Hypoglycemia Detection in Diabetes

Abstract

Hypoglycemia, once detected in a timely manner, is commonly treated by administration of glucose or glucagon in accordance with HCP advice, however, identifying the hypoglycemic event or need to treat is of initial paramount importance. The definition of hypoglycemia is provided, together with the implications of such an event on clinical and economic outcomes. The current accuracy standards are discussed and how they are applied to the low blood glucose range and current technologies.

1. Introduction

Diabetes is a lifelong, chronic disease characterized by episodes of hyperglycemia [1, 2]. Treatment of diabetes, in order to be effective, must lower glucose concentration to a euglycemic level, however, the key barrier to optimal glycemic control is hypoglycemia (low blood glucose levels) despite ongoing improvements in therapies and technology [3].

Hypoglycemia is one of the most impactful adverse events in diabetes and is a common problem for people with both type one (T1D) and type two (T2D) diabetes [4]. Too much insulin or, insulin-producing medications are commonly related to a hypoglycemic event, however other factors such as delayed, missed, or reduced meals other than what was planned, unanticipated strenuous exercise, alcohol consumption or interactions with other drugs are also known contributors. Additionally, individual patient factors such as older age, nutritional status, duration of diabetes, renal or hepatic disease, history of hypoglycemic episodes [5], and hypoglycemic unawareness may increase the risk of events [6].

2. The size of the problem

2.1 Hypoglycemia is the key problem in diabetes management

Despite recent advances in diabetes technology, hypoglycemia remains a key obstacle to achieving adequate glycemic control [3, 7, 8]. Even though the issue is well accepted, the size of the issue varies depending on how hypoglycemia is defined, measured, and reported. The incidence of hypoglycemia reported between randomized controlled trials vs. observational studies vs. patient-reported outcomes was found to differ by a factor of over 100 in one review [9].

2.2 Hypoglycemia is common problem for both T1D and T2D

The frequency of hypoglycemia varies from 42 to 91 events per patient year for adults with Type 1 diabetes (T1D) and from 20.3–44.4 events per patient year for adults with Type 2 diabetes (T2D) [10]. Severe hypoglycemia is not only a problem for insulin-treated patients but is also common among older adults with T2D across all levels of glycemic control. The risk tends to be higher in patients with either near-normal glycemia or very poor glycemic control [4]. Additionally, frequent episodes of mild hypoglycemia may compromise the hormonal counterregulatory response to produce adrenaline and subsequent autonomic warning symptoms such as trembling and sweating leading to hypo-unawareness increasing the risk of severe hypoglycemia further [6].

2.3 Clinical consequences of hypoglycemia are significant

With the general exception of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic syndrome (HHS), the clinical consequences of prolonged hyperglycemia are long-term. These long-term risks were demonstrated in the Diabetes Control and Complications Trial (DCCT) [11] and the United Kingdom Prospective Diabetes Study (UKPDS) [12] for T1 and T2 diabetes respectively and are the result of neuropathy, retinopathy, and/or nephropathic complications.

The clinical consequences of severe hypoglycemia on the other hand can be immediately associated with the event and include acute cerebrovascular disease, myocardial infarction, neurocognitive dysfunction, and loss of vision [13]. If left untreated, severe hypoglycemia can result in significant morbidity and mortality [14, 15].

2.4 Economic consequences and human impact of hypoglycemia are significant

All levels of hypoglycemia are associated with significant indirect costs, not only on employers but also on individuals with diabetes [16]. A recent study showed a clear link between severe hypoglycemia and the costs of lost productivity, with the highest loss in productivity attributed to non-severe nocturnal hypoglycemic events [17]. Numerous studies have shown that hypoglycemia negatively impacts patients’ ability to concentrate and participate in daily activities, thereby negatively impacting the quality of life (QoL) [17]. Even non-severe hypoglycemia, which occurs in 24–60% of patients with diabetes, can adversely affect QoL [18]. The greatest reductions in QoL are seen among those participants reporting a higher frequency of non-severe hypoglycemia [18]. As reported by Geelhoed-Duijvestijn et al., it takes an average of 50.4 min to return to normal functioning following a daytime non-severe hypoglycemic event, but negative feelings persisted for an average of 5.4 hours [19]. Following a nocturnal non-severe hypoglycemic event, functionality was diminished for an average of 80.5 min while negative feelings persisted for 12.2 hours [19].

Severe hypoglycemic episodes not only significantly affect the individual but are associated with long-term cost implications to the health system. One cohort study assessed the costs between a population requiring hospitalization due to severe hypoglycemia and a matched control. The results demonstrated that the group suffering from the severe hypoglycemic episode incurred an additional $10,873 (p < 0.001) in direct and indirect costs vs. the control for that event year [20].

Hypoglycemia detection and management remain the cornerstone of modern diabetes management and it is important that patients and their healthcare providers (HCPs) understand the strengths and limitations of various blood glucose monitoring systems (BGMS) in order to select the most appropriate system that meets their individual needs [13].

3. Hypoglycemia definition and current threshold

3.1 Current classification of hypoglycemia

A joint position statement of the International Hypoglycemia Study Group of ADA and EASD has proposed three glucose severity levels when reporting hypoglycemia in clinical trials of glucose-lowering drugs for the treatment of diabetes (Table 1). The Group recommends that the frequency of detection of a glucose concentration < 3.0 mmol/l (<54 mg/dl), which it considers to be clinically significant biochemical hypoglycemia, should be included in clinical trial reports [21]. These levels are further aligned by the most recent version of the ADA’s Standards of Medical Care in Diabetes 2022 (Table 1).

	ADA – Standards of Care 2022	International Hypoglycaemia Study Group., 2017
Level 1 < 70–54 mg/dL (3.9–3.0 mmol/L) with or without symptoms	Considered clinically important (independent of the severity of acute hypoglycemic symptoms)	This need not be reported routinely in clinical studies, although this would depend on the purpose of the study
Level 2 < 54 mg/dL (3.0 mmol/L) with or without symptoms	The threshold at which neuroglycopenic symptoms begin to occur and require immediate action to resolve the hypoglycemic event	Sufficiently low to indicate serious, clinically important hypoglycemia
Level 3 Severe hypoglycemia not defined by a specific glucose level	Defined as a severe event characterized by altered mental and/or physical functioning that requires assistance from another person for recovery	Severe cognitive impairment requiring external assistance for recovery

Table 1.

Levels of hypoglycemia proposed when reporting in clinical trials and as defined by the ADA.

4. Benefits and limitations of diabetes technologies assessing glucose levels

4.1 BGMS

4.1.1 Limitations of current ISO 2013 and FDA 2020 accuracy requirements for blood glucose monitoring systems in diabetes management

According to current ISO 15197:2013 accuracy requirements, ≥95% of BG results should be demonstrated to be within ±15% of the reference method for samples with BG concentrations ≥100 mg/dL, and ± 15 mg/dL when BG concentrations are <100 mg/dL. (International Organization for Standardization.)

The FDA guidance 2020 recommends that ≥95% of all BGMS results should be within ±15%, and ≥ 99% of all BGMS results should be within ±20% of the reference laboratory method across the entire claimed to measure range of the BGMS. (US Department of Health and Human Services [22]. Food and Drug Administration.)

These more stringent guidelines recognized the limitations of evaluating BG samples at the extreme ends of the measuring range, especially in the low range where very few samples are available [23]. Recognizing the clinical importance of the accuracy of BG measurements for hypo- and hyperglycemic blood samples, both European and US authorities have requested that accuracy data be reported separately for low, normal, and high BG ranges [23]. This issue is however complicated by system accuracy requirements being applied to measurement results from the whole glycemic range. If a BGMS shows 100% accurate results at BG concentrations ≥80 mg/dL (4.44 mmol/L) (80% of results, following ISO 15197:2013) [24], this results in 25% of the samples in the low-glucose range being allowed outside the accuracy limits (5% “results outside of accuracy limits” divided by 20% “results <80 mg/dL [4.44 mmol/L]”) [23].

4.1.2 Difference of accuracy in hypoglycemic range of BGMS compliant with ISO 2013 standards and/or FDA 2020 guidelines

Despite the boundaries of ISO 2013 standards and/or FDA 2020 guidance, (International Organization for Standardization., US Department of Health and Human Services [22]. Food and Drug Administration) considerable differences exist in the performance of commercially available BGMS [25]. Such error patterns over the operating range of BGMS may lead to relevant differences in clinical and economic outcomes. These differences can potentially increase the risk of not detecting hypoglycemic events when they occur, and, therefore, inadequately identifying and treating them [25].

Thus, if a patient’s true BG concentration is 60 mg/dL (3.33 mmol/L), acceptably accurate results range from 45 to 75 mg/dL (2.50 to 4.16 mmol/L) according to the ISO limits and from 51 to 69 mg/dL (2.83 to 3.83 mmol/L) according to FDA criteria. This can make it difficult for a patient to detect and manage their hypoglycemia. If a BGMS cannot reliably differentiate between 50, 60, and 70 mg/dL (2.77, 3.33, and 3.88 mmol/L), the utility of predefined hypoglycemia thresholds comes into question [23].

4.1.3 Evidence shows that the accuracy of different BGMS (compliant with ISO 2013) is not the same in the low-BG range

Multiple post-market studies of BGMS have failed to replicate the accuracy normally required to gain market approval by the regulatory authorities [26, 27, 28, 29, 30]. Many of these products remain on the market today.

Whilst it is not difficult to obtain BG samples in the normal range it is more of a challenge to obtain and subsequently assess the accuracy of devices outside of this range. It may be unethical and potentially dangerous to purposefully cause hypoglycemia in a patient simply for the purposes of testing device accuracy. The remaining choices to assess accuracy at this level is either to accept the smaller sample size, modify the sample prior to testing, or to create a statistical model. These concepts have further been explored in the low blood glucose range and evidence shows that the accuracy of different BGMS (that were approved under ISO 2013 standards) are not the same at these critical levels and some would appear non-compliant [29, 31]. Recently a methodology was developed to demonstrate the differences in accuracy in the low blood glucose range among several BGMSs as demonstrated in Figure 1 [32, 33, 34, 35]. The differences in accuracy between devices was clinically meaningful.

Figure 1.

Probability curves for real-world BGMSs (all meeting ISO 15197:2013 criteria) (adapted from [32]).

4.2 Continuous glucose monitoring technologies

Continuous glucose monitoring (CGM) devices have become more widespread over the past decade. They generally fall into two categories, real-time (rt-CGM) and intermittently scanned (is-CGM) devices. rt-CGM has shown positive improvements in improving HbA1c and reducing hypoglycemia in insulin users in RCTs [36, 37, 38] whereas is-CGM generally relies on observational data to support its use [39]. They predominantly differ from BGMS by measuring glucose concentration in the interstitial fluid, several times per hour, whereas BGMS measure blood (normally capillary) glucose once per test, up to around 10 times per day, depending on individual patient needs [1].

Unlike BGMS that have well-defined FDA and ISO accuracy criteria that must be met prior to obtaining marketing authorization, there remains no such standardized metrics for CGM accuracy requirements. In spite of this, it is commonplace for manufacturers to describe the accuracy of a CGM using Mean Absolute Relative Difference (MARD). This is calculated by averaging the absolute values of relative difference from the comparison method and does not account for positive or negative bias, i.e. all differences are made positive [40]. The MARD of some CGM systems has been reported to be in the 10–12% range whereas some BGMS has demonstrated to be below 5% [40].

One reason for the difference in MARD between some CGMs and BGMS could be attributed to measuring glucose in different compartments of the body. There is an inherent delay between glucose levels in each compartment with one study suggesting that to be between 6 and 10 minutes [41]. This makes it very difficult for a CGM to be as accurate, particularly at times of rapid glucose change. A further study demonstrated that MARD could change considerably throughout the day, approximately doubling between fasting periods and after food (8.0–16.3% and 9.1–16.3% depending on the device) [42]. This brings into question the value of such a metric if it can vary so much. Table 2 provides some examples of when BGM is needed in CGM users.

During the first 24 h following sensor application when differences between blood glucose and ISF glucose are reportedly higher. This is hypothesized to be due to temporary local trauma at the site of application that affects ISF glucose concentration. The application of a new sensor 24 h before the old sensor “runs out” represents a potential solution to this issue.

When a sensor glucose reading and trend arrow indicates a possible hypoglycemic episode or when symptoms suggest a hypoglycemic episode but the reader does not.

Driving: To comply with both EU and UK legislation, the UK Driving and Vehicle Licensing Authority (DVLA) does not consider ISF glucose readings to be sufficient on their own and drivers must also monitor their blood glucose levels using a traditional blood glucose test. Naturally, this may change once there is more confidence in the accuracy of modern CGM and flash monitoring systems.

Device-dependent interferences: When taking medications that have reported interference with ISF glucose values, for example, acetaminophen (paracetamol) or vitamin C (although this only applies to some ISF sensors).

Table 2.

Some examples for adjunct blood glucose testing in CGM users.

ISF: interstitial fluid; CGM: continuous glucose monitoring; EU: European Union; and UK: United Kingdom.

Additionally, the detection of hypoglycemia by a CGM device is dependent on the duration of the hypoglycemic event. A recent study showed that two-thirds of all patients reported hypoglycemic events required minimum duration of 15 minutes in order to be by the CGM device [43].

A low ISF glucose reading below 3.9 mmol/L can prompt corrective actions that may be unnecessary if actual blood glucose, as measured by SMBG, is significantly higher. For instance, a user may develop hypoglycemia and take corrective action. Due to the time lag between blood glucose and ISF glucose, if the user continues to rely only on ISF glucose readings, there may be a lag in the rise of ISF over blood glucose, resulting in further and unnecessary treatment of hypoglycemia.

Similarly, experienced users may become less concerned with ISF low glucose readings than they would be with SMBG readings and take no immediate action. Each of these scenarios potentially creates unwanted risks [44].

The use of a CGM, particularly for the management of T1D, is preferred; however, all patients should learn how to use a BGMS for backup and monitoring if CGM is not available and/or desired [39]. This was further confirmed by the American Diabetes Association [1] which stated, “Every patient using a CGM must have a BGM.” The reasoning for using a BGM when using a CGM includes whenever there is suspicion that the CGM is inaccurate, while waiting for warm-up, for calibration (some sensors) or if a warning message appears, and in any clinical setting where glucose levels are changing rapidly (>2 mg/dL/min), which could cause a discrepancy between CGM and BGM readings.

The definition of hypoglycemia is based on blood glucose readings, therefore the use of BGM in CGM users remains an essential part of their diabetes management.

5. Implications of hypoglycemia

5.1 Which diabetes patient needs the most accurate technology for hypoglycemia detection?

The American Association of Clinical Endocrinologists and American College of Endocrinology 2016 outpatient glucose monitoring consensus statement provided clinical situations and patients groups requiring the highest possible accuracy in glucose monitoring for detection of hypoglycemia [45]. These include those with a history of severe hypoglycemia; hypoglycemia unawareness; infants and children receiving insulin therapy; patients at risk for hypoglycemia, including patients receiving basal insulin or basal/bolus insulin therapy, patients with irregular schedules, skipped or small meals, vigorous exercise, travel between time zones, disrupted sleep schedules, shift work, and people with occupational risks that enhance possible risk from hypoglycemia (e.g., driving or operating hazardous machinery) [45].

Other patient groups include those receiving sulfonylurea or glinides [46], and people with diabetes with comorbidities such as hyperlipidemia or chronic renal disease who may also be taking multiple medications [47]. Age is also an important factor, as risk factors for hypoglycemia such as renal impairment, cardiovascular disease, and polypharmacy all increase with advancing age in adults with T2D [48, 49, 50].

The high accuracy in the low blood glucose range is also necessary for diabetes management during pregnancy, therefore CGM use in this patient population remains adjunctive use only [45, 51]. Blood glucose monitoring remains a cornerstone of glucose management during pregnancy [1].

6. Conclusions

In order to make correct therapy decisions, a correct glucose reading is essential [52]. In order to obtain a correct glucose reading, the correct device must be used. This selection spans both device types, i.e. CGM/BGM, and also specific device within the type. Accuracy variation within both system types is proven to be significant, therefore understanding the importance of education for HCP and patients to make an informed choice based on individual needs.

Acknowledgments

Medical writing was supported by Madano.

Conflict of interest

RS and JR are employees of Ascensia Diabetes Care Holdings AG.