6. Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes—2024

Glycemic status is assessed by A1C measurement, blood glucose monitoring (BGM) by capillary (finger-stick) devices, and continuous glucose monitoring (CGM) using time in range (TIR) or mean CGM glucose. Clinical trials of interventions that lower A1C have demonstrated the benefits of improved glycemia. Glucose monitoring via CGM or BGM (discussed in detail in Section 7, “Diabetes Technology”) is useful for diabetes self-management, can provide nuanced information on glucose responses to meals, physical activity, and medication changes, and may be particularly useful in individuals taking insulin. CGM serves an increasingly important role in optimizing the effectiveness and safety of treatment in many people with type 1 diabetes and in selected people with type 2 diabetes or other forms of diabetes (e.g., cystic fibrosis–related diabetes). Individuals on a variety of insulin treatment plans can benefit from CGM with improved glucose levels, decreased hypoglycemia, and enhanced self-efficacy (Section 7, “Diabetes Technology”) (1).

• 6.1 Assess glycemic status by A1C and/or appropriate continuous glucose monitoring (CGM) metrics at least two times a year. Assess more frequently (e.g., every 3 months) for individuals not meeting treatment goals, with frequent or severe hypoglycemia or hyperglycemia, changing health status, or growth and development in youth. E

• 6.2 Assess glycemic status at least quarterly and as needed in individuals whose therapy has recently changed and/or who are not meeting glycemic goals. E

The A1C test is the primary tool for assessing glycemic status in both clinical practice and clinical trials, and it is strongly linked to diabetes complications (2–4). A1C reflects average glycemia over approximately 2–3 months. The performance of laboratory tests for A1C is generally excellent for National Glycohemoglobin Standardization Program (NGSP)–certified assays (ngsp.org). Thus, A1C testing should be performed routinely in all people with diabetes at initial assessment and as part of continuing care. Measurement approximately every 3 months determines whether glycemic goals have been reached and maintained. Adults with type 1 diabetes or type 2 diabetes with stable glycemia within goal may do well with A1C testing or other glucose assessment only twice per year. Unstable or intensively managed individuals or people not at goal with treatment adjustments may require testing more frequently (every 3 months, with interim assessments as needed) (5). The use of point-of-care A1C testing may provide an opportunity for more timely treatment changes during encounters between individuals with diabetes and health care professionals.

The A1C test is an indirect measure of average glycemia. Factors that affect hemoglobin or red blood cell characteristics or turnover may affect A1C. For example, conditions that affect red blood cell turnover (hemolytic anemia and other anemias, glucose-6-phosphate dehydrogenase deficiency, recent blood transfusion, use of drugs that stimulate erythropoiesis, end-stage kidney disease, and pregnancy) can interfere with the accuracy of A1C (6). Some hemoglobin variants can interfere with some A1C assays; however, most assays in use in the U.S. are accurate in individuals who are heterozygous for the most common variants (7). A1C cannot be measured in individuals with sickle cell disease (HbSS) or other homozygous hemoglobin variants (e.g., HbEE), since these individuals lack HbA (8). In individuals with conditions that interfere with the interpretation of A1C, alternative approaches to monitoring glycemic status should be used, including self-monitoring of blood glucose, CGM, and/or the use of glycated serum protein assays (discussed below). A1C does not provide a measure of glycemic variability or hypoglycemia. For individuals prone to glycemic variability, especially people with type 1 diabetes or type 2 diabetes with severe insulin deficiency, glycemic status is best evaluated by the combination of results from BGM or CGM and A1C. Discordant results between BGM/CGM and A1C can be the result of the conditions outlined above or glycemic variability, with BGM/CGM missing the extremes.

As discussed in Section 2, “Diagnosis and Classification of Diabetes,” there is controversy regarding the clinical significance of racial differences in A1C (9–12). There is an emerging understanding of genetic determinants that may modify the association between A1C and glucose levels (13). However, race is not a good proxy for these genetic differences that are likely present in a small minority of individuals of all racial groups. Therefore, race should not be a consideration for how A1C is used clinically for glycemic monitoring. Limitations of laboratory tests and within-person variability in glucose and A1C underscore the importance of using multiple approaches to glycemic monitoring and further evaluation of discordant results in all racial or ethnic groups.

Fructosamine and glycated albumin are alternative measures of glycemia that are approved for clinical use for monitoring glycemic status in people with diabetes. Fructosamine reflects total glycated serum proteins (mostly albumin). Glycated albumin assays reflect the proportion of total albumin that is glycated. Due to the turnover rate of serum protein, fructosamine and glycated albumin reflect glycemia over the past 2–4 weeks, a shorter-term time frame than that of A1C. Fructosamine and glycated albumin are highly correlated in people with diabetes, and the performance of modern assays is typically excellent. Fructosamine and glycated albumin have been linked to long-term complications in epidemiologic cohort studies (14–18). However, there have been few clinical trials, and the evidence base supporting the use of these biomarkers to monitor glycemic status is much weaker than that for A1C. In people with diabetes who have conditions where the interpretation of A1C may be problematic or when A1C cannot be measured (e.g., homozygous hemoglobin variants), fructosamine or glycated albumin may be useful alternatives to monitor glycemic status (8).

Table 6.1  provides rough equivalents of A1C and mean glucose levels based on data from the international A1C-Derived Average Glucose (ADAG) study. The ADAG study assessed the correlation between A1C and frequent BGM and CGM in 507 adults (83% non-Hispanic White) with type 1, type 2, and no diabetes (19,20). The American Diabetes Association (ADA) and the American Association for Clinical Chemistry have determined that the correlation (r = 0.92) in the ADAG trial is strong enough to justify reporting both the A1C result and the estimated average glucose (eAG) result when a clinician orders the A1C test. Clinicians should note that the mean plasma glucose numbers in Table 6.1  are based on ∼2,700 readings per A1C measurement in the ADAG trial.

For many people with diabetes, glucose monitoring, either using BGM by capillary (finger-stick) devices or CGM in addition to regular A1C testing, is key for achieving glycemic goals. Major clinical trials of insulin-treated individuals have included BGM as part of multifactorial interventions to demonstrate the benefit of intensive glycemic control on diabetes complications (21). BGM is thus an integral component of effective therapy for individuals taking insulin. In recent years, CGM has become a standard method for glucose monitoring for most people with type 1 diabetes. Both approaches to glucose monitoring allow people with diabetes to evaluate individual responses to therapy and assess whether glycemic goals are being safely achieved. The specific needs and goals of individuals with diabetes should dictate BGM frequency and timing. Please refer to Section 7, “Diabetes Technology,” for a more complete discussion of the use of BGM and CGM.

• 6.3 Standardized, single-page glucose reports from CGM devices with visual cues, such as the ambulatory glucose profile, should be considered as a standard summary for all CGM devices. E

• 6.4 Time in range (TIR) is associated with the risk of microvascular complications and can be used for assessment of glycemic status. Additionally, time below range and time above range are useful parameters for the evaluation of the treatment plan (Table 6.2 ). C

CGM is particularly useful in people with diabetes who are at risk for hypoglycemia and is commonly used in people with type 1 diabetes (21). Use of CGM in type 2 diabetes (as well as in several other forms of diabetes) is growing, especially in people who are taking insulin. TIR is a useful metric of glycemic status. A 10- to 14-day CGM assessment of TIR, with CGM wear of 70% or higher, and other CGM metrics can be used to assess glycemic status and are useful in clinical management (22–26). TIR, especially mean CGM glucose, correlates with A1C (27–31). Time below range (<70 and <54 mg/dL [<3.9 and <3.0 mmol/L]) and time above range (>180 mg/dL [>10.0 mmol/L]) are useful parameters for insulin dose adjustments and reevaluation of the treatment plan.

The international consensus on CGM provides guidance on standardized CGM metrics (Table 6.2 ) and their clinical interpretation (32). To make these metrics actionable, standardized reports with visual summaries, such as the ambulatory glucose profile (Fig. 6.1 ), are recommended (32) and can help individuals with diabetes and health care professionals interpret the data to guide treatment decisions (27,30). BGM and CGM can be useful to guide medical nutrition therapy and physical activity, prevent hypoglycemia, and aid medication management. CGM metrics, including TIR (with time below range and time above range), can provide helpful insights to inform a personalized diabetes management plan. Remote access to glucose data is growing and may help improve diabetes management (33–35).

CGM systems have evolved rapidly in both accuracy and affordability. As such, many individuals with diabetes have these data available to assist with self-management and their health care professionals’ assessment of glycemic status. Reports can be generated from CGM that will allow the health care professional and person with diabetes to view TIR, a calculated glucose management indicator, and assess hypoglycemia, hyperglycemia, and glycemic variability. As discussed in a 2019 consensus report, a report formatted as shown in Fig. 6.1  can be generated (32). Published data from two retrospective studies suggest a strong correlation between TIR and A1C, with a goal of 70% TIR aligning with an A1C of ∼7% (25,28). Note the goals of therapy next to each metric in Fig. 6.1  (e.g., low, <4%; very low, <1%) as values to guide changes in therapy.

• 6.5a An A1C goal for many nonpregnant adults of <7% (<53 mmol/mol) without significant hypoglycemia is appropriate. A

• 6.5b If using an ambulatory glucose profile/glucose management indicator to assess glycemia, a parallel goal for many nonpregnant adults is TIR >70% with time below range <4% and time <54 mg/dL (<3 mmol/L) <1%. For those with frailty or at high risk of hypoglycemia, a goal of >50% TIR with <1% time below range is recommended (Fig. 6.1  and Table 6.2 ). B

• 6.6 On the basis of health care professional judgment and the preference of the person with diabetes, achievement of lower A1C levels than the goal of 7% (53 mmol/mol) may be acceptable and even beneficial if it can be achieved safely without significant hypoglycemia or other adverse effects of treatment. B

• 6.7 Less stringent glycemic goals may be appropriate for individuals with limited life expectancy or where the harms of treatment are greater than the benefits. B

• 6.8a Deintensify hypoglycemia-causing medications (insulin, sulfonylureas, or meglitinides), or switch to a medication class with lower hypoglycemia risk, for individuals who are at high risk for hypoglycemia, within individualized glycemic goals. B

• 6.8b Deintensify diabetes medications for individuals for whom the harms and/or burdens of treatment may be greater than the benefits, within individualized glycemic goals. B

• 6.9 Reassess glycemic goals based on the individualized criteria shown in Fig. 6.2 . E

• 6.10 Setting a glycemic goal during consultations is likely to improve patient outcomes. E

For all populations, it is critical that the glycemic goals be woven into the overall person-centered strategy (Fig. 6.2 ) (36). For example, less stringent A1C goals are appropriate for individuals with limited life expectancy and/or significant functional and cognitive impairments. In a very young child, safety and simplicity may outweigh the need for glycemic stability in the short run. Recommended glycemic goals for many nonpregnant adults are shown in Table 6.3 . The recommendations include blood glucose levels that appear to correlate with an A1C of <7% (<53 mmol/mol). For glycemic goals in older adults, please refer to Section 13, “Older Adults.” For glycemic goals in children, please refer to Section 14, “Children and Adolescents.” For glycemic goals during pregnancy, please refer to Section 15, “Management of Diabetes in Pregnancy.”

The health care professional needs to work with the individual (as well as with family members and caregivers) and should consider adjusting goals for simplifying the treatment plan if this change is needed to improve safety and medication-taking behavior. Setting specific glycemic (and other) goals during consultations is likely to improve outcomes for individuals with diabetes (37).

Hyperglycemia defines diabetes, and achieving glycemic goals is fundamental to diabetes management. The level of chronic hyperglycemia is the best-established concomitant risk factor associated with microvascular complications (i.e., diabetic retinopathy, nephropathy, and neuropathy). This is best understood by the fact that nerve, retinal, and kidney cells do not require insulin for intracellular glucose entry. Consequently, these cells, when exposed to elevated ambient glucose levels even in the presence of insulin deficiency (absolute or relative), will result in intracellular metabolic dysfunction and increased risk of microvascular complications.

The Diabetes Control and Complications Trial (DCCT) (38), a prospective randomized controlled trial of intensive (mean A1C ∼7% [53 mmol/mol]) versus standard (mean A1C ∼9% [75 mmol/mol]) glycemic control in people with type 1 diabetes, showed definitively that better glycemic status is associated with 50–76% reductions in rates of development and progression of microvascular complications (retinopathy, neuropathy, and diabetic kidney disease). Follow-up of the DCCT cohorts in the Epidemiology of Diabetes Interventions and Complications (EDIC) study (39,40) demonstrated persistence of these microvascular benefits over two decades even though the glycemic separation between the treatment groups diminished and disappeared during follow-up.

The Kumamoto Study (41) and UK Prospective Diabetes Study (UKPDS) (42,43) examined the effects of “intensive glycemic control” among people with short-duration type 2 diabetes, although glycemic lowering in these studies was not intensive by current standards (mean A1C was 7.1% vs. 9.4% in the Kumamoto Study and 7.0% vs. 7.9% in UKPDS). These trials found lower rates of microvascular complications in the intervention arms, with long-term follow-up of the UKPDS cohorts showing enduring effects on most microvascular complications (44). These studies highlight the long-term benefits of early glycemic lowering in type 2 diabetes.

Therefore, improved glycemia has been shown to reduce microvascular complications of type 1 and type 2 diabetes when instituted early in the course of disease (2,45). The DCCT (38) and UKPDS (46) studies demonstrated a curvilinear relationship between A1C and microvascular complications. Such results suggest that, on a population level, the greatest number of complications will be averted by taking individuals with diabetes from very high to moderate glycemic levels. These analyses also suggest that further lowering of A1C from 7% to 6% (53 mmol/mol to 42 mmol/mol) is associated with further reduction in the risk of microvascular complications, although the absolute risk reductions become much smaller. The implication of these findings is that there is no need to deintensify therapy for an individual with an A1C between 6% and 7% in the setting of low hypoglycemia risk with a long life expectancy. There are newer agents that do not cause hypoglycemia, making it possible to maintain glycemic status without the risk of hypoglycemia (see Section 9, “Pharmacologic Approaches to Glycemic Treatment”). Moreover, CGM use was not as common when these trials were conducted and automated insulin delivery systems were not available, which have been shown to improve glucose levels without increasing hypoglycemia.

Among individuals with type 2 diabetes, three landmark trials (Action to Control Cardiovascular Risk in Diabetes [ACCORD], Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation [ADVANCE], and Veterans Affairs Diabetes Trial [VADT]) were conducted to test the effects of near normalization of blood glucose on cardiovascular outcomes. The ADVANCE and VADT trials found modest reduction in nephropathy with intensive glycemic control; ACCORD was stopped after a median of 3.5 years due to higher mortality in the intervention arm (47–51). Importantly, these landmark studies were conducted prior to the approval of glucagon-like peptide 1 (GLP-1) receptor agonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors, and intensive glycemic control was achieved predominantly through greater use of insulin. Findings from these studies, including the concerning increase in mortality in the intensive treatment arm of ACCORD, suggest caution is needed in treating diabetes to near-normal A1C goals in people with long-standing type 2 diabetes using medications with a high risk for hypoglycemia.

Cardiovascular disease (CVD) is a more common cause of death than microvascular complications in populations with diabetes. The modern multifaceted management of diabetes, with a focus on the treatment of hypertension and the use of statins, has reduced the prevalence of atherosclerotic CVD to around double compared with that of people without diabetes (52).

The DCCT in individuals with type 1 diabetes and the UKPDS, ACCORD, ADVANCE, and VADT studies in type 2 diabetes all attempted to address whether intensive glycemic control reduced CVD events (38,47,48,50). ACCORD, ADVANCE, and VADT were conducted in relatively older participants with a longer duration of diabetes (mean duration 8–11 years) and either CVD or multiple cardiovascular risk factors. Details of these studies are reviewed extensively in the joint ADA position statement “Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials” (53).

No significant reduction in composite CVD events was demonstrated at the end of the intervention in any of these studies, and ACCORD was stopped prematurely at 3.5 years because of an increase in total mortality, particularly sudden CVD deaths. Serious concerns with the intensive glycemic treatment plan used in ACCORD included the rapid escalation of therapies, the early use of large doses of insulin, massive weight gain, and frequent hypoglycemia. These overall negative results were not unexpected, as blood glucose has subsequently been shown to be a relatively weak CVD risk factor in isolation compared with other CVD risk factors, such as hypertension or hypercholesterolemia. Consequently, even if a wide separation in A1C could be safely obtained, it would take a long time for the CVD benefit to accrue. However, meta-analysis of individual participant data from UKPDS, ACCORD, ADVANCE, and VADT demonstrated a significant reduction in myocardial infarctions and major CVD events but no difference in stroke, heart failure, or mortality between intensive and less intensive glycemic control (54).

Longer-term epidemiological follow-up has been performed in these studies, and a clear pattern of CVD benefit has emerged (55–57). In the post-DCCT follow-up of the EDIC cohort, participants previously randomized to the intensive arm had a significant 57% reduction in the risk of nonfatal myocardial infarction, stroke, or cardiovascular death compared with those previously randomized to the standard arm (55). The benefit of intensive glycemic control in this cohort with type 1 diabetes has been shown to persist for several decades (56) and to be associated with a modest reduction in all-cause mortality (58).

UKPDS post-trial monitoring, with 20 years of total follow-up, has shown reductions in myocardial infarctions and total mortality both in the group of overweight individuals treated with metformin and in the group previously treated intensively with sulfonylureas or insulin (44). Shorter overall follow-up of the VADT (10 years) has shown a significant reduction in the primary outcome of major CVD events, with myocardial infarctions and heart failure being the commonest outcomes (57). In contrast, shorter follow-up of the ADVANCE study in the Action in Diabetes and Vascular Disease Preterax and Diamicron MR Controlled Evaluation Post Trial Observational Study (ADVANCE-ON) demonstrated no significant effect on CVD events (59). Even in the epidemiological follow-up of ACCORD in the Action to Control Cardiovascular Risk in Diabetes Follow-On Study (ACCORDION), the excess increase in total mortality that was seen during 3.5 years of intensive treatment was reduced by returning to conventional control, so that there was no difference in total mortality after a total of 9 years of follow-up and the increase in CVD deaths was obtunded (60). Collectively, the results of these studies confirm that long-term intensive glycemic control reduces CVD events, particularly myocardial infarctions.

As discussed above, these landmark studies in individuals with type 2 diabetes need to be considered with the important caveat that GLP-1 receptor agonists and SGLT2 inhibitors were not yet in clinical use. These agents with established cardiovascular and renal benefits appear to be safe and beneficial in this group of individuals at high risk for cardiorenal complications. Randomized clinical trials examining these agents for cardiovascular safety were not designed to test higher versus lower A1C; therefore, beyond post hoc analysis of these trials, we do not have evidence that it is the glucose lowering per se by these agents that confers the CVD and renal benefit (61). Additional beneficial pleotropic effects of these agents may include weight loss, hemodynamic effects, blood pressure lowering, and anti-inflammatory changes.

As discussed further below, severe hypoglycemia is a potent marker of high absolute risk of cardiovascular events and mortality (62). Therefore, health care professionals should be vigilant in preventing hypoglycemia and should not aggressively attempt to achieve near-normal A1C levels in people in whom such targets cannot be safely and reasonably achieved. As discussed in Section 9, “Pharmacologic Approaches to Glycemic Treatment,” addition of specific SGLT2 inhibitors or GLP-1 receptor agonists that have demonstrated CVD benefit is recommended in individuals with established CVD, chronic kidney disease, and heart failure. As outlined in more detail in Section 9, “Pharmacologic Approaches to Glycemic Treatment,” and Section 10, “Cardiovascular Disease and Risk Management,” the cardiovascular benefits of SGLT2 inhibitors or GLP-1 receptor agonists are not contingent upon A1C lowering; therefore, initiation can be considered in people with type 2 diabetes and CVD independent of the current A1C or A1C goal or metformin therapy. Based on these considerations, the following two strategies are offered (63):

1. If already on dual therapy or multiple glucose-lowering therapies and not on an SGLT2 inhibitor or a GLP-1 receptor agonist, consider switching to one of these agents with proven cardiovascular benefit.

2. Introduce SGLT2 inhibitors or GLP-1 receptor agonists in people with CVD at A1C goal (independent of metformin) for cardiovascular benefit, independent of baseline A1C or individualized A1C goal.

Glycemic goals and management should be individualized and not one size fits all. To prevent both microvascular and macrovascular complications of diabetes, there is a major call to overcome therapeutic inertia and treat to individualized goals (53,64).

Numerous factors must be considered when setting a glycemic goal. The ADA proposes general goals that are appropriate for many people but emphasizes the importance of individualization based on key patient characteristics. Glycemic goals must be individualized in the context of shared decision-making to address individual needs and preferences and consider characteristics that influence risks and benefits of therapy; this approach may optimize engagement and self-efficacy.

The factors to consider in individualizing goals are depicted in Fig. 6.2 . This figure is not designed to be applied rigidly in the care of a given individual but to be used as a broad framework to guide clinical decision-making (36) and engage people with type 1 and type 2 diabetes in shared decision-making. More aggressive goals may be recommended if they can be achieved safely and with an acceptable burden of therapy and if life expectancy is sufficient to reap the benefits of stringent goals. Less stringent goals (e.g., A1C up to 8% [64 mmol/mol]) may be recommended if the individual’s life expectancy is such that the benefits of an intensive goal may not be realized or if the risks and burdens outweigh the potential benefits. Severe or frequent hypoglycemia is an absolute indication for the modification of treatment plans, including setting higher glycemic goals.

Diabetes is a chronic disease that progresses over decades. Thus, a goal that might be appropriate for an individual early in the course of their diabetes may change over time. Newly diagnosed individuals and/or those without comorbidities that limit life expectancy may benefit from intensive glycemic goals proven to prevent microvascular complications. Both DCCT/EDIC and UKPDS suggested that there is metabolic memory, or a legacy effect, in which a finite period of intensive glucose lowering yielded benefits that extended for decades after that period ended. However, there are few recent data on the effects of long-term glucose lowering using modern treatment strategies. Thus, a finite period of intensive treatment to near-normal A1C may yield enduring benefits even if treatment is subsequently deintensified as characteristics change. Over time, comorbidities may emerge, decreasing life expectancy and thereby decreasing the potential to reap benefits from intensive treatment. Also, with longer disease duration, diabetes may become more difficult to control, with increasing risks and burdens of therapy. Thus, glycemic goals should be reevaluated over time to balance the risks and benefits.

Accordingly, clinicians should continue to evaluate the balance of risks and benefits of diabetes medications for individuals who have achieved individualized glycemic goals, and they should deintensify (decrease the dose or stop) diabetes medications where their risks exceed their benefits. Hypoglycemia is the major risk to individuals treated with insulin, sulfonylureas, or meglitinides, and it is appropriate to deintensify these medications where there is a high risk for hypoglycemia (see hypoglycemia risk assessment, below). Switching a high-hypoglycemia-risk medication to lower-hypoglycemia-risk therapy (see Section 9, “Pharmacologic Approaches to Glycemic Treatment”) should be considered if needed to achieve individualized glycemic goals or where individuals have evidence-based indications for alternative medications (e.g., use of SGLT2 inhibitors in the setting of heart failure or diabetic kidney disease and use of GLP-1 receptor agonists in the setting of CVD or obesity). Clinicians should also consider medication burdens other than hypoglycemia, including tolerability, difficulties of administration, impact on education or employment, and financial cost. These factors should be balanced against benefits from glycemic lowering and disease-specific benefits of newer medications that may be independent of glycemic lowering (Section 9, “Pharmacologic Approaches to Glycemic Treatment”). Multiple trials have shown that deintensification of diabetes treatment can be achieved successfully and safely (65–68). It is important to partner with people with diabetes during the deintensification process to understand their goals of diabetes treatment and agree upon appropriate glycemic monitoring, glucose levels, and goals of care (69).

• 6.11a History of hypoglycemia should be reviewed at every clinical encounter for all individuals at risk for hypoglycemia and evaluated as indicated. C

• 6.11b Clinicians should screen all individuals at risk for hypoglycemia for impaired hypoglycemia awareness. E

• 6.11c Clinicians should consider an individual’s risk for hypoglycemia (see Table 6.5 ) when selecting diabetes medications and glycemic goals. E

• 6.11d Use of CGM is beneficial and recommended for individuals at high risk for hypoglycemia. A

• 6.12 Glucose is the preferred treatment for the conscious individual with glucose <70 mg/dL (<3.9 mmol/L), although any form of carbohydrate that contains glucose may be used. Fifteen minutes after initial treatment, repeat the treatment if hypoglycemia persists. B

• 6.13 Glucagon should be prescribed for all individuals taking insulin or at high risk for hypoglycemia. Family, caregivers, school personnel, and others providing support to these individuals should know its location and be educated on how to administer it. Glucagon preparations that do not have to be reconstituted are preferred. E

• 6.14 All individuals taking insulin A or at risk for hypoglycemia C should receive structured education for hypoglycemia prevention and treatment, with ongoing education for those who experience hypoglycemic events.

• 6.15 One or more episodes of level 2 or 3 hypoglycemia should prompt reevaluation of the treatment plan, including deintensifying or switching diabetes medications if appropriate. E

• 6.16 Refer individuals with impaired hypoglycemia awareness to a trained health care professional to receive evidence-based intervention to help reestablish awareness of symptoms of hypoglycemia. A

• 6.17 Ongoing assessment of cognitive function is suggested with increased vigilance for hypoglycemia by the clinician, patient, and caregivers if impaired or declining cognition is found. B

Hypoglycemia is often the major limiting factor in the glycemic management of type 1 and type 2 diabetes. Recommendations regarding the classification of hypoglycemia are outlined in Table 6.4  (70). Level 1 hypoglycemia is defined as a measurable glucose concentration <70 mg/dL (<3.9 mmol/L) but ≥54 mg/dL (≥3.0 mmol/L). A blood glucose concentration of 70 mg/dL (3.9 mmol/L) has been recognized as a threshold for neuroendocrine responses to falling glucose in people without diabetes. Symptoms of hypoglycemia include, but are not limited to, shakiness, irritability, confusion, tachycardia, sweating, and hunger (71). Because many people with diabetes demonstrate impaired counterregulatory responses to hypoglycemia and/or experience impaired hypoglycemia awareness, a measured glucose level <70 mg/dL (<3.9 mmol/L) is considered clinically important, regardless of symptoms. Level 2 hypoglycemia (defined as a blood glucose concentration <54 mg/dL [<3.0 mmol/L]) is the threshold at which neuroglycopenic symptoms begin to occur and requires immediate action to resolve the hypoglycemic event. If an individual has level 2 hypoglycemia without adrenergic or neuroglycopenic symptoms, they likely have impaired hypoglycemia awareness (discussed further in hypoglycenmia risk assessment, below). This clinical scenario warrants investigation and review of the treatment plan (72,73). Lastly, level 3 hypoglycemia is defined as a severe event characterized by altered mental and/or physical functioning that requires assistance from another person for recovery, irrespective of glucose level.

Hypoglycemia has a broad range of negative health consequences (74). Level 3 hypoglycemia may be recognized or unrecognized and can progress to loss of consciousness, seizure, coma, or death. Level 3 hypoglycemia was associated with mortality in both the standard and the intensive glycemia arms of the ACCORD trial, but the relationships between hypoglycemia, achieved A1C, and treatment intensity were not straightforward (75). An association of level 3 hypoglycemia with mortality was also found in the ADVANCE trial and in clinical practice (76,77). Hypoglycemia can cause acute harm to the person with diabetes or others, especially if it causes falls, motor vehicle accidents, or other injury (78). Hypoglycemia may also cause substantial anxiety that can reduce the quality of life of individuals with diabetes and their caregivers and may contribute to problems with diabetes self-management and treatment (79–81). Recurrent level 2 hypoglycemia and/or level 3 hypoglycemia is an urgent medical issue and requires intervention with medical treatment plan adjustment, behavioral intervention, delivery of diabetes self-management education and support, and use of technology to assist with hypoglycemia prevention and identification (73,82–85).

Studies of rates of hypoglycemia predominantly rely on claims data for hospitalizations and emergency department visits (86–89). These studies do not capture the level 1 and level 2 hypoglycemia that represent the vast majority of hypoglycemic events, and they also substantially underestimate level 3 hypoglycemia (86,90). Nevertheless, they reveal a substantial burden of hypoglycemia-related hospital utilization in the community (86–89). Level 1 and level 2 hypoglycemia can be ascertained from patient self-report (91) and are strong risk factors for subsequent level 3 hypoglycemia.

Assessment of an individual’s risk for hypoglycemia includes evaluating clinical risk factors as well as relevant social, cultural, and economic factors (Table 6.5 ). Recommendations 6.11–6.17 group individuals with diabetes into two hypoglycemia risk categories with clinical significance. Individuals at risk for hypoglycemia are those treated with insulin, sulfonylureas, or meglitinides; clinically significant hypoglycemia is rare among individuals taking other diabetes medication classes (92,93). Individuals at high risk for hypoglycemia are the subset of individuals at risk for hypoglycemia who either have a major hypoglycemia risk factor or have multiple other risk factors (determined by the health care professional incorporating clinical judgment) (Table 6.5 ). This risk stratification is based on epidemiologic studies of hypoglycemia risk (87,88,92,94–97). Validated tools have been developed to estimate hypoglycemia risk using predominantly electronic health record data (98–100). However, these tools do not include all of the important hypoglycemia risk factors, and more research is needed to determine how they can best be incorporated into clinical care.

Among individuals at risk for hypoglycemia, prior hypoglycemic events, especially level 2 or 3 events, are the strongest risk factors for hypoglycemia recurrence and severity (96,101–103). Hypoglycemia history should be assessed at every clinical encounter and should include hypoglycemic event frequency, severity, precipitants, symptoms (or lack thereof), and approach to treatment. It is essential to correlate home glucose readings, both from glucose meters and CGM systems, with symptoms and treatment, as individuals may experience and treat hypoglycemic symptoms without checking their glucose level (104), treat normal glucose values as hypoglycemic, or tolerate hypoglycemia without treatment either because of lack of symptoms or to avoid hyperglycemia.

Individuals at risk for hypoglycemia should also be screened for impaired hypoglycemia awareness (also called hypoglycemia unawareness or hypoglycemia-associated autonomic failure) at least yearly. Impaired hypoglycemia awareness is defined as not experiencing the typical counterregulatory hormone release at low glucose levels or the associated symptoms, which often occurs in individuals with long-standing diabetes or recurrent hypoglycemia (105). Individuals with impaired hypoglycemia awareness may experience confusion as the first sign of hypoglycemia, which can create fear of hypoglycemia and severely impact quality of life (106). Impaired hypoglycemia awareness dramatically increases the risk for level 3 hypoglycemia (107). The Clark and Gold scores are validated questionnaires to assess impaired hypoglycemia awareness (108,109). However, these questionnaires may be impractical for routine clinical use. A recommended strategy is to screen for impaired hypoglycemia awareness by asking individuals whether they ever have low blood glucose without feeling symptoms, or by asking at what blood glucose levels they typically begin to feel symptoms (and what those symptoms are), and follow up positive responses with a more detailed evaluation (105,110).

Other notable clinical and biological risk factors for hypoglycemia are older age, multimorbidity, cognitive impairment, chronic kidney disease and end-stage kidney disease in particular, CVD, depression, and neuropathy (92,93). Female sex has also been found to be an independent risk factor for hypoglycemia in multiple studies, although the mechanisms of this relationship are unclear and require further research (92). Cognitive impairment has a strong bidirectional association with hypoglycemia, and recurrent severe hypoglycemic episodes were associated with a greater decline in psychomotor and mental efficiency after long-term follow-up of the DCCT/EDIC cohort (111). Therefore, cognitive function should be routinely assessed among older adults with diabetes.

There are a number of important social, cultural, and economic hypoglycemia risk factors that should considered. Food insecurity is associated with increased risk of hypoglycemia-related emergency department visits and hospitalizations in low-income households, and this was shown to be mitigated by increased federal nutrition program benefits (112). In general, individuals with low annual household incomes (93), individuals who live in socioeconomically deprived areas (96), and individuals who are underinsured (97) or homeless (113) experience higher rates of emergency department visits and hospitalizations for hypoglycemia. Clinicians should also be aware of cultural practices that may influence glycemic management (which are discussed in detail in Section 5, “Facilitating Positive Health Behaviors”), such as fasting as part of religious observance. Fasting may increase the risk for hypoglycemia among individuals treated with insulin or insulin secretagogues if not properly planned for, so clinicians need to engage these individuals to codevelop a diabetes treatment plan that is safe and respectful of their traditions (114).

Young children with type 1 diabetes and the elderly, including those with type 1 and type 2 diabetes (115,116), are noted as being particularly vulnerable to hypoglycemia because of their reduced ability to recognize hypoglycemic symptoms and effectively communicate their needs. Individualized glycemic goals, patient education, nutrition intervention (e.g., bedtime snack to prevent overnight hypoglycemia when specifically needed to treat low blood glucose), physical activity management, medication adjustment, glucose monitoring, and routine clinical surveillance may improve outcomes (105). CGM with automated low-glucose suspend and automated insulin delivery systems have been shown to be effective in reducing hypoglycemia in type 1 diabetes (117). For people with type 1 diabetes with level 3 hypoglycemia and hypoglycemia unawareness that persists despite medical treatment, human islet transplantation may be an option, but the approach remains experimental (118,119).

Health care professionals should counsel individuals with diabetes to treat hypoglycemia with fast-acting carbohydrates at the hypoglycemia alert value of 70 mg/dL (3.9 mmol/L) or less (120–122). Individuals should be counseled to recheck their glucose 15 min after ingesting carbohydrates and to repeat carbohydrate ingestion and seek care for ongoing hypoglycemia. These instructions should be reviewed at each clinical visit.

For most individuals, 15 g carbohydrates should be ingested. Individuals using automated insulin delivery systems are recommended to ingest 5–10 g carbohydrates (except for hypoglycemia with exercise or with significant overestimation of carbohydrate/meal bolus) (123). The acute glycemic response to food correlates better with the glucose content than with the total carbohydrate content. Pure glucose is the preferred treatment, but any form of carbohydrate that contains glucose will raise blood glucose. Added fat may slow and then prolong the acute glycemic response. Carbohydrate sources high in protein may increase insulin secretion and should not be used to treat hypoglycemia (124). Ongoing insulin activity or insulin secretagogues may lead to recurrent hypoglycemia unless more food is ingested after recovery.

The use of glucagon is indicated for the treatment of hypoglycemia in people unable or unwilling to consume carbohydrates by mouth. All individuals treated with insulin or who are at high risk of hypoglycemia as discussed above should be prescribed glucagon. For these individuals, clinicians should routinely review their access to glucagon, as appropriate glucagon prescribing is very low in current practice (125,126). An individual does not need to be a health care professional to safely administer glucagon. Those in close contact with, or having custodial care of, these individuals (family members, roommates, school personnel, childcare professionals, correctional institution staff, or coworkers) should be instructed on the use of glucagon, including where the glucagon product is kept and when and how to administer it. It is essential that they be explicitly educated to never administer insulin to individuals experiencing hypoglycemia. Glucagon was traditionally dispensed as a powder that requires reconstitution prior to injection. However, intranasal and ready-to-inject glucagon preparations are now widely available and are preferred due to their ease of administration resulting in more rapid correction of hypoglycemia (127–130). Although physical and chemical stability of glucagon is improved with newer formulations, care should be taken to replace glucagon products when they reach their expiration date and store glucagon based on specific product instructions to ensure safe and effective use. For currently available glucagon products and associated costs, see Table 6.6 . Health insurance providers may prefer only select glucagon products, so it is important to check individuals’ insurance coverage and prescribe formulary products whenever possible.

A multicomponent hypoglycemia prevention plan (Table 6.7 ) is critical to caring for individuals at risk for hypoglycemia. Hypoglycemia prevention begins by establishing an individual’s hypoglycemia history and risk factors, as discussed in hypoglycemia risk assessment above. Structured patient education for hypoglycemia prevention and treatment is critical and has been shown to improve hypoglycemia outcomes (131,132). Education should ideally be provided through a diabetes self-management education and support program or by a trained diabetes educator, although these services are not available in many areas (133,134). If structured education is not available, clinicians should educate individuals at risk for hypoglycemia on hypoglycemia definitions, situations that may precipitate hypoglycemia (fasting, delayed meals, physical activity, and illness), blood glucose self-monitoring, avoidance of driving with hypoglycemia, step-by-step instructions on hypoglycemia treatment as discussed above, and glucagon use as appropriate (131).

CGM can be a valuable tool for detecting and preventing hypoglycemia in many individuals with diabetes, and it is recommended for insulin-treated individuals, especially those using multiple daily insulin injections or continuous subcutaneous insulin infusion. There is clinical trial evidence that CGM reduces rates of hypoglycemia in these populations. CGM can reveal asymptomatic hypoglycemia and help identify patterns and precipitants of hypoglycemic events (135,136). Real-time CGM can provide alarms that can warn individuals of falling glucose so that they can intervene (135,136). For more information on using BGM and CGM for hypoglycemia prevention, see Section 7, “Diabetes Technology.”

An essential component of hypoglycemia prevention is appropriate modification to diabetes treatment in the setting of intercurrent illness (discussed in detail below) or to prevent recurrent hypoglycemic events. Level 2 or 3 hypoglycemic events especially should trigger a reevaluation of the individual’s diabetes treatment plan, with consideration of deintensification of therapy within individualized glycemic goals.

Individuals with impaired awareness of hypoglycemia benefit from, and should be referred to, training programs that can reestablish awareness of hypoglycemia. Fear of hypoglycemia and hypoglycemia unawareness often cooccur, so interventions aimed at treating one often benefit both (137). Formal, evidence-based training programs that have been developed include the Blood Glucose Awareness Training Program, Dose Adjusted for Normal Eating (DAFNE), and DAFNEplus (138–140). Where these programs are not available, training can be provided through qualified behavioral health professionals, diabetes educators, or other professionals with experience in this area, although this approach has not been evaluated in clinical trials. In addition, several weeks of avoidance of hypoglycemia can improve counterregulation and hypoglycemia awareness in many people with diabetes (141). Hence, individuals with one or more episodes of clinically significant hypoglycemia may benefit from at least short-term relaxation of glycemic goals (142).

Stressful events (e.g., illness, trauma, and surgery) increase the risk for both hyperglycemia and hypoglycemia among individuals with diabetes. In severe cases, they may precipitate diabetic ketoacidosis or a nonketotic hyperglycemic hyperosmolar state, life-threatening conditions that require immediate medical care. Any individuals with diabetes experiencing illness or other stressful events should be assessed for the need for more frequent monitoring of glucose; ketosis-prone individuals also require urine or blood ketone monitoring. Clinicians should reevaluate diabetes treatment during these events and make adjustments as appropriate. Clinicians should be aware of medication interactions that may precipitate hypoglycemia. Notably, sulfonylureas interact with a number of commonly used antimicrobials (fluoroquinolones, clarithromycin, sulfamethoxazole-trimethoprim, metronidazole, and fluconazole) that can dramatically increase their effective dose, leading to hypoglycemia (143–145). Clinicians should consider temporarily decreasing or stopping sulfonylureas when these antimicrobials are prescribed.

For further information on management hyperglycemia in the hospital, see Section 16, “Diabetes Care in the Hospital.”