Hypoglycemia is one of the most common adverse drug events that lead to emergency room visits and hospitalization,^7,8 and reduces quality of life^9,10. Although trials to assess the benefits of optimizing glycemic control among type 2 diabetes patients have documented a low incidence of hypoglycemia,^11,12 hypoglycemia may be more common in practice¹³, and little is known about the incidence of hypoglycemia occurrences that do not come to medical attention.

The relationship between limited health literacy and hypoglycemia is unclear. Limited health literacy (HL) has been found to be common among patients with type 2 diabetes^14,15 and has been shown to be a barrier to adequate self-management of medication regimens, with less comprehension of medication instructions, dosing, timing, and warnings^16-18, which could lead to increased risk for hypoglycemia.

Overall, 1,579 (11%) of participants reported experiencing at least one significant hypoglycemic episode in the past year. Hypoglycemia occurrence varied by medication regimen, with the highest risk for those on insulin (59%) followed by, mixed oral medication types (23%), secretagogues alone (13%) and metformin alone (5%). Of these participants who reported at least 1 significant hypoglycemic episode, 8% (129/1579) had evidence of a documented emergency department visit or hospitalization for hypoglycemia in the prior year, compared to 1.6% (202/12,777) of the participants who reported not having significant hypoglycemia, yielding an odds ratio of 19.0 (95% CI 13.0–26.0).

Hypoglycemia, while an important adverse event in and of itself, contributes to poorer diabetes outcomes in other domains. Recent work has shown that acute care visits for hypoglycemia predict future risk for dementia among type 2 diabetes patients⁴². Many have suggested that those who experience hypoglycemia may have lower rates of hypoglycemic medication adherence for fear of recurrence^43,44.

Significant hypoglycemia was especially common among patients reporting limited HL, and this association persisted even after adjusting for known and suspected correlates of HL and hypoglycemia. There are several possible mechanisms by which limited HL could increase hypoglycemia risk. First, limited HL could lead to patient errors in timing or dosage of diabetes medications^16,45. Second, limited HL could interfere with proper adjustment of diabetes medication in response to changing caloric intake or energy expenditure⁴⁶. Third, those with limited HL may not correctly interpret and respond to their blood glucose values and trends obtained through self-monitoring, potentially missing opportunities to adapt self-management behaviors so as to prevent significant hypoglycemia⁴⁷. Importantly, mastery of such self-management skills depends, in part, on adequate patient-clinician communication. Limited HL has been shown to impede both patients’ understanding of clinician information and instructions, and patients’ reporting of symptoms and disease state to clinicians¹⁸.

Study strengths include a large, diverse population with uniform access to care, and detailed assessments of HL and hypoglycemic events within a real world setting. Nevertheless, this study has several limitations. First, the KPNC system provides coordinated and uniform access to care, including diabetes education and comprehensive care management. As such, our results may under-estimate hypoglycemic event rates in the under- and uninsured,⁴⁸ or among populations cared for in non-integrated health systems. Second, because this is a cross-sectional analysis, we cannot infer that limited HL was the cause of increased hypoglycemia risk; although reverse causation is improbable, there may be underlying factors affecting both. Third, we did not directly measure HL, although the self-report HL items we used have been validated against direct measurement instruments^29,30. Moreover, the degree to which these items exactly correlate with HL as assessed by standard, ‘direct’ measurement may be less relevant in practice, insofar as these questions have predictive validity as they appear to identify subgroups at risk for a clinically important adverse event. Fourth, we did not measure numeracy in this study, so we could not address the relative contribution of numeracy versus literacy. Numeracy and literacy have been shown to be highly correlated. Fifth, we could not capture attendance at diabetes education. Sixth, not all participants answered every question in this lengthy survey (184 questions, 52 pages). Nevertheless, this remains the largest observational study of hypoglycemia, and the subjects included in the analysis did not differ from the overall sample in terms of age, race/ ethnicity, educational attainment, which are the best predictors of health literacy, or HbA1c, renal function, or medication type, the clearest correlates of hypoglycemia. In addition, we used multiple imputation to minimize the bias associated with missing items^36,38,39,49. Moreover, results using multiply imputed data did not differ from the complete data-only approach. Seventh, we could not explore individual medications within each class. Finally, consistent with prior studies,^1,10-13,50 we obtained measures of hypoglycemia via patient self-report, albeit an imperfect measure. Since self-report of mild hypoglycemia may be less accurate, we queried only clinically significant episodes of losing consciousness or requiring treatment assistance. The fact that we observed a stepwise increase in hypoglycemia consistent with the established pharmacologic risks of hypoglycemia from different medication regimens (i.e., highest in insulin-treated patients) suggests the validity of patients’ reports. We also found that self-report of hypoglycemia was strongly associated with likelihood of making an emergency room visit or requiring hospitalization for hypoglycemia during the year prior to the survey, providing additional validation of this self-reported measure. Furthermore, while it is possible that those with limited HL were more likely to misattribute non-hypoglycemic events to hypoglycemia, the results of our sensitivity analysis that involved only those participants who demonstrated accurate knowledge of hypoglycemia symptoms and treatment suggest that outcome misclassification does not explain our findings. It is theoretically possible that those with limited HL reported more significant hypoglycemia because they may require help for hypoglycemic episodes while those with adequate HL can manage themselves. Such a heightened need for assistance would, in and of itself, place them at greater risk.

Our findings have several clinical and health policy implications. First, while it is unclear whether treating clinicians’ actions (such as intensifying medications or inadequate communication of safety precautions) contributed to these events or whether treating clinicians were aware of patients’ hypoglycemic episodes, our results suggest that hypoglycemic symptoms should be routinely assessed in patients with type 2 diabetes receiving hyperglycemia-lowering agents. Second, because insulin use confers a particularly high risk for hypoglycemia, we recommend formal hypoglycemia prevention counseling that is appropriate for those with limited health literacy, as well as more vigilant self-management support that includes training family members and caregivers, at the time of insulin initiation. More research is needed to (a) identify whether errors in patient self-management are contributing to hypoglycemia, and (b) determine what actions by patients, families, caregivers and clinicians can reduce hypoglycemia. Third, hypoglycemia risk profile should be an important criteria when choosing medication regimen, favoring medications which are least likely to cause hypoglycemia.