Description

• Abnormally low concentration of glucose in circulating blood of a patient with diabetes mellitus (DM); often referred to as an insulin reaction, as classified by the ADA
  • Level 1: hypoglycemia alert value; <70 mg/dL (<3.9 mmol/L) but ≥54 mg/dL (≥3.0 mmol/L): may or may not be accompanied by symptoms; asymptomatic hypoglycemia if symptoms not present
  • Level 2: clinically significant hypoglycemia; <54 mg/dL (<3.0 mmol/L)
  • Level 3: severe hypoglycemia associated with severe cognitive impairment requiring external assistance for recovery
  • Pseudohypoglycemia: typical symptoms but glucose ≥70 mg/dL (≥3.9 mmol/L)
• Hypoglycemia is the leading limiting factor in the glycemic management of type 1 DM (T1DM) and type 2 DM (T2DM). Severe or frequent hypoglycemia requires modification of treatment regimens, including higher treatment goals (1).

Epidemiology

Incidence

• Most commonly found in patients with long-standing T1DM and children aged <7 years
• From the ACCORD study, the annual incidence of hypoglycemia was the following:
  • 3.14% in the intensive treatment group
  • 1.03% in the standard group
  • Increased risk among women, African Americans, those with less than high school education, aged participants, and those who used insulin at trial entry
• RECAP-DM study: Hypoglycemia was reported in 35.8% of patients with T2DM who added a sulfonylurea or thiazolidinedione to metformin therapy during the past year.

Etiology and Pathophysiology

• Loss of hormonal counterregulatory mechanism in glucose metabolism
• Impaired insulin, glucagon, and epinephrine secretion

Risk Factors

• Nearly 3/4 of severe hypoglycemic episodes occur during sleep.
• Severe hypoglycemia is associated with comorbid conditions in patients aged ≥65 years.
• Intensive insulin therapy (further lowering HbA1c from 7% to 6%) is associated with higher rate of hypoglycemia.
• Comorbidities: renal/liver disease, congestive heart failure (CHF), hypothyroidism, hypoadrenalism, gastroenteritis, gastroparesis (unpredictable carbohydrate (CHO) delivery), autonomic neuropathy, pregnancy, anxiety, depression, disordered eating behavior, illness/stress, and unplanned life events
• Duration of DM: >5 years
• Young children with T1DM
• Advanced age
• Reduced cognitive function, dementia
• Starvation, prolonged fasting, weight loss, or food insecurity
• Current smokers with T1DM
• Alcohol consumption may increase risk of delayed hypoglycemia, especially if on insulin or insulin secretagogues. Evening consumption of alcohol is associated with an increased risk of nocturnal and fasting hypoglycemia, especially in patients with T1DM.
• Insulin secretagogues: Sulfonylureas (glyburide, glimepiride, glipizide, etc.) and glinide derivatives (repaglinide, nateglinide) stimulate insulin secretion.
• Hypoglycemia is rare in diabetics not treated with insulin or insulin secretagogues.
• Other antidiabetes medications such as dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and sodium-glucose contransporter-2 (SGLT-2) agents carry a lower but present risk of hypoglycemia, which may increase when combining agents from different categories.

Geriatric Considerations

• American Geriatric Society Beers Criteria recommend avoiding glyburide and chlorpropamide due to their prolonged half-life in older adults and risk for prolonged hypoglycemic episodes. Medications should be dosed for age and renal function.
• Individualize pharmacologic therapy in older adults to reduce the risk of hypoglycemia, avoid overtreatment, and simplify complex regimens if possible while maintaining the HbA1c target (1)[A].

Pediatric Considerations
Children may not realize when they have hypoglycemia, needing increased supervision during times of higher activity such as competitive sports. Children may have higher glycemic goals for this reason. Caregivers should be instructed in use of glucagon (2)[A].

Pregnancy Considerations
Hypoglycemia management and avoidance education should be reemphasized and blood glucose monitoring increased due to more stringent glycemic goals and increased risk in early pregnancy (1)[A].

General Prevention

• Maintain routine schedule of diet (consistent CHO intake), medication, and exercise (1)[A].
• Self-monitoring of blood glucose (SMBG) or continuous glucose monitoring (CGM)
  • Particularly helpful for asymptomatic hypoglycemia
  • Use if taking insulin or secretagogue.
  • Use ≥3 times daily testing if multiple injections of insulin, insulin pump therapy, or pregnant diabetic; frequency and timing dictated by needs and treatment goals
• Diabetes treatment and teaching programs (DTTPs) especially for high-risk type 1 patients, which teach flexible insulin therapy to enable dietary freedom
• Hypoglycemia may be decreased with use of insulin analogs, continuous SC insulin infusion (CSII) pumps, and CGM systems (1)[A].