Preventing and Managing Hypoglycemia in Patients with Diabetes

(full update August 2024)

Hypoglycemia is a serious concern in patients with diabetes. Hypoglycemia can cause irreversible cognitive impairment, dementia, falls, vehicular accidents, other injuries, and death.1 The table below addresses common clinical questions about hypoglycemia in patients with diabetes.

Clinical Question

Suggested Approach or Resource

Which patients are at highest risk of hypoglycemiaa?
  • Major risk factors (i.e., those posing high risk of level 2 or 3 hypoglycemiaa) for patients receiving insulin or secretogoguesd (per ADA).28
    • level 2 or 3 hypoglycemia episode within the past three to six months*
    • intensive insulin therapy
    • hypoglycemia unawareness
    • end-stage kidney disease
    • cognitive impairment
    • socioeconomic factors (food insecurity, low income, homelessness, religious fasting)
  • Major risk factors for level 3 hypoglycemiaa for patients receiving insulin or sulfonylureas (per Diabetes Canada): history of severe hypoglycemiaa, hypoglycemia unawareness, older age/frailty, low (<7%) or high A1c, long duration of insulin use or diabetes, neuropathy, adolescent, pregnancy, preschool age, cognitive impairment, low health literacy, low economic status/food insecurity, chronic kidney disease24
  • Other risk factors (per ADA):
    • Multiple recent episodes of level 1 hypoglycemiaa, basal insulin use, age ≥75 years, female, variable glycemic control, multiple medications, cardiovascular or chronic kidney disease, neuropathy, retinopathy, depression, low health literacy, substance use disorder28
  • Certain medications may affect perception or response to hypoglycemia:7
    • Beta-blockers, especially noncardioselective agents: may blunt adrenergic symptoms (e.g., anxiety, palpitations, sweating, shaking) and impair counterregulatory response.7 Patients can still feel faint, dizzy, confused, sleepy, weak or irritable, or have problems with speech or vision.2,7 They might also have a headache.2
    • SSRIs (may alter perception of hypoglycemic symptoms)7

What are the symptoms of hypoglycemia?
  • Symptoms can be classified as autonomic (neurogenic) or neuroglycopenic.2
    • Autonomic: shakiness, tachycardia, sweating, anxiety, hunger, nausea, tingling
    • Neuroglycopenic: difficulty concentrating or speaking, confusion, weakness, dizziness, drowsiness, headache, vision changes

Do analog insulins pose a lower risk of hypoglycemia?
  • Basal analogs pose a lower risk of hypoglycemia than NPH insulin. Insulin degludec and insulin glargine
    300 units/mL pose a lower risk of hypoglycemia than insulin glargine 100 units/mL or insulin determir.24
  • Rapid-acting analogs are preferred over regular insulin to reduce hypoglycemic risk in patients with type 1 diabetes.27

What resources are available to help educate patients about hypoglycemia?

From the American Diabetes Association:

  • Understanding and Managing Low Blood Glucose (Hypoglycemia): https://diabetes.org/living-with-diabetes/treatment-care/hypoglycemia

From Diabetes Canada:

  • Hypoglycemia Low Blood Sugar in Adults: https://www.diabetes.ca/diabetescanadawebsite/media/managing-my-diabetes/tools%20and%20resources/hypoglycemia-low-blood-sugar-in-adults.pdf?ext=.pdf

How can hypoglycemia

be prevented?
  • Patients should be educated to manage situations that put them at risk of hypoglycemia: fasting, delayed meals, alcohol use, exercise, or sleep.28 For example:
    • Patients should be educated about adjusting insulin and/or secretagogued use and carbohydrate intake for exercise.1
    • Patients on intensive insulin should periodically check nighttime fingersticks at a time corresponding to peak overnight insulin effect, to identify need for regimen change.2
  • Ask about any hypoglycemic episodes at each visit.28
  • Individualize glycemic targets
    • Choose a preprandial glucose target that balances glycemic control and risk of hypoglycemia: 80 to 130 mg/dL
      (4.4 to 7.2 mmol/L) [Evidence level B-3].28
    • An A1c goal of <7% may not be appropriate for patients with recurrent or severe hypoglycemia,a especially older adults treated with insulin or a secretagogue.d,24,28 Consider a goal of <8% (ADA) or ≤.8.5%) for such patients.11,28
  • Re-think the treatment regimen if the patient experiences hypoglycemia unawareness, recurrent hypoglycemia, or level 2 or 3 hypoglycemia.a,24,28
  • Use agents other than insulin or a secretagogued for type 2 diabetes when possible.24
  • For patients with hypoglycemia unawareness, target glucose should be increased to avoid hypoglycemia for several weeks to three months to help restore awareness.24,28
  • Prescribers, the patient, and caregivers should monitor cognitive function.28
  • Consider continuous glucose monitoring for insulin-treated patients and others at high risk for hypoglycemia.24,28
  • Be watchful for medications that might cause hypoglycemia (e.g., quinolones, tramadol).15,16

What is the general approach to treatment of hypoglycemia?

 

 
  • If the patient is conscious, give glucose 15 to 20 g (20 g if severea) if blood glucose <70 mg/dL (3.9 mmol/L).24,28 See footnote b for glucose source examples. Repeat glucose 15 g in 15 minutes if blood glucose still <70 mg/dL
    (3.9 mmol/L).24,28
  • If the patient is unconscious, or unwilling to cooperate with oral intake, give glucagon IM, SC, IV, or intranasal (route of administration is product-specific [see below]).24,28 If intravenous access is available, 20 to 50 mL of D50W
    (i.e., 10 to 25 g of glucose) over one to three minutes can be given.24
    • It may take five to 15 minutes for the patient to regain consciousness after glucagon administration.4 Turn the patient on their side; they may vomit.4.6 Call emergency services (911).6,9 Glucagon may be repeated in 15 minutes while waiting for emergency help.6
  • Once hypoglycemia is reversed, the patient should eat their usual meal, or snack if the usual mealtime is >1 hour away.24 The snack should consist of carbohydrate (15 g) plus protein (e.g., seven crackers plus a piece of cheese, or a slice of bread plus two tablespoons of peanut butter).2,5
  • Patients taking acarbose or miglitol (Glyset, US) must use oral glucose (one tablespoon honey or one cup non-fat milk if unavailable) or glucagon.2,3,13

Which patients should have a glucagon product on hand?
  • All patients using insulin or those with one major risk factor or multiple other risk factors for hypoglycemia (Canada: patients using insulin or at risk of level 3 hypoglycemiaa) should have unexpired glucagon or dasiglucagon (Zegalogue; US only) on hand.24,28
    • The patient’s caregiver or frequent contacts (e.g., family, friends, school personnel, roommate, coworker, correctional officer) should be told where it is and how to use it.24,28

How should glucagon products be stored?

Baqsimi

  • Keep Baqsimi in its shrink-wrapped tube to protect it from moisture.9,19
  • Avoid storing where the temperature may exceed 86oF (30oC).9,19 Baqsimi has a 24-month shelf-life from date of manufacture.8,21

Glucagon emergency kit (glucagon powder; requires reconstitution with included diluent)

  • Store at 68oF to 77oF (20oC to 25oC), with excursions to 15oC to 30oC (59oF to 86oF) allowed (i.e., USP controlled room temperature).29,30
  • Fresenius Kabi (US) product may be stored for up to 24 months (or up to expiration date, whichever is first) in original packaging to protect from light.29

Gvoke HypoPen, Gvoke PFS, or Gyoke kit (vial and syringe)(US)

  • Store at 68oF to 77oF (20oC to 25oC), with excursions to 15oC to 30oC (59oF to 86oF) allowed.17 Store Gvoke HypoPen and Gvoke PFS in the sealed pouch.17 Gvoke HypoPen shelf-life is ≤24 months from date of manufacture for the pen for children 2 to <12 years of age, and ≤30 months for the pen for patients ≥12 years of age.20

Zegalogueprefilled syringe, Zegalogue autoinjector (US)

  • Store in refrigerator (36°F to 46°F [2°C to 8°C]). May be stored for up to 12 months at room temperature between 68°F and 77°F (20°C and 25°C). Do not return Zegalogue to the refrigerator once it has been removed.22
  • Store in protective case provided and protect from light.22

How do newer glucagon products compare to traditional glucagon kits?

 

Ease of use

  • Traditional glucagon kits provide a powder that requires dilution with a syringe and needle to add diluent.
    • The dose must be drawn up into the syringe and injected IM or SC in the upper arm, thigh, or buttocks, or IV.29,30
    • Fresenius product (US): half the usual dose (i.e., 0.5 mg instead of 1 mg) must be given to children <25 kg (or if weight unknown and <6 years of age).29 Amphastar generic: dose is 0.5 mg (or 20 to 30 mcg/kg) for children weighing <20 kg.30
  • Autoinjectors (US only)
    • Gvoke HypoPen is a prefilled autoinjector for SC administration.17
      • Administered by pushing the autoinjector down on the skin of the lower abdomen, outer thigh, or outer upper arm for five seconds.17 A window on the injector turns red when the dose has been administered.17
      • Available in two strengths: 1 mg and 0.5 mg.17 The dose is 1 mg for patients ≥12 years of age and for patients 2 to <12 years of age who weigh ≥45 kg.17 The dose for patients <45 kg who are 2 to <12 years of age is 0.5 mg.17
    • Zegalogue is available as a prefilled autoinjector for SC administration.22
      • Administered by pushing the autoinjector down on the skin of the lower abdomen, buttocks, front or back of thigh, or outer upper arm until the yellow needle guard is fully pressed down (there may be a click) and holding for ten seconds.22 A window on the injector turns red when the dose has been administered.22
      • The dose (0.6 mg) is the same for all patients ≥6 years of age.22
  • Prefilled syringes (US only)
    • Gvoke PFS is a prefilled syringe for SC administration.17
      • Administered by removing the cap, pinching the skin at the injections site (lower abdomen, outer thigh, outer upper arm), inserting the needle into the skin at a 90o angle, and pushing the plunger.17
      • Available in two strengths: 1 mg and 0.5 mg.17 The dose is 1 mg for patients ≥12 years of age and for patients 2 to <12 years of age who weigh ≥45 kg.17 The dose for patients <45 kg who are 2 to <12 years of age is 0.5 mg.17
    • Zegalogue is available as a prefilled syringe for SC administration.22
      • Administered by removing the cap, pinching the skin at the injection site (lower abdomen, buttocks, front or back of the thigh, or outer upper arm), inserting the needle into the skin at a 45°angle, and pushing the plunger.22
      • The dose (0.6 mg) is the same for all patients ≥6 years of age.22
    • Baqsimi is a single-use, ready-to-use intranasal powder.9,19
      • Administered by inserting the device tip into one nostril, then depressing the plunger until the green line on the plunger is no longer visible.9,19
        • Inhaling is not required.9,19 Nasal congestion or decongestant use does not affect absorption.9,19
      • The dose (3 mg) is the same for all patients ≥4 years of age.9,19
      • A demo product is available for US prescribers. Contact Eli Lilly at 800-545-5979.

Costc

  • US: Gvoke HypoPen ($316.04), Gvoke PFS ($316.04), Baqsimi ($289.20), Zegalogue ($309), glucagon emergency kit (~$280). Gvoke PFS, Gvoke HypoPen, Baqsimi, and Zegalogue are available in a two-pack.
  • Canada: Baqsimi ($166.37). The Amphastar US glucagon product has “designated drug” status in Canada at least through 2024.31 No Canadian cost was available at time of writing.

Efficacy

  • There are no head-to-head studies of Baqsimi, Gvoke (US), and Zegalogue (US).23
  • Time to administer Baqsimi, Gvoke, and Zegalogue is faster than for traditional glucagon products.23 Administration errors are likely with traditional IM injection (e.g., incomplete reconstitution or injection, injection of diluent alone, bent needle, etc).10,18
  • Baqsimi may work faster than Gvoke.23
  • In adults, traditional IM glucagon seems to raise blood glucose to above 70 mg/dL (4 mmol/L) by about four minutes faster than Baqsimi or Gvoke,but this can be offset by the time it takes to prepare injectable glucagon.10,17,18 In children <12 years of age, Baqsimi is about as fast as IM glucagon.9,19 In adults, the time to glucose recovery is similar with Zegalogue (~10 minutes) and traditional IM glucagon (~12 minutes).22
  • The maximum blood glucose achieved with Baqsimi may be lower than with Gvoke or Zegalogue, with lower risk of rebound hyperglycemia than traditional glucagon injection.23

Tolerability

  • Glucagon commonly causes nausea, vomiting, headache, and injection site reactions.13
  • Baqsimi nasal spray can also cause red, watery, and/or itchy eyes; stuffy, itchy, and/or runny nose; sneezing; and itchy throat.9,19
  • In a systematic review, there was a nonsignificant trend suggesting better tolerability with Baqsimi vs Gvoke or Zegalogue.23

Abbreviations: ADA = American Diabetes Association; IM = intramuscular; SC = subcutaneous

  1. SEVERITY OF HYPOGLYCEMIA

American Diabetes Association28

Diabetes Canada24

Level 1: glucose <70 mg/dL (4 mmol/L) but ≥54 mg/dL (3 mmol/L). Considered clinically important, even if asymptomatic.

Autonomic symptoms present, without mental status changes.

Glucose typically 3 to 3.9 mmol/L.

Level 2: glucose <54 mg/dL (3 mmol/L)

Neuroglycopenic symptoms present but without significant mental status changes.

Autonomic symptoms may or may not be present.

Glucose level typically <3 mmol/L.

Level 3: severe episode with impaired mental or physical function requiring assistance. Risk of seizures, unconsciousness, and death.

Neuroglycopenic symptoms present with significantly impaired mental or physical function.

Patient requires assistance to treat.
  1. Glucose sources (15 g):2,4,5,12,14
  • glucose tablets (usually 4 tablets; check label)
  • 1 heaping tablespoon (3 packets) of table sugar
  • 5 sugar cubes
  • Raisins (2 tablespoons)
  • 1/2 to 2/3 cup (~120 to 150 mL) of fruit juice or regular (non-diet) soft drink
  • 6 Life Savers
  • 1 tablespoon (15 mL) of honey or corn syrup
  1. Cost is wholesale acquisition cost (WAC). US medication pricing by Elsevier, accessed August 2024.
  2. Secretogogue = sulfonylurea or meglitinide (nateglinide, repaglinide)

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*
  1. High-quality randomized controlled trial (RCT)
  2. Systematic review (SR)/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*
  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. https://www.aafp.org/pubs/afp/issues/2004/0201/p548.html.]

References

  1. American Diabetes Association Professional Practice Committee. 5. Facilitating Positive Health Behaviors and Well-being to Improve Health Outcomes: Standards of Care in Diabetes-2024. Diabetes Care. 2024 Jan 1;47(Suppl 1):S77-S110. Erratum in: Diabetes Care. 2024 Apr 1;47(4):761-762.
  2. Diabetes Canada Clinical Practice Guidelines Expert Committee; Yale JF, Paty B, Senior PA. Hypoglycemia. Can J Diabetes. 2018 Apr;42 Suppl 1:S104-S108.
  3. Anon. Hypoglycemia? Low blood glucose? Low blood sugar? Clin Diabetes 2012;30:38.
  4. American Diabetes Association. Understanding and Managing Low Blood Glucose (Hypoglycemia). https://diabetes.org/living-with-diabetes/treatment-care/hypoglycemia. (Accessed August 1, 2024).
  5. Diabetes Canada. Hypoglycemia low blood sugar in adults. https://www.diabetes.ca/DiabetesCanadaWebsite/media/Managing-My-Diabetes/Tools%20and%20Resources/hypoglycemia-low-blood-sugar-in-adults.pdf?ext=.pdf. (Accessed August 1, 2024).
  6. Kaiser Permanente. Diabetes: Diabetes: how to give glucagon. Giving the shot. https://healthy.kaiserpermanente.org/health-wellness/health-encyclopedia/he.diabetes-how-to-give-glucagon.aa20664#aco2693. (Accessed August 1, 2024).
  7. John R. White; The Contribution of Medications to Hypoglycemia Unawareness. Diabetes Spectr 1 April 2007; 20 (2): 77–80.
  8. Amphastar Pharmaceuticals. Baqsimi. https://www.baqsimi.com/health-care-providers/adult/. (Accessed August 1, 2024).
  9. Product information for Baqsimi. Amphastar Pharmaceuticals. Rancho Cucamonga, CA 91730. May 2023.
  10. Yale JF, Dulude H, Egeth M, et al.. Faster Use and Fewer Failures with Needle-Free Nasal Glucagon Versus Injectable Glucagon in Severe Hypoglycemia Rescue: A Simulation Study. Diabetes Technol Ther. 2017 Jul;19(7):423-432.
  11. Diabetes Canada Clinical Practice Guidelines Expert Committee; Imran SA, Agarwal G, et al. Targets for Glycemic Control. Can J Diabetes. 2018 Apr;42 Suppl 1:S42-S46.
  12. NIDDK. Low blood glucose (hypoglycemia). Last reviewed July 2021. https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/low-blood-glucose-hypoglycemia. (Accessed August 1, 2024).
  13. Clinical Pharmacology powered by ClinicalKey. Tampa (FL): Elsevier. 2024. http://www.clinicalkey.com. (Accessed August 1, 2024).
  14. McCall AL. Insulin therapy and hypoglycemia. Endocrinol Metab Clin North Am. 2012 Mar;41(1):57-87.
  15. Murad MH, Coto-Yglesias F, Wang AT, et al. Clinical review: Drug-induced hypoglycemia: a systematic review. J Clin Endocrinol Metab. 2009 Mar;94(3):741-5.
  16. Fournier JP, Azoulay L, Yin H, Montastruc JL, Suissa S. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med. 2015 Feb;175(2):186-93.
  17. Product information for Gvoke. Xeris Pharmaceuticals. Chicago, IL 60601. December 2023.
  18. Valentine V, Newswanger B, Prestrelski S, et al. Human Factors Usability and Validation Studies of a Glucagon Autoinjector in a Simulated Severe Hypoglycemia Rescue Situation. Diabetes Technol Ther. 2019 Sep;21(9):522-530.
  19. Product monograph for Baqsimi. Eli Lilly Canada. Toronto, ON M5X 1B1. February 2024.
  20. Xeris Pharmaceuticals. Gvoke HypoPen FAQs. https://www.gvokeglucagon.com/resources/#faqs (Accessed August 3, 2024).
  21. Amphastar Pharmaceuticals/ Baqsimi. https://www.baqsimi.ca/health-care-providers/adult/. (Accessed August 1, 2024).
  22. Product information for Zegalogue. Novo Nordisk. Plainsboro, NJ 08536. January 2023.
  23. Giménez M, Khunti K, Matsuhisa M, et al. Systematic Literature Review and Indirect Treatment Comparison of Three Ready-to-Use Glucagon Treatments for Severe Hypoglycemia. Diabetes Ther. 2023 Nov;14(11):1757-1769.
  24. Diabetes Canada Clinical Practice Guidelines Expert Working Group:; Lega IC, Yale JF, et al. Hypoglycemia in Adults. Can J Diabetes. 2023 Oct;47(7):548-559.
  25. Rodriguez-Gutierrez R, Gonzalez-Gonzalez JG, Zuñiga-Hernandez JA, McCoy RG. Benefits and harms of intensive glycemic control in patients with type 2 diabetes. BMJ. 2019 Nov 5;367:l5887 [abstract].
  26. Nathan DM; DCCT/EDIC Research Group. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care. 2014;37(1):9-16.
  27. American Diabetes Association Professional Practice Committee. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2024. Diabetes Care. 2024 Jan 1;47(Suppl 1):S158-S178. Erratum in: Diabetes Care. 2024 Jul 1;47(7):1238.
  28. American Diabetes Association Professional Practice Committee. 6. Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes-2024. Diabetes Care. 2024 Jan 1;47(Suppl 1):S111-S125.
  29. Product information for glucagon. Fresenius Kabi. Lake Zurich, IL 60047. September 2019.
  30. Product information for glucagon. Amphastar Pharmaceuticals. Rancho Cucamonga, CA 91730. October 2019.
  31. Government of Canada. List of drugs for exceptional importation and sale. https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-shortages/list.html. (Accessed August 4, 2024).

Cite this document as follows: Clinical Resource, Preventing and Managing Hypoglycemia in Patients with Diabetes. Pharmacist’s Letter/Pharmacy Technician’s Letter/Prescriber Insights. August 2024. [400861]




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