The rate limiting step of intensive diabetes management for patients with diabetes is treatment induced hypoglycemia. Thus, hypoglycemia remains a significant barrier in optimizing glycemic control and reducing long-term diabetes related complications including cardiovascular death, stroke, and all cause-mortality.[1] Cardiovascular (CV) events are the leading cause of death among patients with diabetes. The risk of CV death is twice that of patients without diabetes.[2] Severe hypoglycemia (resulting in cognitive impairment) can occur across a broad spectrum of A1C levels. Patients achieving near-normal glycemia (< 6%) and those who were poorly controlled (≥ 9%) appeared to be at the highest risk for severe hypoglycemia.[3] Hypoglycemia triggers a vascular and inflammatory cascade which can result in vascular constriction, tachycardia, thrombosis, and fatal arrythmias.[4] Therefore, patients who have existing CV disease should have their glycemic targets relaxed to mitigate the risk of hypoglycemia.

Recurrent hypoglycemia lowers or even eliminates the blood glucose concentration threshold at which patients develop a sympathetic response likely to prompt them to take evasive action in time to reverse an impending event. Elderly patients may lose their balance without warning, falling to the ground. The subsequent confusion after such a fall is likely to be attributed to "the aging process" rather than to deficient glucose counterregulation.

Clinicians should remind patients with diabetes who use insulin to monitor their blood glucose levels prior to operating a motor vehicle. The single most significant factor associated with driving collisions for drivers with diabetes appears to be a recent history of severe hypoglycemia, regardless of the type of diabetes or the treatment used.[5] A single hypoglycemia event can deplete counterregulatory hormone levels which favor recognition and reversal of low plasma glucose, resulting in a lack of awareness of a hypoglycemic event.

Nocturnal hypoglycemia may result in patients arriving late to work or missing entire days at the office. Patients who experience hypoglycemia are likely to use extra test strips for fear of having a recurrence of low blood glucose levels. Calls to doctors for guidance on glucose management are increased after an episode of hypoglycemia, and patients often inappropriately self-titrate their medications to avoid future events.[6]

Hypoglycemia increases the risk of cardiovascular and all-cause mortality in patients with diabetes.[1] Severe hypoglycemia is associated with a macrovascular events hazards ratio (HR) of 2.88 and a microvascular events HR of 1.81. The mortality HR for a hypoglycemic event in patients with type 2 diabetes is 2.69.[7] Hypoglycemia during hospital admissions is associated with increased lengths of stay and with increased 1-year mortality and inpatient mortality rates (2.96%) for patients who had at least one hypoglycemic episode during the hospitalization vs. 0.82% for patients who had none.[8]

Hypoglycemia can increase vascular inflammation, QT prolongation, intravascular coagulation, life threatening arrhythmias, and delayed clot thrombolysis. Therefore, patients with known cardiovascular disease must minimize their risk of hypoglycemia.[9]

Definition of Hypoglycemia

The American Diabetes Association and the European Association for the Study of Diabetes (ADA/EASD) updated its standards of care and hypoglycemia definitions in 2017.[10] The implications of different blood glucose levels vary from individual to individual, but < 70 mg/dL is considered an alert for hypoglycemia and allows patients time to take corrective action. A glucose level of < 54 mg/dL is considered clinically significant and unequivocally hypoglycemic. Severe hypoglycemia has no assigned biochemical value and is defined simply and starkly as a glucose level low enough to cause cognitive impairment such that the assistance of another person is required to administer carbohydrates or glucagon in order to achieve a recovery. Table 1 lists the American Diabetes Association definition of hypoglycemia levels.

Primary Issues Table 1

Case Introduction - Tammy

Tammy is 68 years of age and has had poorly controlled type 2 diabetes. She is a former kindergarten teacher who neither smokes or drinks. Tammy had an inferior wall infarction a year ago after which she received 3 stents. She is adherent with her prescribed diabetes treatment regimen yet is unable to achieve her prescribed A1C target of 7.5%. She is currently taking metformin 1 gram with breakfast and dinner, and liraglutide 1.8 mg/d. Her blood pressure and lipids are at the American Diabetes Association recommended targets. Her A1C is 8.7%. A download of her continuous glucose monitor (CGM) is shown in Figure 1a:

Primary Issues Figure 1a
Question #1:
Which of the following statements accurately reflects the findings of the continuous glucose monitor?
  a. Patient's blood glucose levels are elevated throughout the day
  b. Patient is not experiencing any hypoglycemic events
  c. Patient is experiencing very little glycemic variability
  d. All of the above
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