participants remained for analysis. Mean age was 76 years, 31% were black, and 72 (3%) had a history of severe hypoglycemia. Individuals with prior severe hypoglycemia were more likely to be black (48% vs. 31%; p = 0.002), have prior CHD or HF (51% vs. 25%; p < 0.001), or have a longer duration of diabetes (median 20 years vs. 9 years; p < 0.001). Median time from severe hypoglycemic episode to hs-cTnT measurement was 4.3 years (25th to 75th percentile: 1.9 to 8.0 years).
Hs-cTnT values were substantially higher for individuals with a history of severe hypoglycemia compared to those without that history, regardless of prior CHD or HF status, after standardization to sex-specific reference values (Figure 1). The prevalence of elevated hs-cTnT in persons with both prior severe hypoglycemia and history of CHD or HF was extremely high, 70%. A history of CHD or HF did not modify the adjusted association between prior severe hypoglycemia and elevated hs-cTnT (p for interaction = 0.58). The prevalence of elevated hs-cTnT was nearly twice as high in those with prior severe hypoglycemia after adjustment for age, sex, race-center, and prior CHD or HF (adjusted prevalence ratio [aPR]: 1.85; 95% confidence interval [CI]: 1.40 to 2.43). The effect estimate remained elevated but was attenuated and became nonsignificant after adjustment for HbA1c and diabetes duration (aPR: 1.34; 95% CI: 0.99 to 1.81) and additional adjustment for estimated glomerular filtration rate (aPR: 1.15; 95% CI: 0.89 to 1.49).
Limitations of this study include: 1) hypoglycemic events in this community-based population were rare and thus limited the precision of our estimates; 2) we were only able to capture severe hypoglycemic episodes, as many persons with hypoglycemia do not seek immediate medical attention (5); 3) selection bias is a concern because participants with severe hypoglycemia were less likely to attend visit 5; and 4) we were unable to assess medication use at the time of hypoglycemia.
To our knowledge, this is the first study to demonstrate an association between severe hypoglycemia and elevated hs-cTnT in older adults with diabetes. By decreasing energy supply to the myocardium, hypoglycemia may result in myocardial damage and, consequently, elevated hs-cTnT, particularly among persons prone to ischemia. As such, subclinical elevation in hs-cTnT could represent an intermediate step linking hypoglycemia to cardiovascular risk. Whether causal or a marker of risk, severe hypoglycemia should raise concern about subclinical as well as clinical CVD risk.
Please note: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). This research was supported by grant NIH/NIDDK grants K24DK106414 and 2R01DK089174 to Dr. Selvin. Ms. Lee was supported by NIH/NHLBI grant T32HL007024. Mr. McEvoy has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Hoogeveen is a coinvestigator on a provisional patent (patent #61721475) filed by Roche entitled “Biomarkers to Improve Prediction of Heart Failure Risk”; and has received research grant support from Denka Seiken Ltd. Dr. Ballantyne has received grant or research support from Abbott Diagnostic, Amarin, Amgen, Eli Lilly, Esperion, Novartis, Pfizer, Otsuka, Regeneron, Roche Diagnostics, Sanofi-Synthelabo, Takeda, NIH, AHA, and ADA (all significant and all paid to institution, not individual); has served as a consultant to Abbott Diagnostics, Amarin, Eli Lilly, Esperion, Genzyme, Ionis, Matinas BioPharma Inc, Novartis, Regeneron, Roche, and Sanofi-Synthelabo (all modest [<$10,000]); and Merck, Pfizer, Amgen, and AstraZeneca (all significant [>$10,000]); and has served on an advisory board for Roche Diagnostics and is a coinvestigator on a provisional patent (patent #61721475) filed by Roche entitled “Biomarkers to Improve Prediction of Heart Failure Risk.” Dr. Selvin has served on an advisory board for Roche Diagnostics. Reagents for the high-sensitivity cardiac troponin assays were donated by Roche Diagnostics. The authors thank the staff and participants of the ARIC study for their important contributions.
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