6. Glycemic Targets

Two primary techniques are available for health providers and patients to assess the effectiveness of the management plan on glycemic control: patient self-monitoring of blood glucose (SMBG) or interstitial glucose and A1C. Continuous glucose monitoring (CGM) may be a useful adjunct to SMBG in selected patients.

• When prescribed as part of a broader educational context, SMBG results may help guide treatment decisions and/or self-management for patients using 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

• Patients on multiple-dose insulin or insulin pump therapy should perform SMBG prior to meals and snacks, occasionally postprandially, at bedtime, 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 used properly, CGM in conjunction with intensive insulin regimens is a useful tool to lower A1C in selected adults (aged ≥25 years) with type 1 diabetes. A

• Although the evidence for A1C lowering is less strong in children, teens, and younger adults, CGM may be helpful in these groups. Success correlates with adherence to ongoing use of the device. B

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

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

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

Major clinical trials of insulin-treated patients have included SMBG as part of the multifactorial interventions to demonstrate the benefit of intensive glycemic control on diabetes complications. SMBG is thus an integral component of effective therapy (1). 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). Evidence supports a correlation between greater SMBG frequency and lower A1C (2). The patient’s specific needs and goals should dictate SMBG frequency and timing.

SMBG accuracy is dependent on the instrument and user (3), 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, both by the patient and provider. Among patients who check their blood glucose at least once daily, many report taking no action when results are high or low (4). In a yearlong study of insulin-naïve 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 (5). Patients should be taught how to use SMBG data to adjust food intake, exercise, or pharmacological therapy to achieve specific goals. The ongoing need for and frequency of SMBG should be reevaluated at each routine visit. SMBG is especially important for insulin-treated patients to monitor for and prevent asymptomatic hypoglycemia and hyperglycemia.

Most patients on intensive insulin regimens (multiple-dose insulin or insulin pump therapy, including patients with type 1 diabetes) should consider SMBG prior to meals and snacks, occasionally postprandially, at bedtime, 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 (6).

The evidence is insufficient regarding when to prescribe SMBG and how often testing is needed for patients who do not use an intensive insulin regimen, such as those with type 2 diabetes using basal insulin or oral agents.

Several randomized trials have called into question the clinical utility and cost-effectiveness of routine SMBG in noninsulin-treated patients (7–9). A meta-analysis suggested that SMBG reduced A1C by 0.25% at 6 months (10), but the reduction subsides after 12 months (11). 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.

Real-time CGM measures interstitial glucose (which correlates well with plasma glucose) and includes sophisticated alarms for hypo- and hyperglycemic excursions, but the devices are still not approved by the U.S. Food and Drug Administration as a sole agent to monitor glucose. CGMs require calibration with SMBG, with the latter still required for making acute treatment decisions.

A 26-week randomized trial of 322 type 1 diabetic patients 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%), compared with those using intensive insulin therapy with SMBG (12). Sensor use in those aged <25 years (children, teens, and adults) did not result in significant A1C lowering, and there was no significant difference in hypoglycemia in any group. 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.

A recent registry study of 17,317 participants confirmed that more frequent CGM use is associated with lower A1C (13), while another study showed that children with >70% sensor use missed fewer school days (14). Small randomized controlled trials in adults and children with baseline A1C 7.0–7.5% have confirmed favorable outcomes (A1C and hypoglycemia occurrence) in groups using CGM, suggesting that CGM may provide further benefit for individuals with type 1 diabetes who already have tight control (15,16).

A meta-analysis suggests that, compared with SMBG, CGM is associated with short-term A1C lowering of ∼0.26% (17). The long-term effectiveness of CGM needs to be determined. This technology may be particularly useful in those with hypoglycemia unawareness and/or frequent hypoglycemic episodes, although studies have not shown significant reductions in severe hypoglycemia (17,18). A CGM device equipped with an automatic low glucose suspend feature has been approved by the U.S. Food and Drug Administration. The Automation to Simulate Pancreatic Insulin Response (ASPIRE) trial of 247 patients showed that sensor-augmented insulin pump therapy with a low glucose suspend significantly reduced nocturnal hypoglycemia, without increasing A1C levels for those over 16 years of age (19). These devices may offer the opportunity to reduce severe hypoglycemia for those with a history of nocturnal hypoglycemia. 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 (13,20,21).

• 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

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

A1C reflects average glycemia over several months (3) and has strong predictive value for diabetes complications (22,23). 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. Some patients with stable glycemia well within target may do well with testing only twice per year. Unstable or highly intensively managed patients (e.g., pregnant women with type 1 diabetes) may require testing more frequently than every 3 months (24).

The A1C test is subject to certain limitations. Conditions that affect red blood cell turnover (hemolysis, blood loss) and hemoglobin variants must be considered, particularly when the A1C result does not correlate with the patient’s blood glucose levels (3). For patients in whom A1C/estimated average glucose (eAG) and measured blood glucose appear discrepant, clinicians should consider the possibilities of hemoglobinopathy or altered red blood cell turnover and the options of more frequent and/or different timing of SMBG or CGM use. Other measures of chronic glycemia such as fructosamine are available, but their linkage to average glucose and their prognostic significance are not as clear as for A1C.

The A1C does not provide a measure of glycemic variability or hypoglycemia. For patients prone to glycemic variability, especially type 1 diabetic patients or type 2 diabetic patients with severe insulin deficiency, glycemic control is best evaluated by the combination of results from self-monitoring and the A1C. The 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) trial, which based the correlation with A1C on frequent SMBG and CGM in 507 adults (83% non-Hispanic whites) with type 1, type 2, and no diabetes (25), 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 (21). 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 eAG result when a clinician orders the A1C test. Clinicians should note that the mean plasma glucose numbers in the table are based on ∼2,800 readings per A1C in the ADAG trial.

In the ADAG study, there were no significant differences among racial and ethnic groups in the regression lines between A1C and mean glucose, although there was a trend toward a difference between the African/African American and non-Hispanic white cohorts. 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 (26). Whether there are significant differences in how A1C relates to average glucose in children or in different ethnicities is an area for further study (27,28). For the time being, the question has not led to different recommendations about testing A1C or to different interpretations of the clinical meaning of given levels of A1C in those populations.

For glycemic goals in children, please refer to Section 11. Children and Adolescents. For glycemic goals in pregnant women, please refer to Section 12. Management of Diabetes in Pregnancy.

• Lowering A1C to approximately 7% or less has been shown to reduce microvascular complications of diabetes, and, if implemented soon after the diagnosis of diabetes, it is associated with long-term reduction in macrovascular disease. Therefore, a reasonable A1C goal for many nonpregnant adults is <7%. B

• Providers might reasonably suggest more stringent A1C goals (such as <6.5%) for selected individual patients if this can be achieved without significant hypoglycemia or other adverse effects of treatment. 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 (CVD). C

• Less stringent A1C goals (such as <8%) 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 general goal is difficult to attain 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) (1), a prospective randomized controlled trial of intensive versus standard glycemic control in patients with relatively recently diagnosed type 1 diabetes showed definitively that improved glycemic control is associated with significantly decreased rates of microvascular (retinopathy and diabetic kidney disease) and neuropathic complications. Follow-up of the DCCT cohorts in the Epidemiology of Diabetes Interventions and Complications (EDIC) study (29,30) demonstrated persistence of these microvascular benefits in previously intensively treated subjects, even though their glycemic control approximated that of previous standard arm subjects during follow-up.

The Kumamoto Study (31) and UK Prospective Diabetes Study (UKPDS) (32,33) confirmed that intensive glycemic control was associated with significantly decreased rates of microvascular and neuropathic complications in type 2 diabetic patients. Long-term follow-up of the UKPDS cohorts showed enduring effects of early glycemic control on most microvascular complications (34).

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 microvascular complications (35–37).

Epidemiological analyses of the DCCT (1) and UKPDS (38) 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% is associated with further reduction in the risk of microvascular complications, though the absolute risk reductions become much smaller. Given the substantially increased risk of hypoglycemia in type 1 diabetes trials and in recent type 2 diabetes trials, the risks of lower glycemic targets may, on a population level, outweigh the potential benefits on microvascular complications.

The concerning mortality findings in the ACCORD trial, discussed below (39), and the relatively intense efforts required to achieve near-euglycemia should also be considered when setting glycemic targets. However, based on 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%) as long as significant hypoglycemia does not become a barrier.

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 study cohorts treated early in the course of type 1 and type 2 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 CVD death compared with those previously in the standard arm (40). The benefit of intensive glycemic control in this type 1 diabetic cohort has recently been shown to persist for several decades (41).

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 trial, 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 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) (34).

The 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 participants with more long-standing diabetes (mean duration 8–11 years) and either known CVD or multiple cardiovascular risk factors. The target A1C among intensive control subjects was <6% in ACCORD, <6.5% in ADVANCE, and a 1.5% reduction in A1C compared with control subjects in VADT. Details of these studies are reviewed extensively in the ADA position statement “Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials: A Position Statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association” (42).

The glycemic control comparison in ACCORD was halted early due to an increased mortality rate in the intensive compared with the standard 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.

1. Analysis of the ACCORD data did not identify a clear explanation for the excess mortality in the intensive arm (39).

2. A group-level meta-analysis of ACCORD, ADVANCE, and VADT suggested that glucose lowering had a modest (9%) but statistically significant reduction in major CVD outcomes, primarily nonfatal MI, with no significant effect on mortality.

3. Heterogeneity of the mortality effects across studies was noted.

4. A prespecified subgroup analysis suggested that major CVD outcome reduction occurred in patients without known CVD at baseline (hazard ratio 0.84 [95% CI 0.74–0.94]) (43).

5. Mortality findings in ACCORD (39) and subgroup analyses of the VADT (44) suggested that the potential risks of intensive glycemic control may outweigh its benefits in some patients.

6. Those with long duration of diabetes, known history of severe hypoglycemia, advanced atherosclerosis, or advanced age/frailty may benefit from less aggressive targets.

7. Severe hypoglycemia was significantly more likely in participants in all three trials randomized to the intensive glycemic control arm.

Providers should be vigilant in preventing severe hypoglycemia in patients with advanced disease 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 their disease factors. When possible, such decisions should be made with the patient, reflecting his or her preferences, needs, and values. Figure 6.1 is not designed to be applied rigidly but used as a broad construct to guide clinical decision making (45), both in 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%. The issue of preprandial versus postprandial SMBG targets is complex (46). 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. In subjects with diabetes, surrogate measures of vascular pathology, such as endothelial dysfunction, are negatively affected by postprandial hyperglycemia (47). 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%. However, outcome studies have clearly shown A1C to be the primary predictor of complications, and landmark glycemic control trials 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 (48). 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. Taking postprandial plasma glucose measurements 1–2 h after the start of a meal and using treatments aimed at reducing postprandial plasma glucose values to <180 mg/dL (10 mmol/L) may help lower A1C.

An analysis of data from 470 participants of 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) (21,25). These findings support that premeal glucose targets may be relaxed without undermining overall glycemic control as measured by A1C. These data have prompted a revision in the ADA-recommended premeal target to 80–130 mg/dL (4.4–7.2 mmol/L).

• 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 hypoglycemia, 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 an increased risk of severe hypoglycemia, and caregivers or family members of these individuals should be instructed on its administration. 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 severe hypoglycemia should be advised to raise their glycemic targets to strictly avoid further 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 and/or declining cognition is found. B

Hypoglycemia is the leading limiting factor in the glycemic management of type 1 and insulin-treated type 2 diabetes (49). Mild hypoglycemia may be inconvenient or frightening to patients with diabetes. Severe 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 (50). 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 (51). Evidence from the DCCT/EDIC, which involved younger adults and adolescents with type 1 diabetes, found no association between frequency of severe hypoglycemia and cognitive decline (52), as discussed in Section 11. Children and Adolescents.

Severe hypoglycemia was associated with mortality in participants in both the standard and 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 (53). An association between self-reported severe hypoglycemia and 5-year mortality has also been reported in clinical practice (54).

In 2013, the ADA and the Endocrine Society published the consensus report “Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and the Endocrine Society” (55) on the effect and treatment of hypoglycemia in patients with diabetes. Severe hypoglycemia was defined as an event requiring the assistance of another person. Young children with type 1 diabetes and the elderly were noted as particularly vulnerable due to their limited ability to recognize hypoglycemic symptoms and effectively communicate their needs. Individualized patient education, dietary intervention (e.g., bedtime snack to prevent overnight hypoglycemia), exercise management, medication adjustment, glucose monitoring, and routine clinical surveillance may improve patient outcomes.

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. Ongoing insulin activity or insulin secretagogues may lead to recurrent hypoglycemia unless further food is ingested after recovery.

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. An individual does not need to be a health care professional to safely administer glucagon. A glucagon kit requires a prescription. 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, 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 awareness to some extent in many patients (56). Hence, patients with one or more episodes of severe 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 13. Diabetes Care in the Hospital, Nursing Home, and Skilled Nursing Facility. Stressful events (e.g., illness, trauma, surgery, etc.) frequently aggravate glycemic control and may 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 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 assured. 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 diabetic ketoacidosis management or hyperglycemic nonketotic hyperosmolar state, please refer to the ADA statement “Hyperglycemic Crises in Adult Patients With Diabetes” (57).