Hypoglycemia in Patients With Type 1 Diabetes

US Pharm. 2023;48(11):8-12.

ABSTRACT: Diabetes is a chronic and complex disease that affects 37.3 million people in the United States. It is associated with numerous complications and often requires multifaceted and interdisciplinary management approaches to mitigate disease severity and maintain or improve quality of life. Hypoglycemia is a common and potentially life-threatening consequence of many medications used for diabetes, especially insulin in the treatment of type 1 diabetes. Strategies to prevent such serious consequences should be prioritized and discussed during patient-care interactions. Pharmacists are healthcare professionals who can provide tailored and comprehensive patient education, support resources, and therapeutic management to help achieve therapeutic goals and minimize the risk of hypoglycemia among patients.

According to the 2022 National Diabetes Statistics Report, approximately 37.3 million people in the United States (11.3% of the population) have diabetes.¹ Diabetes is a disease that results from the disruption of glucose homeostasis, which is normally regulated by a series of physiologic responses and hormones—primarily insulin and glucagon.² Glucagon elevates blood glucose to prevent low levels, while insulin decreases blood glucose when levels are elevated. In patients with diabetes, the production of insulin and/or its actions on cells of the body are disrupted and glucose remains elevated in the blood.^2,3

Type 1 Diabetes

Individuals with type 1 diabetes lack the ability to produce insulin as a result of the autoimmune destruction of pancreatic beta cells.⁴ Thus, mainstay therapy for the management of type 1 diabetes is insulin.⁵ Insulin must be carefully dosed, along with dietary and physical activity considerations, to prevent hypoglycemia since glucose counterregulatory responses are altered in patients with type 1 diabetes.^2,5 In cases of severe hypoglycemia, cognitive dysfunction (e.g., obtundation and seizures), coma, or death may occur.²

The consequences of hypoglycemia and the blunting of glucose counterregulation may present significant challenges in achieving individualized glycemic targets and preventing complications among individuals receiving insulin for the management of type 1 diabetes.⁶ In 2018, 242,000 emergency department visits and 60,000 hospitalizations in the U.S. were attributed to hypoglycemia in patients with type 1 and type 2 diabetes.^7,8 However, patients with type 1 diabetes have been found to be at increased risk for morbidity and mortality associated with hypoglycemia as a result of greater insulin use.^4,9,10 A patient with type 1 diabetes experiences an average of two symptomatic hypoglycemic events per week, one episode of severe hypoglycemia per year, and an unknown number of asymptomatic hypoglycemic occurrences.¹¹

Hypoglycemia

Hypoglycemia may be caused by a variety of factors, including changes in diet, physical activity, medications, and uncontrolled diabetes.¹² In type 1 diabetes, the mechanism of disease and insulin treatment contribute most to hypoglycemic occurrences.^12-15 It is important to note that the type(s) of insulin used and daily insulin requirements vary among patients.^5,6 TABLE 1 summarizes commonly prescribed insulin products.

The American Diabetes Association classifies hypoglycemia according to three levels but considers any blood glucose level <70 mg/dL as clinically important.^6,12 Level 1 hypoglycemia is defined as a blood glucose <70 mg/dL and ≥54 mg/dL, level 2 as a blood glucose <54 mg/dL, and level 3 as a severe event characterized by altered mental and/or physical status that requires assistance or intervention for recovery.⁶ Most individuals begin to experience symptoms (e.g., shakiness, irritability, confusion, tachycardia, hunger) as they reach level 2 hypoglycemia.^6,12 If individuals remain asymptomatic at this level, they likely have hypoglycemia unawareness.⁶

Hypoglycemia Unawareness

Hypoglycemia unawareness refers to a diminished ability to recognize symptoms frequently associated with level 2 hypoglycemia (blood glucose level <54 mg/dL).⁶ It is estimated that 25% of people with type 1 diabetes experience hypoglycemia unawareness.^8,16 As the number of hypoglycemic episodes increases, the glucose level threshold that causes symptoms will decrease, potentially leading to dangerous situations for individuals who remain asymptomatic or do not recognize the manifestations of hypoglycemia.^13,16 Hypoglycemia unawareness may result in loss of consciousness, alterations in brain and heart function, and psychological consequences (e.g., fear, anxiety, medication nonadherence).¹⁷

Recurrent Episodes

Patients with recurrent episodes of hypoglycemia develop diminished autonomic responses that may lead to further reductions in their awareness of subsequent episodes.¹³ Frequent and severe hypoglycemia in patients with type 1 diabetes is also associated with poor glycemic control and increased risk of neuroglycopenic symptoms that may progress to mental impairment, confusion, coma, or even death.¹⁸ In addition, recurrent hypoglycemic episodes can cause difficulty in achieving long-term glycemic control (i.e., hemoglobin A1C [A1C] levels).¹⁹ Although there is an unclear relationship between A1C and hypoglycemia in patients with diabetes, studies have shown that severe hypoglycemia is associated with increasing A1C levels and the development of long-term complications, such as cardiovascular diseases, retinopathy, nephropathy, neuropathy, ischemia, and dementia.^19-21

Treatment of Hypoglycemia

Treatment is warranted for all levels of hypoglycemia.^6,12 In patients who experience a sudden onset of symptoms and/or have a blood glucose level <70 mg/dL, glucose should be administered as soon as possible.^12,22 Based on the “15-15 rule,” 15 grams of carbohydrates is advised to increase blood glucose levels and/or resolve the associated hypoglycemic symptoms.^6,12,22 If levels remain low or symptoms persist after 15 minutes, an additional 15 grams of carbohydrates should be taken.^6,12,22 This should be repeated until the blood glucose level is at least 70 mg/dL, at which time a snack or a meal is recommended to prevent another episode.^12,22 Examples of drinks and snacks that patients can take immediately include 4 ounces of juice or regular soda, five to six pieces of hard candies, 1 tablespoon of sugar or honey, glucose tablets, and glucose gel.²² All patients with type 1 diabetes taking insulin should be counseled on the 15-15 rule and encouraged to carry a glucagon product for emergency situations when hypoglycemia may be life-threatening and medical attention is needed.^12,22 Currently available glucagon products are presented in TABLE 2.

Glucagon products that deliver the endogenous hormone responsible for rapidly increasing blood glucose levels include GlucaGen HypoKit (Novo Nordisk), Glucagon for injection (Amphastar), Baqsimi nasal powder (Eli Lilly), and Gvoke for injection (Xeris Pharmaceuticals). Baqsimi and Gvoke HypoPen are frequently preferred, as they provide patients more efficient delivery of endogenous glucagon via simple inhalation or autoinjection, respectively.³⁰ In March 2021, Zegalogue (dasiglucagon) was approved by the FDA as the first and only glucagon analogue for severe hypoglycemia.³¹ Like glucagon, it is composed of 29 amino acids with seven substitutions to increase physical and chemical stability in liquid media to avoid the need for reconstitution.³² In June 2023, the FDA approved another first and only medication, Lantidra (donislecel), for the treatment of adults with type 1 diabetes who are unable to approach target A1C due to current repeated episodes of severe hypoglycemia despite intensive diabetes management and education.²⁹ This therapy consists of allogeneic pancreatic islet cells that produce and secrete insulin, potentially eliminating the need for external insulin in patients with type 1 diabetes.³³  

Continuous Glucose Monitors

Self-monitoring of glucose at home using continuous glucose monitors (CGMs) is one of the most effective measures to help prevent episodes of hypoglycemia and increase glycemic time in range, which correlates with improved A1C levels.³⁴ CGMs chart and trend glucose levels in real time or intermittently and may be sent to patients’ healthcare providers via downloadable electronic files.³⁵ These devices can detect when glucose is approaching hypoglycemic levels, and alerts are delivered to patients via haptic feedback or smartphone notifications.^35,36 The use and efficacy of CGMs over A1C measurements alone in the management of diabetes have also been demonstrated in various studies.^37-39 Currently, most commonly prescribed CGMs in the U.S. are the Dexcom, FreeStyle Libre, Medtronic Guardian, and Eversense systems.⁴⁰

Conclusion

Patients with type 1 diabetes on insulin therapy are at increased risk for hypoglycemia and related challenges in achieving glycemic control. Education on proper medication use, self-monitoring of glucose, and treatment options for hypoglycemia are essential in mitigating potential consequences, and these remedies may be provided by pharmacists. Empowering patients with knowledge and strategies for the management of type 1 diabetes can lead to stronger relationships between pharmacists and patients, better patient outcomes, and improvements in quality of life.

REFERENCES

1. CDC. Gestational diabetes. December 30, 2022. www.cdc.gov/1. CDC. Diabetes in America: National Diabetes Statistics Report, 2002. www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed September 1, 2023.
2. Sprague JE, Arbeláez AM. Glucose counterregulatory responses to hypoglycemia. Pediatr Endocrinol Rev. 2011;9(1):463-73.
3. Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018;98(4):2133-2223.
4. Burrack AL, Martinov T, Fife BT. T cell-mediated beta cell destruction: autoimmunity and alloimmunity in the context of type 1 diabetes. Front Endocrinol. 2017;8:343.
5. ElSayed NA, Aleppo G, Aroda VR, et al. Pharmacologic approaches to glycemic treatment: standards of care in diabetes—2023. Diabetes Care. 2023; 46(1):S140–S157.
6. Nuha A, ElSayed NA, Grazia A, et al. Glycemic targets: standards of care in diabetes—2023. Diabetes Care. 2023;46(1):S97-S10.
7. CDC. Coexisting conditions and complications. www.cdc.gov/diabetes/data/statistics-report/coexisting-conditions-complications.html. Accessed September 1, 2023.
8. McCoy RG, Lipska KJ, Van Houten HK, Shah ND. Association of cumulative multimorbidity, glycemic control, and medication use with hypoglycemia-related emergency department visits and hospitalizations among adults with diabetes. JAMA Netw Open. 2020;3(1):e1919099.
9. Hassan A, Alaa A, Li W, et al. Incidence and prevalence of hypoglycemia in type 1 and type 2 diabetes individuals: a systematic review and meta-analysis. Diabetes Research and Clinical Practice. 2020;170.108522.
10. McCoy RG, Herrin J, Galindo RJ, et al. Rates of hypoglycemic and hyperglycemic emergencies among U.S. adults with diabetes, 2011-2020. Diabetes Care. 2023;46(2):e69-e71.
11. Cryer P. Hypoglycemia in type 1 diabetes mellitus. Endocrinol Metab Clin North Am. 2010;39(3):641-654.
12. National Institute of Diabetes and Digestive and Kidney Diseases. Low blood glucose (hypoglycemia). www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/low-blood-glucose-hypoglycemia#:~:text=Low%20blood%20glucose%2C%20also%20called,deciliter%20(mg%2FdL). Accessed September 1, 2023.
13. McCrimmon RJ, Sherwin RS. Hypoglycemia in type 1 diabetes: Diabetes. 2010;59(10):2333-2339.
14. CDC. Types of insulin. www.cdc.gov/diabetes/basics/type-1-types-of-insulin.html. Accessed September 1, 2023.
15. American Diabetes Association. Insulin basics. https://diabetes.org/healthy-living/medication-treatments/insulin-other-injectables/insulin-basics. Accessed September 1, 2023.
16. National Institute of Diabetes and Digestive and Kidney Diseases. How hypoglycemia unawareness affects people with diabetes. www.niddk.nih.gov. Accessed September 1, 2023.
17. Martín-Timón I, Del Cañizo-Gómez FJ. Mechanisms of hypoglycemia unawareness and implications in diabetic patients. World J Diabetes. 2015;6(7):912-926.
18. Briscoe VJ, Davis SN. Hypoglycemia in type 1 and type 2 diabetes: physiology, pathophysiology, and management. Clin Diabetes. 2006;24(3):115-121.
19. Zhao M, Prentice J, Mohr D, Conlin P. Association between hemoglobin A1c variability and hypoglycemia-related hospitalizations in veterans with diabetes mellitus. BMJ Open Diabetes Res Care. 2021;9(1):e001797.
20. Gorst C, Kwok C, Aslam S, et al. Long-term glycemic variability and risk of adverse outcomes: a systematic review and meta-analysis. Diabetes Care. 2015;38(12):2354-2369.
21. Snell-Bergeon J, Wadwa R. Hypoglycemia, diabetes, and cardiovascular disease. Diabetes Technol Ther. 2012;14(1):S51-S58.
22. American Diabetes Association. Hypoglycemia. https://diabetes.org. Accessed September 1, 2023.
23. GlucaGen Hypokit prescribing information. Plainsboro Township, NJ: Novo Nordisk, Inc. March 2021. www.novo-pi.com/glucagenhypokit.pdf. Accessed September 1, 2023.
24. Eli Lilly and Company. Product discontinuation update: Glucagon Emergency Kit (Glucagon for injection, rDNA origin, DIN 02243297). www.lilly.ca/en-CA/news/press-releases/22.08.25-glucagon-discontinuation-update. Accessed September 1, 2023.
25. Glucagon for injection prescribing information. Rancho Cucamongo, CA: Amphastar Pharmaceuticals, Inc. October 2019. https://amphastar.com/assets/01-025-01_12-22.pdf. Accessed September 1, 2023.
26. Baqsimi (glucagon) nasal powder prescribing information. Indianapolis, IN: Eli Lilly and Company. October 2020. https://uspl.lilly.com/baqsimi/baqsimi.html#pi. Accessed September 1, 2023.
27. Gvoke (glucagon) injection prescribing information. Chicago, IL: Xeris Pharmaceuticals, Inc. May 2023. www.gvokeglucagon.com/wp-content/uploads/2023/07/gvoke-prescribing-information-1.pdf. Accessed September 1, 2023.
28. Zegalogue (dasiglucagon) injection prescribing information. Plainsboro Township, NJ: Novo Nordisk, Inc. January 2023. www.novo-pi.com/zegalogue.pdf. Accessed September 1, 2023.
29. Lantidra (donislecel-jujn) prescribing information. Chicago, IL: CellTrans Inc. June 2023. www.fda.gov/media/169920/download. Accessed September 1, 2023.
30. American Diabetes Association. Glucagon & other emergency glucose products. https://diabetes.org/healthy-living/medication-treatments/glucagon-other-emergency-glucose-products. Accessed September 1, 2023.
31. Blair, HA. Dasiglucagon: first approval. Drugs. 2021;81(9):1115-1120.
32. Pieber TR, Aronson R, Hovelmann U, et al. Dasiglucagon—a next-generation glucagon analog for rapid and effective treatment of severe hypoglycemia: results of Phase 3 randomized double-blind clinical trial. Diabetes Care. 2021;44(6):1361-1367.
33. FDA. FDA Approves first cellular therapy to treat patients with type 1 diabetes. www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-type-1-diabetes.
34. Miller EM. Using continuous glucose monitoring in clinical practice. Clin Diabetes. 2020;38(5):429-438.
35. National Institute of Diabetes and Digestive and Kidney Diseases. Continuous glucose monitoring. www.niddk.nih.gov/health-information/diabetes/overview/managing-diabetes/continuous-glucose-monitoring. Accessed September 1, 2023.
36. Friedman JG, Matos ZC, Szmuilowicz ED, Aleppo G. Use of continuous glucose monitors to manage type 1 diabetes mellitus: progress, challenges, and recommendations. Pharmgenomics Pers Med. 2023;16:263-276.
37. Toschi E, Slyne C, Sifre K, et al. The relationship between CGM-derived metrics, A1C, and risk of hypoglycemia in older adults with type 1 diabetes. Diabetes Care. 2020;43(10):2349-2354.
38. Oliver N, Freckmann G, Gimenez M, et al. The relationship between A1C and hypoglycemia in the HypoDE Study. Diabetes. 2018;67(1):9-LB.
39. Reddy M, Gimenez M, Moscardo V, Oliver N. The relationship between A1C and hypoglycemia in the Diamond Study. Diabetes. 2018:67(1):7-LB.
40. Funtanilla VD, Caliendo T, Hilas O. Continuous glucose monitoring: a review of available systems. Pharm Times. 2019;44(9):550-553.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

To comment on this article, contact rdavidson@uspharmacist.com.