November/December 2019 Issue

Game-Changing Meds for Severe Hypoglycemia
By Hope Warshaw, MMSc, RD, CDE, BC-ADM, FAADE
Today’s Dietitian
Vol. 21, No. 11, P. 24

The FDA’s recent approvals of innovative treatments will help more people with diabetes be better prepared.

It was 2007, the year Mark defended his dissertation to earn his PhD in psychology. His decision to become a psychologist who specialized in diabetes, rather than a lawyer, was influenced by his own diagnosis of type 1 diabetes several years earlier.1

Now it was time to celebrate. Mark hosted a party at his home where he was surrounded by lots of friends and good food. To prepare for the party, he recalls taking a decent dose of rapid-acting insulin, figuring he would graze on the wide variety of food throughout the evening. Instead, Mark spent most of his time socializing with guests and not grazing on food. Hours later, after the party ended, he went to bed and fell asleep. While he was asleep, his blood sugar dipped dangerously low, and he was unable to regain consciousness. When his girlfriend noticed him sweating and making jerking motions, she called the paramedics. They arrived quickly and treated his severe hypoglycemia. The paramedics didn’t take him to the emergency department, since Mark’s blood glucose slowly rose and his symptoms subsided.

Severe Hypoglycemia
To be sure, all episodes of diabetes-related hypoglycemia require treatment, but level 1 (blood glucose <70 mg/dL but ≥54 mg/dL) and level 2 (blood glucose <54 mg/dL) hypoglycemia (see table on page 29), don’t warrant a medical emergency, as they usually can be treated with a source of glucose or carbohydrate either by the person with diabetes or a caregiver, depending on age and capabilities. Severe hypoglycemia (defined as level 3 hypoglycemia) does constitute a medical emergency. The person with diabetes may be unable to safely consume glucose or carbohydrate; may be unconscious, as in Mark’s case; or may be having a seizure. The bottom line: They need assistance.

The go-to treatment for severe hypoglycemia since 1960 has been one of two FDA-approved available glucagon kits: Eli Lilly’s Glucagon Emergency Kit or Novo Nordisk’s GlucaGen HypoKit. The kits are similar. They contain two items: a needle filled with diluent and a vial of glucagon powder. The diluent is injected into the powder, mixed, drawn into the syringe, and given subcutaneously as a full dose (1 mg/mL) or one-half the dose for individuals who weigh less than 44 lbs. Though the American Diabetes Association recommends that people at risk of level 2 hypoglycemia be prescribed a kit, many people, particularly adults, don’t get a prescription, or get one initially and don’t remember to check the expiration date.2 This is due in part to the challenging nature of using the kit in a stressful situation and the need for a non–health care provider (eg, parent, school nurse, athletic coach, coworker) to use it. “The older glucagon formulations require too many steps and are complicated to use, especially in an emergency, life-threatening situation,” says Diana Isaacs, PharmD, BCPS, BC-ADM, CDE, clinical pharmacy specialist at the Cleveland Clinic Diabetes Center in Cleveland and the American Association of Diabetes Educators’ 2020 Diabetes Educator of the Year.

60-Year Innovation Drought Now Over
Fast-forward to August 2019 when the FDA approved the first of potentially three treatments for severe hypoglycemia that are much easier to carry and administer. Then, just one month later, the FDA approved a second easier-to-use treatment available in two forms. Now, being prepared to treat severe hypoglycemia has a new look and feel for the person with diabetes and, more importantly, for the person who may be called on in an emergency to use it. “They’re a total game-changer because they’re so simple to use,” Isaacs says.

Developing these new products didn’t happen overnight. They were a decade or two in the making. For starters, “It’s very challenging to make glucagon stable in a ready-to-use formulation,” Isaacs continues. “Glucagon is a peptide that isn’t stable for long periods in an aqueous solution.” In addition, it takes years and dollars to conduct the research studies required to file a New Drug Application with the FDA and global regulatory bodies.3 Then, the company must develop a system to bring the product to market. Countless steps and significant expertise must be taken to accomplish each milestone. “I’m grateful that several companies have taken on this challenge,” Isaacs says.

The Three Innovative Treatments
The two companies that developed easy, ready-to-use glucagon for severe hypoglycemia are Eli Lilly and Company and Xeris Pharmaceuticals, Inc. The FDA recently approved these two products. Zealand Pharma currently is developing an innovative treatment. Following are the details of each of the new or potentially new medications.

Manufacturer: Eli Lilly
Website for product: www.baqsimi.com
Medication name: Generic, (glucagon) nasal powder; trade, BAQSIMI (pronounced BAK-see-mee)
Dosing: Single, fixed 3-mg dose in a tube. Ready to use. One-time use. No reconstitution or priming. No need for refrigeration. Keep in shrink-wrapped tube until ready to use to keep dry and unexposed to moisture.
Shelf life: 18 months from date of manufacture
Route of delivery: Absorbed passively in the nose (not an injectable)
Mechanism of action: Acts like the hormone glucagon that’s secreted from pancreatic alpha cells. Glucagon raises the concentration of glucose by activating hepatic glucagon receptors. This, in turn, stimulates glycogen breakdown in the liver and release of glucose into the blood stream.
Indication: Treatment of severe hypoglycemia in people with diabetes
Adverse reactions (possible): Nausea and/or vomiting (common side effects of glucagon administration), headache, runny nose (see website for others)
FDA approval/status: Approved July 24, 2019, for individuals aged 4 and older (not tested in younger children)
Cost/savings coupons: Lilly is trying to make BAQSIMI available to people at limited cost. Encourage clients and others to sign up for the Got Your BAQ program at www.baqsimi.com/patient-support.  

Manufacturer: Xeris Pharmaceuticals, Inc
Website: www.gvokeglucagon.com (consumers); www.gvokeglucagonpro.com (health care providers)
Medication name: Generic, glucagon injection (liquid stable glucagon); trade, Gvoke (uses patented XeriSol technology to prevent the peptide glucagon from breaking down)
Dosing: Two dosage forms. Gvoke HypoPen (autoinjector) will be available in 2020. The needle in the autoinjector pen retracts and autolocks after use and isn’t visible during administration; and Gvoke PFS (prefilled syringe) is available late October/early November 2019. The form prescribed is based on prescriber and personal preference. Premeasured and prefilled ready-to-use in two doses, adult: 1 mg; younger than age 12: 0.5 mg. Can be purchased in 1- or 2-pack.
Shelf life: 24 months from the date of manufacture
Route of delivery: Subcutaneous injection
Mechanism of action: Same as BAQSIMI (see above)
Indication: Treatment of severe hypoglycemia in people aged 2 and older
Adverse reactions (possible): Nausea and/or vomiting (common side effect of glucagon administration)
FDA approval/status: Approved September 10, 2019, for individuals aged 2 and older
Cost/savings coupons: Gvoke PFS may be available with a copay at no cost through the end of 2019. Not valid for prescriptions reimbursed under Medicaid, a Medicare drug benefit plan, Tricare, or other federal or state health programs (such as medical assistance programs).

Manufacturer: Zealand Pharma
Website: www.zealandpharma.com
Medication name: Dasiglucagon HypoPal rescue pen
Dosing: One dose for all ages, pending FDA approval: 0.6 mg. Two forms: ready-to-use prefilled syringe and autoinjector (needle isn’t visible during administration).
Route of delivery: Subcutaneous injection
Mechanism of action: Same as BAQSIMI (see page 27)
Indication: Treatment of severe hypoglycemia (age range not yet determined)
Adverse reactions (possible): Undetermined
FDA approval/status: Company expects to file New Drug Application submission in early 2020, with earliest approval likely early 2021.3

Drugs in the Pipeline
Xeris Pharmaceuticals, Inc, and Zealand Pharma have related products in their pipeline of interest to RDs.

Xeris currently is investigating the use of a much smaller dose of their liquid-stable glucagon for people who struggle with postbariatric hypoglycemia, which can result in recurrent episodes of severe hypoglycemia after meals; this condition occurs more often in people who have had the Roux-en-Y surgery. This application is being studied in a small, double-blinded, placebo-controlled phase 2 study.4 FDA filing and approval is several years away.

Zealand is collaborating on another application for dasiglucagon. The formulation would be a 1-mL cartridge containing 4 mg for use in Beta Bionics’ iLet, the pocket-sized, dual-chamber, autonomous glycemic control system intended to mimic a biological pancreas.5 Currently, there’s no liquid-stable glucagon approved by the FDA to use in this type of delivery system. A phase 2 study comparing the performance of the dual-hormone with the insulin-only system may start soon. For approval and use, the FDA would need to approve both Zealand’s dasiglucagon and the delivery device.

Three New Levels of Hypoglycemia Defined
Hypoglycemia is the major limiting factor to achieving glycemic control (including both A1c and daily glucose levels) in people with diabetes who are prescribed one or more blood glucose-lowering medication that can cause hypoglycemia (see “Determining Hypoglycemia Risk” sidebar).2 For years, hypoglycemia was classified as mild, moderate, and severe. In 2017, the definitions changed to level 1, level 2, and level 3, based on a consensus statement from leading diabetes organizations (see table on page 29).6

Glycemic goals and the prevention or minimization of hypoglycemia may be different for young children with type 1 diabetes and older people with type 1 or type 2 diabetes. Both groups are at higher risk of hypoglycemia due to their inability or reduced ability to recognize the symptoms and communicate their needs for treatment. Recent publications discuss these increased risks, different glycemic targets, and strategies to minimize hypoglycemic events in pediatrics.7-10

The American Diabetes Association recommends health care providers ask everyone at risk of hypoglycemia about symptomatic and asymptomatic hypoglycemia at each visit (see “Determining Hypoglycemia Risk” sidebar).2 That’s because at any time through the years of managing diabetes, people’s risk of any level of hypoglycemia can change. In fact, the risks of severe hypoglycemia increase over time because the potential for hypoglycemia unawareness rises as a person’s duration of diabetes increases.

Take Action
The cadre of new severe hypoglycemia treatments are a game changer. Make sure your clients at risk of severe hypoglycemia know about them. Encourage them to ask their health care provider for a prescription so loved ones and others in their circle of life may be prepared to treat an episode of severe hypoglycemia.

Stephen Shaul, a person who’s had type 1 diabetes for 28 years, and his wife, Maureen, have taken this step. Stephen filled a prescription for BAQSIMI just after it was initially stocked on his pharmacy’s shelf. Reflecting on this treatment evolution, Stephen says, “I’ve had a glucagon kit at home for many years, and my wife Maureen was trained on it. But we’ve never used it.” Maureen says, “The idea of going through the many steps to properly use it while watching Stephen under duress was never a viable option. Calling 911 was preferable.”

Stephen adds, “While we hope we’ll never have to use BAQSIMI, we already feel we have a treatment that Maureen, or anyone for that matter, can easily use. Now we feel more prepared than ever before.”

Stephen and Maureen run Champion Athletes with Diabetes, in which they award medals to people with diabetes who meet their big or small athletic goals. Learn more at https://happy-medium.net/calling-all-athletes-with-diabetes-heres-your-award.

— Hope Warshaw, MMSc, RD, CDE, BC-ADM, FAADE, is owner of Hope Warshaw Associates, LLC, a diabetes- and nutrition-focused consultancy based in Asheville, North Carolina. She’s the author of numerous books published by the American Diabetes Association. Warshaw served as the 2016 president of AADE and currently serves on the board of the Academy of Nutrition and Dietetics Foundation as secretary.

Hope Warshaw, MMSc, RD, CDE, BC-ADM, FAADE, reports the following relevant disclosure. She provided consulting services to Locemia Solutions, the developer of BAQSIMI, before Eli Lilly purchased it in 2015. On behalf of the American Association of Diabetes Educators, she serves on the steering committee for the Endocrine Society’s Hypoglycemia Prevention Initiative.

References
1. Warshaw H. Making lemonade from lemons: meet PWD Mark Heyman, PhD, CDE. https://www.tandemdiabetes.com/blog/post/general/2019/09/13/making-lemonade-from-lemons-meet-pwd-mark-heyman-phd-cde. Published September 12, 2019.

2. American Diabetes Association. 6. Glycemic targets: standards of medical care in diabetes - 2019. Diabetes Care. 2019;42(Suppl 1):S61-S70.

3. New Drug Application (NDA). Food and Drug Administration website. https://www.fda.gov/drugs/types-applications/new-drug-application-nda. Updated June 10, 2019. Accessed September 5, 2019.

4. Glucagon ready to use (RTU) in subjects with hyperinsulinemic hypoglycemia after bariatric surgery. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03770637?term=glucagon+PBH&rank=2. Updated June 6, 2019.

5. Beta Bionics website. https://www.betabionics.com/. Accessed September 7, 2019.

6. Agiostratidou G, Anhalt H, Ball D, et al. Standardizing clinically meaningful outcome measures beyond HbA1c for type 1 diabetes: a consensus report of the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange. Diabetes Care. 2017;40(12):1622-1630.

7. American Diabetes Association. 13. Children and adolescents: standards of medical care in diabetes - 2019. Diabetes Care. 2019;42(Suppl 1):S148-S164.

8. American Diabetes Association. 12. Older adults: standards of medical care in diabetes - 2019. Diabetes Care. 2019;42(Suppl 1):S139-S147.

9. LeRoith D, Biessels GJ, Braithwaite SS, et al. Treatment of diabetes in older adults: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1520-1574.

10. Academy Nutrition and Dietetics, Diabetes Care and Education Dietetic Practice Group. Navigating care for the older adult with diabetes. On the Cutting Edge. 2019;40(2):1-39.