para>Hypoglycemia unawareness
EPIDEMIOLOGY
Incidence
- From the Accord Study, the annual incidence of hypoglycemia was the following (2)[A]:
- 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
- From the RECAP-DM study (3)[A]: 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
- Diet: too little food (skipping or delaying meals), decreased carbohydrate (CHO) intake
- Medication: too much insulin or oral hypoglycemic agent (improper dose, timing, or erratic absorption)
- Exercise/physical activity: unplanned or excessive
- Alcohol consumption
- Vomiting or diarrhea
RISK FACTORS
- Nearly 3/4 of severe hypoglycemic episodes occur during sleep.
- Autonomic neuropathy
- Illness, stress, and unplanned life events
- Duration of DM >5 years, advanced age, renal/liver disease, congestive heart failure (CHF), hypothyroidism, hypoadrenalism, gastroenteritis, gastroparesis (unpredictable CHO delivery)
- Starvation or prolonged fasting
- Alcoholism: 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.
- Current smokers 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 glucagon-like peptide-1 (GLP-1) agonist and sodium-glucose contransporter-2 (SGLT-2) agents carry a lower but present risk of hypoglycemia.
- Severe hypoglycemia is associated with comorbid conditions in patients aged ≥65 years and in users of a long-acting sulfonylurea.
- Intensive insulin therapy (further lowering A1C from 7% to 6%) is associated with higher rate of hypoglycemia.
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.
Pediatric Considerations
Children may not realize when they have hypoglycemia, needing increased supervision during times of higher activity. Children may have higher glycemic goals for this reason. Caregivers should be instructed in use of glucagon (1,4)[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.
GENERAL PREVENTION
- Maintain routine schedule of diet (consistent CHO intake), medication, and exercise (4)[A].
- Regular self-monitoring of blood glucose (SMBG), if taking insulin or secretagogue
- ≥3 times daily testing if multiple injections of insulin, insulin pump therapy, or pregnant diabetic; frequency and timing dictated by needs and treatment goals
- Particularly helpful for asymptomatic hypoglycemia
- 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 prevented with use of insulin analogs, continuous SC insulin infusion (CSII) pumps, and continuous glucose monitoring (CGM) systems.
- If preexercise glucose is <100 mg/dL and taking insulin or secretagogue, then CHO consumption or reduction in medication may prevent hypoglycemia.
COMMONLY ASSOCIATED CONDITIONS
- Autonomic dysfunction
- Neuropathies
- Cardiomyopathies
- Older type 2 diabetics with severe hypoglycemia have a higher risk of dementia.
DIAGNOSIS
HISTORY
- Discuss frequency and cause of hypoglycemia (4)[A].
- Symptoms vary considerably between individuals.
- Adrenergic symptoms
- Hunger, trembling, pallor, sweating, shaking, pounding heart, anxiety
- Neurologic symptoms
- Dizziness, poor concentration, drowsiness, weakness, confusion, lightheadedness, slurred speech, blurred vision, double vision, unsteadiness, poor coordination
- Hypoglycemia causes a significant deterioration in reading span and subject-verb agreement, demonstrating that language processing is impaired during moderate hypoglycemia (5)[A].
- Behavioral symptoms
- Tearfulness, confusion, fatigue, irritability, aggressiveness
- If altered cognition, consider hypoglycemia
PHYSICAL EXAM
- General: confusion, lethargy
- HEENT: diplopia
- Coronary: tachycardia
- Neurologic: tremulousness, weakness, paresthesias, stupor, seizure, or coma
- Mental status: irritability, inability to concentrate, or short-term memory loss
- Skin: pale, diaphoresis
- End-organ damage: microvascular, macrovascular, ophthalmologic, neurologic, renal
DIFFERENTIAL DIAGNOSIS
Hypoglycemia not associated with DM may be seen in:
- Chronic alcoholics and binge drinkers
- GI dysfunction causing postprandial hypoglycemia or alimentary reactive hypoglycemia
- Hormonal deficiency states (hormonal reactive hypoglycemia)
- Hypoglycemia of sepsis
- Islet cell tumors
- Factitious hypoglycemia from surreptitious injection of insulin
DIAGNOSTIC TESTS & INTERPRETATION
- Plasma, serum, or whole-blood glucose <70 mg/dL
- SMBG and CGM are especially useful for asymptomatic hypoglycemia (1)[A].
- A hypoglycemic reading from a CGM sensor should be verified by SMBG fingerstick glucose testing prior to treatment (4)[A].
- Suspect hypoglycemic unawareness in T1DM with low/normal HgbA1c (1)[A].
- Chronic hypoglycemia is indicated by low HgbA1c level.
- Disorders that may alter lab results
- Conditions that affect erythrocyte turnover, such as hemolysis or blood loss, and hemoglobin variants may alter HbgA1c (4)[A].
TREATMENT
GENERAL MEASURES
- Glucose: preferred; any form of CHO that contains glucose should be effective (see "Medication" section below) (4)[A].
- Glucagon should be prescribed to patients at significant risk of severe hypoglycemia. People in close contact with these individuals should be instructed in using an emergency glucagon kit (4)[A].
- Alpha-glucosidase inhibitors (acarbose, precise) prevent digestion of complex CHOs; therefore, hypoglycemia must be treated with monosaccharides, such as glucose tablets.
- Patients with severe hypoglycemia combined with hypoglycemic unawareness should have glycemic targets raised to avoid hypoglycemia (4)[A].
- Patients with T1DM should use insulin analogs to reduce hypoglycemia risk (4)[A].
- CGM augmented CSII with automated insulin suspension when blood glucose falls below a threshold value reduces the combined rate of severe and moderate hypoglycemia in T1DM and reduces nocturnal hypoglycemia without increasing A1c levels in patients >16 years old (4,6)[A].
MEDICATION
- Conscious patients (4)[A]:
- Glucose (15 to 20 g) is preferred, although any form of CHO may be used.
- Any sugar-containing food or beverage that can be rapidly absorbed: juice or nondiet soda (4 to 5 oz), candy (5 to 6 pieces of hard candy), or OTC glucose tablets (4 tablets = 16 g CHO)
- Takes ~15 minutes for CHOs to be digested and enter bloodstream as glucose
- Blood glucose value may correct prior to symptoms resolving.
- "Rule of 15": 15 to 20 g CHO (~60 to 80 calories simple CHO) repeated q15min until blood sugar is ≥70 mg/dL
- Once sugar has normalized, a meal or snack should be consumed to prevent recurrence of hypoglycemia.
- Loss of consciousness at home (6)[A]:
- Administer glucagon
- IM or SC in the deltoid or anterior thigh
- Age <6 years and/or weight <20 to 25 kg: 0.50 mg
- Age ≥6 years and/or weight >20 to 25 kg: 1 mg
- May repeat dose in 15 minutes if needed
- In unconscious, with emergency medical personnel present or patient hospitalized (6)[A]:
- Give 25 g IV 50% dextrose every 5 to 10 minutes until patient awakens.
- Then, feed orally and/or administer 5% dextrose IV at level that will maintain blood glucose >100 mg/dL.
- Patients with hypoglycemia secondary to oral hypoglycemics should be monitored for 24 to 48 hours because hypoglycemia may recur after apparent clinical recovery.
- Significant possible interactions:
- Overtreatment may cause hyperglycemia.
- Clearance of certain oral hypoglycemics may be prolonged in persons with renal or liver disease.
ISSUES FOR REFERRAL
- Frequent or recurring episodes that do not readily respond to treatment
- Consultant pharmacists in long-term care facilities
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
- Any doubt of cause
- Expectation of prolonged hypoglycemia (e.g., caused by sulfonylurea drug)
- Inability to drink
- Treatment has not resulted in prompt sensory recovery.
- Seizures, coma, or altered behavior (e.g., ataxia, disorientation, unstable motor coordination, dysphasia) secondary to documented or suspected hypoglycemia
Discharge Criteria
Normoglycemia and risk of severe hypoglycemia is negligible.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Rest until glucose is normal.
Patient Monitoring
SMBG
DIET
- If alcohol consumed, combine with food to reduce risk of hypoglycemia.
- CHO sources high in protein should not be used to treat or prevent hypoglycemia (4)[A].
- Fats may slow absorption of CHOs and may retard and then prolong the acute glycemic response (6)[A].
PATIENT EDUCATION
- Always have access to quick-acting CHO.
- For planned exercise, consider a reduced insulin dose; additional CHOs are needed for unplanned exercise.
- Educate patients and their relatives, close friends, teachers, and supervisors to be aware of DM diagnosis and signs/symptoms of hypoglycemia and treatment.
- Teach SMBG and self-adjustment for insulin therapy, diet control, and exercise regimen.
- Wear medical alert identification bracelet or necklace.
PROGNOSIS
Full recovery usually depends on rapidity of diagnosis and treatment.
COMPLICATIONS
- Coma, seizure, myocardial infarction, stroke (especially in elderly)
- Prolonged or severe hypoglycemia may cause permanent neurologic damage and/or cognitive impairment.
- Children with T1DM have a greater vulnerability to neurologic manifestations of hypoglycemia.
ALERT
The ACCORD trial (adults with T2DM) demonstrated that intensively lowering blood glucose below current recommendations increased the risk of death versus standard treatment strategy (2)[A].
REFERENCES
11 Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and The Endocrine Society. J Clin Endocrinol Metab. 2013;98(5):1845-1859.22 Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559.33 Alvarez Guisasola F, Tof © Povedano S, Krishnarajah G, et al. Hypoglycaemic symptoms, treatment satisfaction, adherence and their associations with glycaemic goal in patients with type 2 diabetes mellitus: findings from the Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) Study. Diabetes Obes Metab. 2008;10(Suppl 1):25-32.44 American Diabetes Association. Standards of medical care in diabetes-2015: summary of revisions. Diabetes Care. 2015;38(Suppl):S4.55 Allen KV, Pickering MJ, Zammitt NN, et al. Effects of acute hypoglycemia on working memory and language processing in adults with and without type 1 diabetes. Diabetes Care. 2015;38(6):1108-1115.66 Cryer PE, Axelrod L, Grossmann AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009;94(3):709-728.
ADDITIONAL READING
Thompson AE. JAMA patient page. Hypoglycemia. JAMA. 2015;313(12):1284.
SEE ALSO
- Diabetes Mellitus, Type 1
- Algorithm: Hypoglycemia
CODES
ICD10
- E11.649 Type 2 diabetes mellitus with hypoglycemia without coma
- E10.649 Type 1 diabetes mellitus with hypoglycemia without coma
- E13.649 Oth diabetes mellitus with hypoglycemia without coma
ICD9
- 250.80 Diabetes with other specified manifestations, type II or unspecified type, not stated as uncontrolled
- 250.81 Diabetes with other specified manifestations, type I [juvenile type], not stated as uncontrolled
SNOMED
- 237633009 Hypoglycemic state in diabetes (disorder)
- 120731000119103 Hypoglycemia due to type 2 diabetes mellitus (disorder)
- 84371000119108 Hypoglycemia due to type 1 diabetes mellitus (disorder)
CLINICAL PEARLS
- Address hypoglycemia in every visit with patients at risk.
- Best treatment includes:
- Patient education and empowerment
- Frequent SMBG
- Flexible insulin (or other drug) regimens
- Regular professional guidance and support
- Iindividualized glycemic goals based in part on the risk of hypoglycemia.
- Hypoglycemia unawareness should be recognized and addressed by less aggressive glycemic goals.
- Any form of CHO that contains glucose should be effective, such as sugar-containing food or beverage that can be rapidly absorbed:
- Using the "rule of 15": is an easy way to teach patients to manage hypoglycemia at home. "Rule of 15": 15 to 20 g CHO (~60 to 80 calories simple CHO) repeated q15min until blood sugar is ≥70 mg/dL.