Evaluation and Management of Adult Hypoglycemic Disorders

Publication Date: March 1, 2009
Last Updated: February 9, 2023

Guideline Status

This guideline has been retired by the Endocrine Society


 Workup for a hypoglycemic disorder

We recommend evaluation and management of hypoglycemia only in patients in whom Whipple’s triad—symptoms, signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised—is documented. (1, H)

Evaluation and management of hypoglycemia in persons without diabetes mellitus

Compared with a much less thorough workup, we recommend the following strategy in patients with hypoglycemia without diabetes mellitus. (1, M)
  • Review the history, physical findings, and all available laboratory data seeking clues to specific disorders—drugs, critical illnesses, hormone deficiencies, nonislet cell tumors.

  • When the cause of the hypoglycemic disorder is not evident, i.e. in a seemingly well individual, measure plasma glucose, insulin, C-peptide, proinsulin, and β-hydroxybutyrate concentrations and screen for oral hypoglycemic agents, during an episode of spontaneous hypoglycemia, and observe the plasma glucose response to iv injection of 1.0 mg glucagon. These steps will distinguish hypoglycemia caused by endogenous (or exogenous) insulin from that caused by other mechanisms. Also, measure insulin antibodies.

  • When a spontaneous hypoglycemic episode cannot be observed, formally recreate the circumstances in which symptomatic hypoglycemia is likely to occur, i.e. during a fast of up to 72 h or after a mixed meal. The findings of symptoms, signs, or both with plasma concentrations of glucose less than 55 mg/dl (3.0 mmol/liter), insulin of at least 3.0 μU/ml (18 pmol/liter), C-peptide of at least 0.6 ng/ml (0.2 nmol/liter), and proinsulin of at least 5.0 pmol/liter document endogenous hyperinsulinism; β-hydroxybutyrate levels of 2.7 mmol/liter or less and an increase in plasma glucose of at least 25 mg/dl (1.4 mmol/liter) after iv glucagon indicate mediation of the hypoglycemia by insulin (or by an IGF).

  • In a patient with documented fasting or postprandial endogenous hyperinsulinemic hypoglycemia, negative screening for oral hypoglycemic agents, and no circulating insulin antibodies, conduct procedures for localizing an insulinoma. These may include computed tomography or magnetic resonance imaging (MRI), transabdominal and endoscopic ultrasonography, and, if necessary, selective pancreatic arterial calcium injections with measurements of hepatic venous insulin levels.

  • Tailor treatment to the specific hypoglycemic disorder, taking into account the burden of hypoglycemia on patient well-being and patient preferences.


 Evaluation and management of hypoglycemia in persons with diabetes mellitus

We suggest that persons with diabetes become concerned about the possibility of developing hypoglycemia when the self-monitored blood glucose concentration is falling rapidly or is no greater than 70 mg/dl (3.9 mmol/liter). (2, VL)
Given the established long-term microvascular benefits of glycemic control, we recommend that the therapeutic glycemic goal be the lowest mean glycemia [e.g. hemoglobin A1c (HbA1C)] that can be accomplished safely in a given patient at a given point in the progression of that individual patient’s diabetes. (1, H)
We recommend that the prevention of hypoglycemia in diabetes involve addressing the issue in each patient contact and, if hypoglycemia is a problem, making adjustments in the regimen based on review and application of the principles of intensive glycemic therapy—diabetes self-management (supported by education and empowerment), frequent self-monitoring of blood glucose, flexible and appropriate insulin or insulin secretagogue regimens, individualized glycemic goals, and ongoing professional guidance and support—and consideration of each of the known risk factors for hypoglycemia. (1, M)
We recommend that both the conventional risk factors and those indicative of compromised defenses against hypoglycemia be considered in a patient with recurrent treatment-induced hypoglycemia. (1, H)
The conventional risk factors are excessive or ill-timed dosing of, or wrong type of, insulin or insulin secretagogue and conditions under which exogenous glucose delivery or endogenous glucose production is decreased, glucose utilization is increased, sensitivity to insulin is increased, or insulin clearance is decreased. Compromised defenses against hypoglycemia are indicated by the degree of endogenous insulin deficiency, a history of severe hypoglycemia, hypoglycemia unawareness, or both as well as recent antecedent hypoglycemia, prior exercise or sleep, and lower glycemic goals per se.
With a history of hypoglycemia unawareness (i.e. recurrent hypoglycemia without symptoms), we recommend a 2- to 3-wk period of scrupulous avoidance of hypoglycemia, with the anticipation that awareness of hypoglycemia will return in many patients. (1, L)
Unless the cause is easily remediable, we recommend that an episode of severe hypoglycemia should lead to a fundamental review of the treatment regimen and the glycemic goals. (1, H)
We recommend that urgent treatment of hypoglycemia should be accomplished by ingestion of carbohydrates if that is feasible, or by parenteral glucagon or glucose if it is not feasible. (1, H)

Recommendation Grading




Evaluation and Management of Adult Hypoglycemic Disorders

Authoring Organization

Publication Month/Year

March 1, 2009

Last Updated Month/Year

March 16, 2023

Supplemental Implementation Tools

Document Type


External Publication Status


Country of Publication


Inclusion Criteria

Female, Male, Adolescent, Adult, Child, Infant, Older adult

Health Care Settings


Intended Users

Nurse, nurse practitioner, physician, physician assistant


Assessment and screening, Diagnosis, Prevention, Management, Treatment

Diseases/Conditions (MeSH)

D007003 - Hypoglycemia


diabetes, hypoglycemia, hypoglycemic

Source Citation

Philip E. Cryer, Lloyd Axelrod, Ashley B. Grossman, Simon R. Heller, Victor M. Montori, Elizabeth R. Seaquist, F. John Service, Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 94, Issue 3, 1 March 2009, Pages 709–728, https://doi.org/10.1210/jc.2008-1410