Conclusions
Hypoglycemia is a common, serious, yet potentially preventable, adverse health outcome in the management of type 2 diabetes.7–9 Hypoglycemia prevention is predicted on the ability to capture, track and evaluate events as they occur in real-world practice. In this meta-epidemiological review of observational studies of patients with type 2 diabetes, we found substantial heterogeneity in the definition, ascertainment and report of hypoglycemia, particularly for non-severe events.
Recognizing the importance of a uniform definition for hypoglycemia, on 21 November 2016, the IHSG proposed a taxonomy for non-severe (further subdivided into level 1 and level 2) and severe (level 3) hypoglycemia.12 13 The IHSG further advised that all clinical trials of diabetes management report on level 2 and level 3 hypoglycemia, with an option to also report level 1 hypoglycemia.12 13 However, observational (ie, non-randomized) studies are an invaluable source of information on adverse events in real-world settings and as such it was critical to examine how hypoglycemia was defined in such studies. This is especially important for retrospective studies that rely on secondary analyses of existing data collected for other reasons, whether for clinical care or billing/administrative purposes. To our knowledge, this is the first study to systematically examine the definitions of non-severe and severe hypoglycemia used by observational studies that form the evidence base for hypoglycemia prevention among adults with type 2 diabetes. Although most of the recent studies tend to adhere to the IHSG recommendations, the hypoglycemia definitions remained inconsistent. Overall, almost a fifth of the studies provided no definition of hypoglycemia at all. An additional 17% were loosely adherent, as they relied on ICD diagnosis codes from clinical encounters and may be construed to indirectly imply need for medication attention. Such heterogeneity in hypoglycemia reporting hinders comparisons across studies and precludes generalizable inferences about the safety of diabetes management across populations and settings.
Our study builds on earlier work demonstrating heterogeneity in hypoglycemia definitions in randomized controlled trials (RCTs) of diabetes therapies.14 Despite the IHSG recommendation, Balijepalli et al14 found that 40% of RCTs included in the Canadian Agency for Drugs and Technologies in Health report for second-line and third-line therapies for type 2 diabetes either did not report on hypoglycemia or did not specify the definition of reported events. Of the 60% that reported and defined hypoglycemia, only 14% used the IHSG definition for level 1 hypoglycemia and 20.8% for level 2 hypoglycemia.14 In contrast, our analyses that were restricted to the post-IHSG recommendation period found that hypoglycemia reporting in observational studies of type 2 diabetes was better, with 62.5% of studies on non-severe hypoglycemia and 54.1% of studies on severe hypoglycemia consistent with IHSG definitions. Nevertheless, substantial opportunity for improvement remains.
An important consideration for studies that leverage real-world data is how to optimally use administrative claims and electronic health records (EHRs) for large-scale hypoglycemia ascertainment and reporting. Doing so requires accurate and reliable identification of events, which in turn is predicated on patient’s reliably reporting events, healthcare providers consistently and uniformly documenting them and such documentation to be available in a format amenable to large scale ascertainment. Our analysis included both prospective and retrospective observational studies, and both study designs demonstrated heterogeneity in how hypoglycemia is defined. However, while prospective studies can homogenize their approach to hypoglycemia ascertainment by adopting IHSG definitions, retrospective studies that rely on secondary analysis of data collected for other reasons (eg, billing or routine care) require that hypoglycemia be uniformly defined and documented across all settings and not just research.
In our analysis, 3 of 116 (2.6%) studies that reported on non-severe hypoglycemia and 30 of 189 (15.9%) studies that reported on severe hypoglycemia used ICD codes to identify events. Because the IHSG definition of non-severe hypoglycemia is predicated solely on glucose levels, diagnosis codes and claims data cannot be used to establish a corresponding definition. Severe hypoglycemia is characterized by the need for third party or medical assistance. It can be inferred that ED or hospital encounters for hypoglycemia represent acute severe events. However, ambulatory documentation of hypoglycemia may reflect prior events being discussed in the office, both severe and non-severe, and not convey the frequency or timing of those events relative to the encounter. Diagnosis codes from ED-based or hospital-based encounters are less likely to be misclassified, particularly if the hypoglycemia code is listed as the primary or principle diagnosis for the acute event. This is the approach used by the Centers for Disease Control and Prevention to quantify severe hypoglycemic events.21 In contrast, many of the studies examined here did not specify the position of the hypoglycemia code in the encounter, what date range of claims was considered (ie, only from the date of hospital admission, only on the date of discharge or any day throughout the hospitalization) or even the setting(s) eligible for inclusion (ie, office evaluation and management visit, any ambulatory visit, ED visit, observation or inpatient hospital stay). Finally, there is heterogeneity in the specific ICD codes used to define hypoglycemia and whether studies relied on the Ginde algorithm,18 a modified version of the Ginde algorithm, or other codes entirely. Each of these parameters has the potential to alter event rates and study inferences. Nevertheless, it is important to note that up to 95% of severe hypoglycemic events do not culminate in an ED visit or hospitalization,7 22 23 and as such, studies that rely solely on claims data greatly underestimate their frequency.
Many observational studies rely on events documented as part of routine care (eg, registries, EHR and claims), yet collecting data about hypoglycemia in the real-world is challenging. Patients rarely volunteer information about hypoglycemia to their clinicians,24–28 and clinicians do not routinely screen their patients for hypoglycemia even when they are at risk for these events.7 29 As a result, patient-reported hypoglycemia is not easily captured in clinical practice, despite its association with increased all-cause mortality and impaired quality of life.30 31 Data from glucometers and continuous glucose monitors (CGMs), while valuable, is also not commonly available in the EHR, whether due to patients not using these devices (particularly in developing countries) or the inability of many practices, particularly in primary care, to consistently download device information into the EHR. Additionally, CGM use among patients with type 2 diabetes remains uncommon particularly when not treated with intensive insulin therapy.32 Reliance on events that do come to medical attention, whether in the ambulatory setting, ED or hospital, will miss most events and patients who experience them. Thus, it is critical to raise awareness among clinicians, patients and policy makers about the importance of routine and standardized hypoglycemia ascertainment and documentation, in accordance with ADA guidelines.33
This study should be considered in the context of its limitations. We focused on observational studies conducted among patients with type 2 diabetes. A large number of studies were excluded from analysis because they did not specify diabetes type and thus included patients with both type 1 and type 2 diabetes, as reliable classification of diabetes is often challenging in real-world data sources (references 214–243 of the online supplemental material).17 This contributed to the relatively small number of observational research studies analyzed. Our analyses included studies through May 2018, and hypoglycemia reporting may have improved over the past 2 years with greater attention and awareness paid to hypoglycemia by clinicians, professional societies and regulatory agencies. Nevertheless, our data point to the substantial gap in the quality of hypoglycemia ascertainment and reporting in research. This is confounded by persistent gaps in clinical hypoglycemia ascertainment7 and ultimately may contribute to inadequate understanding and correction of hypoglycemia risk factors among patients with diabetes.
Observational studies and real-world data are an invaluable evidence base for comparative effectiveness and safety research that complement knowledge gleaned from interventional trials. They are particularly useful when studying adverse drug events such as hypoglycemia. The marked heterogeneity in how hypoglycemia is defined, documented and reported is a major barrier to assessing its prevalence, identifying highest risk subpopulations, promoting screening for and disclosure of events and developing prevention strategies. As such, this work reinforces the urgent need to promote, facilitate and use standardized ascertainment, documentation and reporting of hypoglycemia in observational studies and in the data sources that feed them. Using tools such as the IHSG hypoglycemia definitions in research studies could homogenize hypoglycemia reporting and evaluation. Furthermore, patients’ education to recognize, report and manage hypoglycemia is a very important tool we can use right now to decrease mortality and morbidity. Ultimately, the ability to reliably study hypoglycemic events in real-world settings will support better risk stratification and prevention strategies aimed to stopping these common, harmful yet potentially preventable adverse events.
