6. Glycemic Targets: Standards of Medical Care in Diabetes—2018

Patient self-monitoring of blood glucose (SMBG) and A1C are available to health care providers and patients to assess the effectiveness and safety of a management plan on glycemic control. Continuous glucose monitoring (CGM) also has an important role in assessing the effectiveness and safety of treatment in subgroups of patients with type 1 diabetes and in selected patients with type 2 diabetes. Data indicate similar A1C and safety with the use of CGM compared with SMBG (1).

• Most patients using intensive insulin regimens (multiple-dose insulin or insulin pump therapy) should perform self-monitoring of blood glucose (SMBG) prior to meals and snacks, at bedtime, occasionally postprandially, prior to exercise, when they suspect low blood glucose, after treating low blood glucose until they are normoglycemic, and prior to critical tasks such as driving. B

• When prescribed as part of a broad educational program, SMBG may help to guide treatment decisions and/or self-management for patients taking less frequent insulin injections B or noninsulin therapies. E

• When prescribing SMBG, ensure that patients receive ongoing instruction and regular evaluation of SMBG technique, SMBG results, and their ability to use SMBG data to adjust therapy. E

• When used properly, continuous glucose monitoring (CGM) in conjunction with intensive insulin regimens is a useful tool to lower A1C in adults with type 1 diabetes who are not meeting glycemic targets. A

• CGM may be a useful tool in those with hypoglycemia unawareness and/or frequent hypoglycemic episodes. C

• Given the variable adherence to CGM, assess individual readiness for continuing CGM use prior to prescribing. E

• When prescribing CGM, robust diabetes education, training, and support are required for optimal CGM implementation and ongoing use. E

• People who have been successfully using CGM should have continued access after they turn 65 years of age. E

Major clinical trials of insulin-treated patients have included SMBG as part of multifactorial interventions to demonstrate the benefit of intensive glycemic control on diabetes complications. SMBG is thus an integral component of effective therapy (2). SMBG allows patients to evaluate their individual response to therapy and assess whether glycemic targets are being achieved. Integrating SMBG results into diabetes management can be a useful tool for guiding medical nutrition therapy and physical activity, preventing hypoglycemia, and adjusting medications (particularly prandial insulin doses). Among patients with type 1 diabetes, there is a correlation between greater SMBG frequency and lower A1C (3). The patient's specific needs and goals should dictate SMBG frequency and timing.

SMBG accuracy is dependent on the instrument and user, so it is important to evaluate each patient's monitoring technique, both initially and at regular intervals thereafter. Optimal use of SMBG requires proper review and interpretation of the data, by both the patient and the provider. Among patients who check their blood glucose at least once daily, many report taking no action when results are high or low. In a yearlong study of insulin-naive patients with suboptimal initial glycemic control, a group trained in structured SMBG (a paper tool was used at least quarterly to collect and interpret 7-point SMBG profiles taken on 3 consecutive days) reduced their A1C by 0.3 percentage points more than the control group (4). Patients should be taught how to use SMBG data to adjust food intake, exercise, or pharmacologic therapy to achieve specific goals. The ongoing need for and frequency of SMBG should be reevaluated at each routine visit to avoid overuse (5–7). SMBG is especially important for insulin-treated patients to monitor for and prevent asymptomatic hypoglycemia and hyperglycemia. Patients should be advised against purchasing or reselling preowned or secondhand test strips, as these may give incorrect results. Only unopened vials of glucose test strips should be used to ensure SMBG accuracy.

Most patients using intensive insulin regimens (multiple-dose insulin or insulin pump therapy) should perform SMBG prior to meals and snacks, at bedtime, occasionally postprandially, prior to exercise, when they suspect low blood glucose, after treating low blood glucose until they are normoglycemic, and prior to critical tasks such as driving. For many patients, this will require testing 6–10 (or more) times daily, although individual needs may vary. A database study of almost 27,000 children and adolescents with type 1 diabetes showed that, after adjustment for multiple confounders, increased daily frequency of SMBG was significantly associated with lower A1C (–0.2% per additional test per day) and with fewer acute complications (8).

The evidence is insufficient regarding when to prescribe SMBG and how often testing is needed for patients who do not use intensive insulin regimens, such as those with type 2 diabetes using oral agents and/or basal insulin. For patients using basal insulin, assessing fasting glucose with SMBG to inform dose adjustments to achieve blood glucose targets results in lower A1Cs (9,10).

For individuals with type 2 diabetes on less intensive insulin therapy, more frequent SMBG (e.g., fasting, before/after meals) may be helpful, as increased frequency is associated with meeting A1C targets (11).

Several randomized trials have called into question the clinical utility and cost-effectiveness of routine SMBG in noninsulin-treated patients (12–15). Meta-analyses have suggested that SMBG can reduce A1C by 0.25–0.3% at 6 months (16,17), but the effect was attenuated at 12 months in one analysis (16). A key consideration is that performing SMBG alone does not lower blood glucose levels. To be useful, the information must be integrated into clinical and self-management plans.

CGM measures interstitial glucose (which correlates well with plasma glucose), and most CGM devices include alarms for hypo- and hyperglycemic excursions. The intermittent or “flash” CGM device, very recently approved for adult use only (18), differs from previous CGM devices. Specifically, it does not have alarms, does not require calibration with SMBG, and does not communicate continuously (only on demand). It is reported to have a lower cost than traditional systems. A study in adults with well-controlled type 1 diabetes found that flash CGM users spent less time in hypoglycemia than those using SMBG (19). However, due to significant differences between flash CGM and other CGM devices, more discussion is needed on outcomes and regarding specific recommendations.

For most CGM systems, confirmatory SMBG is required to make treatment decisions, though a randomized controlled trial of 226 adults suggested that an enhanced CGM device could be used safely and effectively without regular confirmatory SMBG in patients with well-controlled type 1 diabetes at low risk of severe hypoglycemia (1). Two CGM devices are now approved by the U.S. Food and Drug Administration (FDA) for making treatment decisions without SMBG confirmation (18,20), including the flash CGM device.

Although performed with older generation CGM devices, a 26-week randomized trial of 322 patients with type 1 diabetes showed that adults aged ≥25 years using intensive insulin therapy and CGM experienced a 0.5% reduction in A1C (from ∼7.6% to 7.1% [∼60 mmol/mol to 54 mmol/mol]) compared with those using intensive insulin therapy with SMBG (21). The greatest predictor of A1C lowering for all age-groups was frequency of sensor use, which was highest in those aged ≥25 years and lower in younger age-groups. Two clinical trials in adults with type 1 diabetes not meeting A1C targets and using multiple daily injections also found that the use of CGM compared with usual care resulted in lower A1C levels than SMBG over 24–26 weeks (22,23). Other small, short-term studies have demonstrated similar A1C reductions using CGM compared with SMBG in adults with A1C levels ≥7% (53 mmol/mol) (24,25).

A registry study of 17,317 participants confirmed that more frequent CGM use is associated with lower A1C (26), whereas another study showed that children with >70% sensor use (i.e., ≥5 days per week) missed fewer school days (27). Small randomized controlled trials in adults and children with baseline A1C <7.0–7.5% (53–58 mmol/mol) have confirmed favorable outcomes including a reduced frequency of hypoglycemia (defined as a blood glucose level <70 mg/dL [3.9 mmol/L]) and maintaining A1C <7% (53 mmol/mol) during the study period in groups using CGM, suggesting that CGM may provide further benefit for individuals with type 1 diabetes who already have good glycemic control (28–30).

A meta-analysis suggests that compared with SMBG, CGM is associated with short-term A1C lowering of ∼0.26% in insulin-treated patients (31). The long-term effectiveness of CGM needs to be determined. This technology may be particularly useful in insulin-treated patients with hypoglycemia unawareness and/or frequent hypoglycemic episodes, although studies have not shown consistent reductions in severe hypoglycemia (31–33). A CGM device equipped with an automatic low glucose suspend feature has been approved by the FDA. The Automation to Simulate Pancreatic Insulin Response (ASPIRE) trial of 247 patients with type 1 diabetes and documented nocturnal hypoglycemia showed that sensor-augmented insulin pump therapy with a low glucose suspend function significantly reduced nocturnal hypoglycemia over 3 months without increasing A1C levels (34). These devices may offer the opportunity to reduce hypoglycemia for those with a history of nocturnal hypoglycemia. The FDA has also approved the first hybrid closed-loop system. The safety of hybrid closed-loop systems has been supported in the literature (35) and may have advantages over sensor-augmented pump therapy in specific populations, such as pregnant women with type 1 diabetes (36).

Due to variable adherence, optimal CGM use requires an assessment of individual readiness for the technology as well as initial and ongoing education and support (26,37). Additionally, providers need to provide robust diabetes education, training, and support for optimal CGM implementation and ongoing use. As people with type 1 or type 2 diabetes are living longer, healthier lives, individuals who have been successfully using CGM should have continued access to these devices after they turn 65 years of age (38).

• Perform the A1C test at least two times a year in patients who are meeting treatment goals (and who have stable glycemic control). E

• Perform the A1C test quarterly in patients whose therapy has changed or who are not meeting glycemic goals. E

• Point-of-care testing for A1C provides the opportunity for more timely treatment changes. E

A1C reflects average glycemia over approximately 3 months and has strong predictive value for diabetes complications (39,40). Thus, A1C testing should be performed routinely in all patients with diabetes—at initial assessment and as part of continuing care. Measurement approximately every 3 months determines whether patients' glycemic targets have been reached and maintained. The frequency of A1C testing should depend on the clinical situation, the treatment regimen, and the clinician's judgment. The use of point-of-care A1C testing may provide an opportunity for more timely treatment changes during encounters between patients and providers. Patients with type 2 diabetes with stable glycemia well within target may do well with A1C testing only twice per year. Unstable or intensively managed patients (e.g., pregnant women with type 1 diabetes) may require testing more frequently than every 3 months (41).

The A1C test is an indirect measure of average glycemia and, as such, is subject to limitations. As with any laboratory test, there is variability in the measurement of A1C. Although such variability is less on an intraindividual basis than that of blood glucose measurements, clinicians should exercise judgment when using A1C as the sole basis for assessing glycemic control, particularly if the result is close to the threshold that might prompt a change in medication therapy. Conditions that affect red blood cell turnover (hemolytic and other anemias, recent blood transfusion, use of drugs that stimulate erythropoesis, end-stage kidney disease, and pregnancy) may result in discrepancies between the A1C result and the patient’s true mean glycemia. Hemoglobin variants must be considered, particularly when the A1C result does not correlate with the patient's SMBG levels. Options for monitoring include more frequent and/or different timing of SMBG or CGM use. Other measures of average glycemia such as fructosamine and 1,5-anhydroglucitol are available, but their translation into average glucose levels and their prognostic significance are not as clear as for A1C. Though some variability exists among different individuals, generally the association between mean glucose and A1C within an individual correlates over time (42).

A1C does not provide a measure of glycemic variability or hypoglycemia. For patients prone to glycemic variability, especially patients with type 1 diabetes or type 2 diabetes with severe insulin deficiency, glycemic control is best evaluated by the combination of results from A1C and SMBG or CGM. A1C may also confirm the accuracy of the patient's meter (or the patient's reported SMBG results) and the adequacy of the SMBG testing schedule.

Table 6.1 shows the correlation between A1C levels and mean glucose levels based on two studies: the international A1C-Derived Average Glucose (ADAG) study, which assessed the correlation between A1C and frequent SMBG and CGM in 507 adults (83% non-Hispanic whites) with type 1, type 2, and no diabetes (43), and an empirical study of the average blood glucose levels at premeal, postmeal, and bedtime associated with specified A1C levels using data from the ADAG trial (37). 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 the table are based on ∼2,700 readings per A1C in the ADAG trial. In a recent report, mean glucose measured with CGM versus central laboratory–measured A1C in 387 participants in three randomized trials demonstrated that A1C may underestimate or overestimate mean glucose. Thus, as suggested, a patient’s CGM profile has considerable potential for optimizing his or her glycemic management (42).

In the ADAG study, there were no significant differences among racial and ethnic groups in the regression lines between A1C and mean glucose, although the study was underpowered to detect a difference and there was a trend toward a difference between the African/African American and non-Hispanic white cohorts, with higher A1C values observed in Africans/African Americans compared with non-Hispanic whites for a given mean glucose. Other studies have also demonstrated higher A1C levels in African Americans than in whites at a given mean glucose concentration (44,45). Moreover, African Americans heterozygous for the common hemoglobin variant HbS may have, for any level of mean glycemia, lower A1C by about 0.3 percentage points than those without the trait (46). Another genetic variant, X-linked glucose-6-phosphate dehydrogenase G202A, carried by 11% of African Americans, was associated with a decrease in A1C of about 0.8% in hemizygous men and 0.7% in homozygous women compared to those without the trait (47).

A small study comparing A1C to CGM data in children with type 1 diabetes found a highly statistically significant correlation between A1C and mean blood glucose, although the correlation (r = 0.7) was significantly lower than in the ADAG trial (48). Whether there are clinically meaningful differences in how A1C relates to average glucose in children or in different ethnicities is an area for further study (44,49,50). Until further evidence is available, it seems prudent to establish A1C goals in these populations with consideration of both individualized SMBG and A1C results.

For glycemic goals in children, please refer to Section 12 “Children and Adolescents.” For glycemic goals in pregnant women, please refer to Section 13 “Management of Diabetes in Pregnancy.”

• A reasonable A1C goal for many nonpregnant adults is <7% (53 mmol/mol). A

• Providers might reasonably suggest more stringent A1C goals (such as <6.5% [48 mmol/mol]) for selected individual patients if this can be achieved without significant hypoglycemia or other adverse effects of treatment (i.e., polypharmacy). Appropriate patients might include those with short duration of diabetes, type 2 diabetes treated with lifestyle or metformin only, long life expectancy, or no significant cardiovascular disease. C

• Less stringent A1C goals (such as <8% [64 mmol/mol]) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, or long-standing diabetes in whom the goal is difficult to achieve despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin. B

Hyperglycemia defines diabetes, and glycemic control is fundamental to diabetes management. The Diabetes Control and Complications Trial (DCCT) (2), a prospective randomized controlled trial of intensive versus standard glycemic control in patients with type 1 diabetes, showed definitively that better glycemic control is associated with significantly decreased rates of development and progression of microvascular (retinopathy [51], neuropathy, and diabetic kidney disease) complications. Follow-up of the DCCT cohorts in the Epidemiology of Diabetes Interventions and Complications (EDIC) study (52) demonstrated persistence of these microvascular benefits despite the fact that the glycemic separation between the treatment groups diminished and disappeared during follow-up.

The Kumamoto Study (53) and UK Prospective Diabetes Study (UKPDS) (54,55) confirmed that intensive glycemic control significantly decreased rates of microvascular complications in patients with type 2 diabetes. Long-term follow-up of the UKPDS cohorts showed enduring effects of early glycemic control on most microvascular complications (56).

Therefore, achieving A1C targets of <7% (53 mmol/mol) has been shown to reduce microvascular complications of diabetes. Epidemiological analyses of the DCCT (2) and UKPDS (57) demonstrate a curvilinear relationship between A1C and microvascular complications. Such analyses suggest that, on a population level, the greatest number of complications will be averted by taking patients from very poor control to fair/good control. 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. Given the substantially increased risk of hypoglycemia in type 1 diabetes trials and with polypharmacy in type 2 diabetes, the risks of lower glycemic targets outweigh the potential benefits on microvascular complications.

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]) showed that lower A1C levels were associated with reduced onset or progression of some microvascular complications (58–60).

The concerning mortality findings in the ACCORD trial (61), discussed below, and the relatively intense efforts required to achieve near-euglycemia should also be considered when setting glycemic targets. However, on the basis of physician judgment and patient preferences, select patients, especially those with little comorbidity and long life expectancy, may benefit from adopting more intensive glycemic targets (e.g., A1C target <6.5% [48 mmol/mol]) as long as significant hypoglycemia does not become a barrier.

Cardiovascular disease (CVD) is a more common cause of death than microvascular complications in populations with diabetes. There is evidence for a cardiovascular benefit of intensive glycemic control after long-term follow-up of cohorts treated early in the course of type 1 diabetes. In the DCCT, there was a trend toward lower risk of CVD events with intensive control. In the 9-year 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 (MI), stroke, or cardiovascular death compared with those previously randomized to the standard arm (62). The benefit of intensive glycemic control in this cohort with type 1 diabetes has been shown to persist for several decades (63) and to be associated with a modest reduction in all-cause mortality (64).

In type 2 diabetes, there is evidence that more intensive treatment of glycemia in newly diagnosed patients may reduce long-term CVD rates. During the UKPDS, there was a 16% reduction in CVD events (combined fatal or nonfatal MI and sudden death) in the intensive glycemic control arm that did not reach statistical significance (P = 0.052), and there was no suggestion of benefit on other CVD outcomes (e.g., stroke). However, after 10 years of observational follow-up, those originally randomized to intensive glycemic control had significant long-term reductions in MI (15% with sulfonylurea or insulin as initial pharmacotherapy, 33% with metformin as initial pharmacotherapy) and in all-cause mortality (13% and 27%, respectively) (56).

ACCORD, ADVANCE, and VADT suggested no significant reduction in CVD outcomes with intensive glycemic control in participants followed for 3.5–5.6 years who had more advanced type 2 diabetes than UKPDS participants. All three trials were conducted in relatively older participants with longer known duration of diabetes (mean duration 8–11 years) and either CVD or multiple cardiovascular risk factors. The target A1C among intensive control subjects was <6% (42 mmol/mol) in ACCORD, <6.5% (48 mmol/mol) in ADVANCE, and a 1.5% reduction in A1C compared with control subjects in VADT, with achieved A1C of 6.4% vs. 7.5% (46 mmol/mol vs. 58 mmol/mol) in ACCORD, 6.5% vs. 7.3% (48 mmol/mol vs. 56 mmol/mol) in ADVANCE, and 6.9% vs. 8.4% (52 mmol/mol vs. 68 mmol/mol) in VADT. Details of these studies are reviewed extensively in “Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials” (65).

The glycemic control comparison in ACCORD was halted early due to an increased mortality rate in the intensive compared with the standard treatment arm (1.41% vs. 1.14% per year; hazard ratio 1.22 [95% CI 1.01–1.46]), with a similar increase in cardiovascular deaths. Analysis of the ACCORD data did not identify a clear explanation for the excess mortality in the intensive treatment arm (61).

Longer-term follow-up has shown no evidence of cardiovascular benefit or harm in the ADVANCE trial (66). The end-stage renal disease rate was lower in the intensive treatment group over follow-up. However, 10-year follow-up of the VADT cohort (67) showed a reduction in the risk of cardiovascular events (52.7 [control group] vs. 44.1 [intervention group] events per 1,000 person-years) with no benefit in cardiovascular or overall mortality. Heterogeneity of mortality effects across studies was noted, which may reflect differences in glycemic targets, therapeutic approaches, and population characteristics (68).

Mortality findings in ACCORD (61) and subgroup analyses of VADT (69) suggest that the potential risks of intensive glycemic control may outweigh its benefits in higher-risk patients. In all three trials, severe hypoglycemia was significantly more likely in participants who were randomly assigned to the intensive glycemic control arm. Those patients with long duration of diabetes, a known history of hypoglycemia, advanced atherosclerosis, or advanced age/frailty may benefit from less aggressive targets (70,71).

Providers should be vigilant in preventing hypoglycemia and should not aggressively attempt to achieve near-normal A1C levels in patients in whom such targets cannot be safely and reasonably achieved. Severe or frequent hypoglycemia is an absolute indication for the modification of treatment regimens, including setting higher glycemic goals.

Many factors, including patient preferences, should be taken into account when developing a patient's individualized goals (Table 6.2).

Numerous aspects must be considered when setting glycemic targets. The ADA proposes optimal targets, but each target must be individualized to the needs of each patient and his or her disease factors.

When possible, such decisions should be made with the patient, reflecting his or her preferences, needs, and values. Fig. 6.1 is not designed to be applied rigidly but to be used as a broad construct to guide clinical decision-making (72), in both type 1 and type 2 diabetes.

Recommended glycemic targets for many nonpregnant adults are shown in Table 6.2. The recommendations include blood glucose levels that appear to correlate with achievement of an A1C of <7% (53 mmol/mol). The issue of preprandial versus postprandial SMBG targets is complex (73). Elevated postchallenge (2-h oral glucose tolerance test) glucose values have been associated with increased cardiovascular risk independent of fasting plasma glucose in some epidemiological studies, but intervention trials have not shown postprandial glucose to be a cardiovascular risk factor independent of A1C. In subjects with diabetes, surrogate measures of vascular pathology, such as endothelial dysfunction, are negatively affected by postprandial hyperglycemia. It is clear that postprandial hyperglycemia, like preprandial hyperglycemia, contributes to elevated A1C levels, with its relative contribution being greater at A1C levels that are closer to 7% (53 mmol/mol). However, outcome studies have clearly shown A1C to be the primary predictor of complications, and landmark trials of glycemic control such as the DCCT and UKPDS relied overwhelmingly on preprandial SMBG. Additionally, a randomized controlled trial in patients with known CVD found no CVD benefit of insulin regimens targeting postprandial glucose compared with those targeting preprandial glucose (74). Therefore, it is reasonable for postprandial testing to be recommended for individuals who have premeal glucose values within target but have A1C values above target. Measuring postprandial plasma glucose 1–2 h after the start of a meal and using treatments aimed at reducing postprandial plasma glucose values to <180 mg/dL (10.0 mmol/L) may help to lower A1C.

An analysis of data from 470 participants in the ADAG study (237 with type 1 diabetes and 147 with type 2 diabetes) found that actual average glucose levels associated with conventional A1C targets were higher than older DCCT and ADA targets (Table 6.1 ) (37,39). These findings support that premeal glucose targets may be relaxed without undermining overall glycemic control as measured by A1C. These data prompted the revision in the ADA-recommended premeal glucose target to 80–130 mg/dL (4.4–7.2 mmol/L) but did not affect the definition of hypoglycemia.

• Individuals at risk for hypoglycemia should be asked about symptomatic and asymptomatic hypoglycemia at each encounter. C

• Glucose (15–20 g) is the preferred treatment for the conscious individual with blood glucose ≤70 mg/dL [3.9 mmol/L]), although any form of carbohydrate that contains glucose may be used. Fifteen minutes after treatment, if SMBG shows continued hypoglycemia, the treatment should be repeated. Once SMBG returns to normal, the individual should consume a meal or snack to prevent recurrence of hypoglycemia. E

• Glucagon should be prescribed for all individuals at increased risk of clinically significant hypoglycemia, defined as blood glucose <54 mg/dL (3.0 mmol/L), so it is available should it be needed. Caregivers, school personnel, or family members of these individuals should know where it is and when and how to administer it. Glucagon administration is not limited to health care professionals. E

• Hypoglycemia unawareness or one or more episodes of severe hypoglycemia should trigger reevaluation of the treatment regimen. E

• Insulin-treated patients with hypoglycemia unawareness or an episode of clinically significant hypoglycemia should be advised to raise their glycemic targets to strictly avoid hypoglycemia for at least several weeks in order to partially reverse hypoglycemia unawareness and reduce risk of future episodes. A

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

Hypoglycemia is the major limiting factor in the glycemic management of type 1 and type 2 diabetes. Recommendations from the International Hypoglycemia Study Group regarding the classification of hypoglycemia in clinical trials are outlined in Table 6.3 (75). Of note, this classification scheme considers a blood glucose <54 mg/dL (3.0 mmol/L) detected by SMBG, CGM (for at least 20 min), or laboratory measurement of plasma glucose as sufficiently low to indicate clinically significant hypoglycemia that should be included in reports of clinical trials of glucose-lowering drugs for the treatment of diabetes (75). However, a hypoglycemia alert value of ≤70 mg/dL (3.9 mmol/L) can be important for therapeutic dose adjustment of glucose-lowering drugs in clinical care and is often related to symptomatic hypoglycemia. Severe hypoglycemia is defined as severe cognitive impairment requiring assistance from another person for recovery (76).

Symptoms of hypoglycemia include, but are not limited to, shakiness, irritability, confusion, tachycardia, and hunger. Hypoglycemia may be inconvenient or frightening to patients with diabetes. Severe hypoglycemia may be recognized or unrecognized and can progress to loss of consciousness, seizure, coma, or death. It is reversed by administration of rapid-acting glucose or glucagon. Clinically significant hypoglycemia can cause acute harm to the person with diabetes or others, especially if it causes falls, motor vehicle accidents, or other injury. A large cohort study suggested that among older adults with type 2 diabetes, a history of severe hypoglycemia was associated with greater risk of dementia (77). Conversely, in a substudy of the ACCORD trial, cognitive impairment at baseline or decline in cognitive function during the trial was significantly associated with subsequent episodes of severe hypoglycemia (78). Evidence from DCCT/EDIC, which involved adolescents and younger adults with type 1 diabetes, found no association between frequency of severe hypoglycemia and cognitive decline (79), as discussed in Section 12 “Children and Adolescents.”

Severe hypoglycemia was associated with mortality in participants 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. An association of severe hypoglycemia with mortality was also found in the ADVANCE trial (80). An association between self-reported severe hypoglycemia and 5-year mortality has also been reported in clinical practice (81).

Young children with type 1 diabetes and the elderly, including those with type 1 and type 2 diabetes (77,82), are noted as particularly vulnerable to clinically significant hypoglycemia because of their reduced ability to recognize hypoglycemic symptoms and effectively communicate their needs. Individualized glucose targets, patient education, dietary intervention (e.g., bedtime snack to prevent overnight hypoglycemia when specifically needed to treat low blood glucose), exercise management, medication adjustment, glucose monitoring, and routine clinical surveillance may improve patient outcomes (76). CGM with automated low glucose suspend has been shown to be effective in reducing hypoglycemia in type 1 diabetes (34). For patients with type 1 diabetes with severe hypoglycemia and hypoglycemia unawareness that persists despite medical treatment, human islet transplantation may be an option, but the approach remains experimental (83,84).

In 2015, the ADA changed its preprandial glycemic target from 70–130 mg/dL (3.9–7.2 mmol/L) to 80–130 mg/dL (4.4–7.2 mmol/L). This change reflects the results of the ADAG study, which demonstrated that higher glycemic targets corresponded to A1C goals (37). An additional goal of raising the lower range of the glycemic target was to limit overtreatment and provide a safety margin in patients titrating glucose-lowering drugs such as insulin to glycemic targets.

Providers should continue to counsel patients to treat hypoglycemia with fast-acting carbohydrates at the hypoglycemia alert value of 70 mg/dL (3.9 mmol/L) or less. Hypoglycemia treatment requires ingestion of glucose- or carbohydrate-containing foods. The acute glycemic response correlates better with the glucose content of food than with the carbohydrate content of food. Pure glucose is the preferred treatment, but any form of carbohydrate that contains glucose will raise blood glucose. Added fat may retard and then prolong the acute glycemic response. In type 2 diabetes, ingested protein may increase insulin response without increasing plasma glucose concentrations (85). Therefore, carbohydrate sources high in protein should not be used to treat or prevent hypoglycemia. Ongoing insulin activity or insulin secretagogues may lead to recurrent hypoglycemia unless further food is ingested after recovery. Once the glucose returns to normal, the individual should be counseled to eat a meal or snack to prevent recurrent hypoglycemia.

The use of glucagon is indicated for the treatment of hypoglycemia in people unable or unwilling to consume carbohydrates by mouth. Those in close contact with, or having custodial care of, people with hypoglycemia-prone diabetes (family members, roommates, school personnel, child care providers, correctional institution staff, or coworkers) should be instructed on the use of glucagon kits including where the kit is and when and how to administer glucagon. An individual does not need to be a health care professional to safely administer glucagon. Care should be taken to ensure that glucagon kits are not expired.

Hypoglycemia prevention is a critical component of diabetes management. SMBG and, for some patients, CGM are essential tools to assess therapy and detect incipient hypoglycemia. Patients should understand situations that increase their risk of hypoglycemia, such as fasting for tests or procedures, delayed meals, during or after intense exercise, and during sleep. Hypoglycemia may increase the risk of harm to self or others, such as with driving. Teaching people with diabetes to balance insulin use and carbohydrate intake and exercise are necessary, but these strategies are not always sufficient for prevention.

In type 1 diabetes and severely insulin-deficient type 2 diabetes, hypoglycemia unawareness (or hypoglycemia-associated autonomic failure) can severely compromise stringent diabetes control and quality of life. This syndrome is characterized by deficient counterregulatory hormone release, especially in older adults, and a diminished autonomic response, which both are risk factors for, and caused by, hypoglycemia. A corollary to this “vicious cycle” is that several weeks of avoidance of hypoglycemia has been demonstrated to improve counterregulation and hypoglycemia awareness in many patients (86). Hence, patients with one or more episodes of clinically significant hypoglycemia may benefit from at least short-term relaxation of glycemic targets.

For further information on management of patients with hyperglycemia in the hospital, please refer to Section 14 “Diabetes Care in the Hospital.”

Stressful events (e.g., illness, trauma, surgery, etc.) may worsen glycemic control and precipitate diabetic ketoacidosis or nonketotic hyperosmolar state, life-threatening conditions that require immediate medical care to prevent complications and death. Any condition leading to deterioration in glycemic control necessitates more frequent monitoring of blood glucose; ketosis-prone patients also require urine or blood ketone monitoring. If accompanied by ketosis, vomiting, or alteration in the level of consciousness, marked hyperglycemia requires temporary adjustment of the treatment regimen and immediate interaction with the diabetes care team. The patient treated with noninsulin therapies or medical nutrition therapy alone may temporarily require insulin. Adequate fluid and caloric intake must be ensured. Infection or dehydration is more likely to necessitate hospitalization of the person with diabetes than the person without diabetes.

A physician with expertise in diabetes management should treat the hospitalized patient. For further information on the management of diabetic ketoacidosis and the hyperglycemic nonketotic hyperosmolar state, please refer to the ADA consensus report “Hyperglycemic Crises in Adult Patients With Diabetes” (87).