INTRODUCTION

Pharmacists and pharmacy technicians often think of medication safety in terms of human patients, families, and caregivers. But what about their pets? Companion animals are increasingly victims of preventable medication poisoning. Many of these cases start with a dropped pill, an open purse, or a topical patch worn on the skin.

 

According to the American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center (APCC), prescription and over-the-counter (OTC) drugs are in the top three causes of pet toxicities reported each year. OTC medications were reported as #1, accounting for 16.5% of all exposures, and human prescription medications as #3. Human food and drinks are at #2, with 16.1% of exposures.¹ This trend shouldn’t be surprising. Many homes contain a wide array of medications, increasing the risk of accidental pet exposure.² Our environments are filled with substances that can be fatal to a curious cat or an aimless labrador.

 

Since 2020, pet ownership in the United States (U.S.) has surged. According to the American Pet Products Association, nearly 70% of U.S. households now own at least one pet.³ As medication safety educators, pharmacists are increasingly expected to support patients as pet owners, not just as individuals. Technicians, too, often serve as the first line of communication at the pharmacy counter. Pharmacy employees might wonder, "But how am I supposed to help? I don’t treat animals." Pharmacy teams don’t have to treat animals. Pharmacy employees’ jobs include protecting the whole household—including pets. That means

• Educating pet-owning patients about safe storage and disposal
• Recognizing red flags during patient conversations
• Referring to the correct veterinary resources when exposure is suspected

 

Veterinarians can’t be the only line of defense. Poisonings can happen at home, where nearly every room poses a risk.⁴ By the time a pet reaches the animal hospital, irreversible damage may have already occurred. Pharmacy professionals are positioned to intervene upstream, at the point of medication access.

 

HIDDEN RISKS AT HOME

Pets are curious by nature. Their attraction to novel smells, crinkling containers, or flavored suspensions often leads to unintentional ingestion. If a patient says, "My dog ate my pills, but it was only a few," how would a responsible, educated pharmacy employee respond? Many pharmacy professionals would hesitate. It's easy to assume that exposure is rare or that a small amount won't matter. But the reality is that pets are exposed to human drugs every day, often in ways humans don’t think about. Understanding the routes of exposure helps pharmacy professionals anticipate risk and educate patients more effectively. Below are the three most common ways pets come into contact with toxic medications.

 

Direct Ingestion

This is the most well-known route—and often the most severe due to immediate high exposure.⁴ Examples include

• A pill falls on the floor and the pet swallows it before the owner notices
• A dog chews through a medication bottle, blister pack, or weekly organizer
• A cat licks liquid formulations left on a countertop

 

It’s reasonable to wonder, "Wouldn’t a dog spit out a bitter-tasting pill?" (like most do when given their own pills). Not necessarily. Dogs may chew through plastic out of boredom, and some drugs (like venlafaxine [Effexor] or amphetamine/dextroamphetamine [Adderall] tablets) have sweeteners or coatings that make them more palatable.

 

Secondary Exposure

Pets may lick topical medications—like estrogen creams or lidocaine patches—directly from human skin. This route is especially dangerous because it often happens without anyone noticing. For example, if a patient applies a lidocaine patch and then holds her pet for an hour, the pet could absorb significant amounts of the drug. This could happen transdermally or orally if the pet grooms after exposure.⁵

 

Toxic exposure is not only a problem for pets—it’s a problem for children. According to a review of adverse event reports collected by the Swedish Medical Products Agency, children experienced serious health effects after contact with transdermal hormone-containing products. Documented symptoms include precocious (early) puberty, accelerated growth, unresolved virilization, and female infertility.⁵ These cases highlight the need for better public awareness and clearer instructions for storage and use to protect pets and children.

 

PRO TIP: When patients pick up topical or transdermal medications, ask, "Do you have pets or children at home that come into contact with your skin or laundry?" If the answer is yes, explain the risk and recommend covering the treated area or changing clothes before interacting with pets and children. A 20-second conversation might prevent a life-threatening exposure.

 

Environmental Contamination

Improperly discarded medications or drug-laced household waste can lead to inhalation or ingestion of drug residues by pets. Trash scavenging is common—pets often ingest discarded medications, wrappers, or even tissues soaked in drug residue.⁴ Some medications are excreted in urine or feces; pets that drink from the toilet may be exposed. Pharmacy technicians can help here. During OTC purchases or casual conversations, technicians may hear, "My dog gets into everything!" That’s a red flag that indicates it’s time to include a pharmacist and educate the pet owner on trash safety, sealed storage, and disposal. Never assume a drug is pet-safe unless it has a veterinary-approved label.

 

PAUSE AND PONDER: How would you explain the difference between a pet’s metabolism and a human’s?

 

LOW DOSE, HIGH RISK

Small doses that are safe for humans can be dangerous for pets due to differences in size, metabolism, and enzyme activity. Doses of ibuprofen exceeding 250 mg/kg of body weight can cause gastric ulcers or kidney failure in a small dog or cat.⁶

 

Let’s break it down^7-9

1. Researchers develop flat dosing for medications for humans. But most cats and dogs weigh a fraction of the average human weight. A 10 lb dog or 8 lb cat might receive a lethal dose from licking a coated tablet. Sustained-release medications can remain in an animal’s system far longer than in a human’s, causing extended toxicity.
2. Pets sometimes lack the enzymes humans rely on. Specifically, cats lack glucuronyl transferase—an enzyme essential to eliminate NSAIDs, acetaminophen, and opioids—making them highly susceptible to toxicity. Studies show that dogs often excrete a portion of certain drugs—such as NSAIDs and extended-release formulations—in the feces unchanged. This highlights pets’ limited ability to metabolize and eliminate these substances compared to humans. Both species have different gastric pH levels and gut flora that can affect absorption and breakdown.

 

Counseling should address two things. First, the pharmacist should explain that pets process medications differently than humans. Second, when accidental poisonings occur, pet owners should call a veterinary poison control hotline. They have veterinarians on staff around the clock and can determine if the dose the pet consumed is dangerous. The ASPCA APCC and Pet Poison Helpline are excellent, reliable resources. These calls often prevent unnecessary vet visits and guide lifesaving intervention when minutes matter.¹⁰ The SIDEBAR provides contact information for these resources.

 

SIDEBAR: Animal-specific Poison Control Centers

Human poison control centers do not manage veterinary cases. Instead, pharmacy teams and pet owners should be aware of the following specialized services.¹⁰

ASPCA Animal Poison Control Center (APCC)
	Phone: 1-888-426-4435
	Website: www.aspca.org/apcc
	Available 24/7; staffed by veterinary toxicologists
	Fee: $95 per case (covers phone consultation and follow-up)

Pet Poison Helpline
	Phone: 1-855-764-7661
	Website: www.petpoisonhelpline.com
	Available 24/7; includes licensed veterinarians
	Fee: $89 per case (includes updates to the attending veterinarian)

 

These hotlines charge a fee because they don’t receive government funding like human poison centers do. The cost supports rapid access to board-certified veterinary toxicologists and real-time risk assessments. After the client/pet owner pays for the consultation and the poison control specialist creates a case number, there are no further costs for following up on the case. The poison control center will work with the customer and a veterinarian until the case is resolved.¹⁰ In many cases, a single call can mean the difference between a $90 consultation and a $3,000 emergency vet bill.

 

TOP OFFENDERS

In veterinary toxicology, several drug classes account for most pet poisoning cases reported to animal poison control centers every year. Table 1 describes the five categories that are critical to know and how to recognize when a pet may be at risk.^2,11,12

 

Table 1. Impact of Common Drug Poisonings on Pets^6,11,13-15

Medication Type	Common Symptoms
ADHD medications (amphetamine/dextroamphetamine [Adderall], methylphenidate [Ritalin, Concerta], lisdexamfetamine [Vyvanse])	Agitation, hyperactivity, hypertension, mydriasis (dilation of the pupil), overheating, pacing, seizures, tachycardia, tremors
Antidepressants (fluoxetine [Prozac], sertraline [Zoloft], venlafaxine [Effexor])	Agitation, diarrhea, hyperactivity, hypertension, rapid heartbeat, seizures, tremors, vomiting
NSAIDs (ibuprofen [Advil], naproxen [Aleve, Naprosyn], diclofenac [Voltaren])	Abdominal pain, black or tarry stools, diarrhea, frequent urination, increased thirst, lethargy, loss of appetite, seizures, vomiting
Opioids (hydrocodone/acetaminophen [Norco], oxycodone [Oxycontin], fentanyl transdermal patch [Duragesic], buprenorphine [Suboxone])	Collapse, coma, lethargy, low body temperature, pinpoint pupils, sedation, slowed breathing, unresponsiveness
Recreational drugs (Cannabis, cocaine, methamphetamine [Desoxyn])	Dilated pupils, disorientation, high body temperature, hyperactivity, lethargy, seizures, stumbling, tremors, vomiting
ABBREVIATIONS: CNS = central nervous system

 

SIDEBAR: Universal Early Symptoms Across Agents

• Behavioral changes – restlessness, vocalization, agitation
• Cardiovascular distress – irregular heartbeat, high blood pressure, collapse
• Gastrointestinal symptoms – vomiting, excessive drooling, diarrhea
• Hyperthermia – elevated body temperature, excessive panting, drooling
• Neurological signs – tremors, disorientation, seizures, agitation
• Respiratory changes – labored breathing, excessive panting, wheezing

 

ADHD Medications

ADHD medications are potent central nervous system (CNS) stimulants. They have a narrow margin of safety in animals and can result in life-threatening cardiovascular or neurologic complications. Fast referral is critical. The symptoms described in Table 1 may appear within two hours.¹¹

Antidepressants

Many antidepressants increase serotonin in humans and animals, which can cause serotonin syndrome in both species. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are common in homes and highly dangerous to pets.

NSAIDs

As noted above, pets metabolize NSAIDs designed for humans poorly, if at all. Cats and dogs tolerate diclofenac, ibuprofen, and naproxen poorly. These medications can cause ulcers, renal injury, or liver failure at human therapeutic doses. One important sign of toxicity is blood in vomit.⁶ Some pet owners may assume human and pet NSAIDs are interchangeable. It's important to note cats and dogs have their own species-approved NSAIDs and analgesics formulated for safer metabolism. Use of human medications without veterinary guidance can lead to serious harm.

 

Carprofen (Rimadyl) is a Food and Drug Administration (FDA) approved in dogs for osteoarthritis and soft tissue pain. It is highly protein‑bound and eliminated via hepatic metabolism, with metabolites excreted in feces and urine. Meloxicam (Metacam) is approved for use in dogs in the U.S., and in some regions for cats in single‑dose or limited regimens. In cats, it undergoes oxidative metabolism (rather than glucuronidation) with approximately 80% of the drug eliminated in feces. Robenacoxib (Onsior) is another NSAID used in cats and dogs (for short durations), with cautious use in cats due to their limited ability to detoxify NSAIDs. These formulations are engineered to match each species’ pharmacokinetics, metabolism, and safety thresholds, making them safer than human NSAIDs.¹⁶

Opioids

Topical patches pose a particular risk if chewed or licked. Naloxone access in veterinary settings has become increasingly important. A 2020 study looked at 189,594 calls to the ASPCA’s APCC involving opioids from 2006 to 2014.¹⁴ It found small, young, intact (compared to neutered) dogs living in areas with high opioid prescribing were more likely to be involved in opioid-related emergency calls. Smaller and younger dogs were at higher risk than larger and older dogs. These researchers also found veterinarians were more likely to call the poison control hotline than owners. Owners may be reluctant to report exposures to illicit opioids. The research showed a strong positive non-linear link between dog poisonings and local opioid prescription rates.¹⁴

Recreational Drugs (Marijuana, Cocaine, Methamphetamine, Psilocybin)

Tetrahydrocannabinol (THC) and stimulants affect pets differently than humans, often with prolonged or unpredictable effects. Marijuana, cocaine, and methamphetamine can cause severe toxicity.¹⁵ Pets may appear frightened or "zoned out."

 

As marijuana becomes legal in more states, accidental pet exposures are rising—and costly. Pet health insurance provider Trupanion reported 1,852 marijuana-related toxicity claims over five years, mostly from pets ingesting edibles, plants, or baked goods. Figure 1 shows poisoning rates are higher in states with legalized recreational marijuana. Since 2020, California led with 428 claims, followed by Massachusetts, New York, and Florida.¹⁷

 

Figure 1. Marijuana Toxicity-Related Claims in Dogs & Cats in 2024¹⁷

 

Pharmacists and technicians should treat any known ingestion of these medications by a pet as an urgent referral to ASPCA APCC or Pet Poison Helpline. Ideal documentation would include the brand, strength, dosage form, and time of ingestion. Pharmacy staff should encourage owners to have the information handy when calling and to take the packaging with them to the veterinarian. Even if the owner reports their pet “seems fine” hours after exposure, toxicity can be delayed or progressive and serious harm may still occur without visible symptoms. Erring on the side of caution and referring patients and their pets to a veterinarian immediately is crucial.

Other Common Toxins

Human formulations may contain excipients or flavoring agents that are hazardous to pets. Certain gabapentin oral solutions contain xylitol (also labeled as birch sugar), which is rapidly toxic to dogs in small amounts. Xylitol triggers a potent insulin release in dogs, leading to hypoglycemia within 15 to 30 minutes. Symptoms often begin with vomiting and progress to lethargy, ataxia, tremors, seizures, or collapse. In severe cases or with higher doses, liver failure can occur.¹⁸ Pharmacists must check for inactive ingredients in liquid formulations and educate pet owners about this. It is important to note that xylitol is found in many common household items, including peanut butter and sugar-free candy.

 

Dogs are commonly prescribed levothyroxine to treat hypothyroidism and typically require significantly higher doses per kilogram of body weight than humans. Dosing must be carefully titrated, with regular monitoring of serum T₄ levels to avoid under- or over-dosing. Cats experience hyperthyroidism more often, and are treated with methimazole or radioactive iodine. They rarely need levothyroxine unless iatrogenic hypothyroidism occurs. Differences in thyroid disorders, metabolism, and treatment protocols make it dangerous to assume human thyroid medication doses apply to pets.¹⁹

 

Prednisone dosages vary based on whether the animal is being treated for inflammation or for immune suppression, as higher doses are typically required for immunosuppressive effects. Cats metabolize corticosteroids differently than dogs and humans, requiring different dosing protocols and careful consideration of duration and tapering. In dogs, veterinarians commonly use prednisone to manage allergic, musculoskeletal, or autoimmune conditions. Prolonged use requires monitoring for adverse effects such as polyuria (frequent urination), polydipsia (unusual thirst), or gastrointestinal ulceration.²⁰ In cats, prescribers often prefer prednisolone (rather than prednisone) because of their reduced hepatic conversion capacity, making direct administration of the active form more effective and safer.²¹

 

Even a single tablet of acetaminophen may be enough to kill a cat. In one published case, a cat experienced acetaminophen toxicity after exposure to a single dose. The patient exhibited hallmark signs such as cyanosis and facial swelling. The case highlighted the need for rapid intervention, and the diagnostic challenge this toxicosis can present. This report highlights the narrow safety margin of acetaminophen in cats and the importance of pharmacist awareness when reviewing shared medications between humans and pets.²²

 

PAUSE AND PONDER: If a pet owner says, “My dog is acting weird today after I dropped my pill,” what specific behaviors or symptoms should prompt you to refer them to a veterinarian or poison control center?

 

CLINICAL SIGNS OF TOXICITY IN PETS

A common question a pharmacy professional might hear from a pet owner is, "How do I know if my pet is poisoned?" Often, symptoms go unnoticed until they’re severe, and by then, the window for successful treatment may have narrowed. Pharmacists and technicians can recognize red flags early.

 

This section outlines key clinical signs of toxicity in pets across various drug classes, with an emphasis on phrases owners might use when describing the issue. This helps pharmacy teams know when to probe further and when to refer to a veterinarian or animal poison control center.

Tails of Toxicity

Pets may exhibit nonspecific signs that warrant urgent attention. Since pets cannot verbalize how they are feeling, owners must rely on observation of behavioral changes or physical symptoms. Table 2 lists ways to determine if a pet is ill.

 

Table 2. Analyzing Pet Behaviors for Signs of Poisoning^{4, 23-25}

Clinical Manifestation	Points to Remember
Lethargy or weakness	The owner may say “She’s not acting like herself,” or “He’s been sleeping all day.”
Vomiting and/or diarrhea	Immediate referral is warranted, especially if it is persistent, contains blood, or is paired with other symptoms.
Loss of appetite	The owner may report the pet eating only part of the regular meal size, skipping meals, or refusing favorite treats.
Tremors or seizures	●       Often, owners see twitching, drooling, or frothing at the mouth and don’t realize the pet is experiencing a seizure. This often appears with exposure to stimulants (e.g., ADHD medications, pseudoephedrine, caffeine). ●       Pet owners should stay calm, move nearby objects so the pets cannot knock them over or harm themselves. They should not touch or restrain the animal. They should also time how long the seizure lasts.
Hyperthermia	●       Cats and dogs have a narrow normal temperature range (approximately 100-102.5°F). ●       A body temperature of above 102.5-103°F in cats and dogs is considered hyperthermic and can lead to tissue damage or organ stress. ●       Having a rectal or digital thermometer at home is important because pets don’t display fever the way humans do. The only reliable way to detect a fever in cats and dogs is by taking their rectal temperature.
Ataxia (uncoordinated movement)	The owner might say “He’s stumbling all over the place.”
Collapse or unconsciousness	●       This is an emergency situation—immediate referral is critical. ●       Advise owners to call ahead and tell the veterinary service they are on the way. If the pet is large, advise them to get help, and place the animal on a hard flat surface (i.e., an ironing board or a piece of plywood).
Changes in urination	This includes increased frequency (polyuria) or total suppression (anuria, especially with NSAID or antidepressant toxicity).

VETERINARY RESPONSE: MANAGEMENT & TREATMENT

Veterinary intervention is critical in pet poisoning cases. Most toxic exposures require decontamination, symptomatic management, and monitoring.⁷

Assessment and Diagnosis

Veterinarians rely heavily on the owner’s report. The most helpful information a pharmacy professional can encourage owners to bring to the vet includes ²⁶

• The exact name of the medication ingested
• Strength and dosage form (e.g., extended-release, chewable, liquid)
• Approximate time of ingestion
• Estimated number of pills or quantity consumed
• The observed symptoms
• The pet’s weight and species

Veterinarians perform a thorough clinical examination, medical history, and toxicology screening. They will assess the pet’s vital signs (heart rate, respiratory rate, temperature) and observe neurologic status (agitation, tremors, seizures). They will also determine if the pet is suffering with dehydration or shock, and start supportive care based on the suspected toxin and symptoms.

 

Common diagnostic tests used in suspected poisoning cases include bloodwork and biochemical panels to assess organ function, glucose levels, and electrolyte imbalances. Urinalysis is often performed to detect drug metabolites and evaluate kidney function. Imaging techniques, such as X-rays and ultrasound, help identify ingested pills. Electrocardiography is used to monitor for cardiac abnormalities.⁷

Decontamination Strategies

Removing toxins from the body prevents further absorption. Veterinarians use multiple decontamination methods based on the substance and time since ingestion. Induced emesis (causing the animal to vomit) is often used within two hours of exposure. Apomorphine (in dogs) or xylazine/medetomidine (in cats) are commonly used to induce vomiting when appropriate. Hydrogen peroxide may be used in dogs, but its use is declining due to the risk of esophagitis and gastroenteritis even at therapeutic doses.²⁵ Highly acidic or alkaline chemicals can burn the mouth and digestive tract wall if regurgitated. The veterinarian may administer activated charcoal to absorb toxins and limit further drug absorption in the gastrointestinal tract. In more severe cases, gastric lavage (stomach pumping) is performed under anesthesia, particularly for life-threatening poisonings involving opioids or stimulants.²⁵

 

PRO TIP: Pharmacy teams can emphasize that inducing vomiting at home using hydrogen peroxide or other DIY methods can be dangerous. Owners shouldn’t attempt it without veterinary instruction.

Symptom Management

Veterinary treatment focuses on stabilization and organ protection. Table 3 describes specific therapies depending on the drug involved and clinical symptoms. Outcomes depend on the timing of intervention, known or suspected dosage, and pet health status. Delayed treatment increases risks of organ damage, seizures, or fatal outcomes. Follow-up veterinary care ensures no lingering effects on liver, kidneys, or heart function.

Table 3. Pet Toxicity Treatments^15,27

Toxicity Type	Treatment	Purpose
Cardiovascular	Beta-blockers (propranolol, atenolol)	Stabilizes heart rate and blood pressure
	IV lipid emulsion therapy	Reduces systemic circulation of lipophilic drugs like THC and certain antidepressants
	Oxygen therapy and mechanical ventilation	Used in opioid-induced respiratory depression
Gastrointestinal	Gastroprotectants (sucralfate, omeprazole, misoprostol)	Prevent stomach ulcers caused by NSAIDs.
	Liver protectants (SAMe, silymarin)	Supports liver function in cases of acetaminophen or NSAID toxicity
Neurological	Cooling measures	Used in hyperthermic pets with stimulant toxicity
	Sedation (benzodiazepines, barbiturates)	Controls seizures and agitation
	IV fluid therapy	Prevents dehydration and supports kidney function
ABBREVIATIONS: IV = intravenous; NSAID = nonsteroidal anti-inflammatory drug; THC = tetrahydrocannabinol

Antidotes and Specialized Therapies

In some poisonings, antidotes are available. Table 4 lists specific reversal agents.

 

Table 4. Toxins and Their Antidotes⁷

Toxin	Antidote
Acetaminophen	N-acetylcysteine
Alpha-2 agonists	Atipamezole (in some cases)
Benzodiazepines	Flumazenil
Opioids	Naloxone

 

Use of naloxone deserves extra attention. If a pet consumes an opioid and has collapsed, lost consciousness and/or has shallow breathing, owners can administer naloxone intranasally. Ideally, owners should administer naloxone under the direction of a veterinarian, who would determine the dose. Canine police officers have naloxone on hand because they have a prescription and are given detailed instructions on how to administer it. Regardless of who administers the naloxone, pets need to be taken to emergency care immediately after receiving the dose. Owners who have opioids in the home for prescribed or recreational use should be trained to use naloxone before an emergency happens.²⁸

 

Exposures to many medications, like antidepressants or ADHD medications, have no direct antidote. Management focuses on controlling symptoms and preventing complications. While many pets make full recoveries, outcomes depend on the type and amount of drug ingested, the time between ingestion and treatment, the pet’s size and species, and access to antidotes or critical care. Some cases (e.g., extended-release ADHD medications in small dogs) can be fatal even with treatment.

 

Costs and Outcomes

Veterinary care for toxicity can be expensive. Some ER visit costs include²⁹

• ER exam: ~ $100 – $200
• IV catheter: ~ $60 – $75
• IV fluids (per bag): ~ $60 – $95
• Blood tests (basic): ~$80 – $200
• Urine tests (basic): ~$40 – $70
• X-ray (basic): ~$150 – $250
• Ultrasound: ~ $300 – $600
• Blood pressure measurement: ~ $25 – $75
• Pain medication: ~ $40 – $80
• Oxygen therapy: ~ $500 – $3,000
• Wound treatment and repair: ~ $800 – $2,500
• Emergency surgery (bloat, foreign body, hit by care, caesarian): ~ $1,500 – $5,000
• Hospitalization and monitoring:
  • 1 – 2 days (vomiting, diarrhea, seizures cases): ~ $600 – 1,700
  • 3 – 5 days (parvo, blocked cat, kidney failure): ~ $1,500 – $3,500

The Pharmacy Team’s Duty

When a poisoning occurs or is suspected, pharmacy employees can help in three ways. They can provide medication bottle labels or manufacturer information for veterinarians, reinforce that owners shouldn’t wait for symptoms to appear, and help set expectations about potential costs. A better way to deal with this issue is to implement preventive measures.

 

PREVENTION: PAWS OFF THE PILLS

Veterinary professionals stress education, secure medication storage, and responsible disposal practices to reduce the chances of pet poisonings. Pet owners are responsible for ensuring a safe environment free from toxic drug exposure.

 

Keeping drugs out of reach helps prevent accidental ingestion. Veterinary toxicologists recommend using childproof containers, since pets can easily chew through standard plastic pill bottles. Pet owners should store medications in cabinets with secure latches, as pets—especially cats—can access countertops and nightstands.³⁰ It is important to keep bags closed, because pets can get into backpacks or handbags containing loose medications.

 

Improper disposal of medications increases the risk of pet exposure. Veterinary professionals advise using take-back programs, as many pharmacies and veterinary clinics offer safe disposal services for unused medications. ​Discarded medications should be sealed in containers, such as plastic bags filled with coffee grounds or cat litter, to discourage pets from scavenging through trash bins. In some cases, the FDA recommends flushing high-risk drugs, such as opioids, to prevent exposure to humans and pets. These drugs are on the FDA's "Flush List" due to their danger if used by anyone other than the prescribed individual. Flushing these medications is only advised when a take-back option is not readily available.³⁰

COUNSELING POINTS FOR PET-OWNING PATIENTS

Pharmacists and pharmacy technicians are well-positioned to help prevent pet poisonings by proactively counseling pet-owning patients. These conversations don’t need to be long—but they need to be specific, timely, and relevant to the patient’s situation. The goal is to raise awareness, encourage safe practices, and direct patients to resources before an emergency occurs.³¹

 

Proactive counseling doesn’t just protect pets. It builds trust with patients, strengthens the pharmacist’s contribution in the community, and positions the pharmacy as a reliable source for pet-related safety guidance.³¹

 

Sniffing Out Red Flags

Counseling opportunities often arise when patients pick up medications known to be toxic to pets (e.g., antidepressants, ADHD medications, liquid gabapentin, NSAIDs, opioids). Patients may mention they have a new pet or ask about pet-related topics. Pharmacy staff may also notice a customer has pet-related OTC products in their basket (e.g., flea treatments, joint supplements, pet toothpaste). Sometimes, pets appear in the background of a telepharmacy call or accompany the owner into the store. All of these situations may prompt a discussion about medication toxicity.

Tips for Technicians

Technicians are often the first team member a patient interacts with. They can ³¹

• Ask, "Do you have pets at home?" when checking out medications
• Flag high-risk medications that are toxic to pets
• Share printed materials or magnets with animal poison control info
• Update standard operating procedures to include referral language for veterinary poison concerns
• Give a reminder at the register when a patient picks up a flavored ADHD medication
• Refer to the pharmacist any time a pet is mentioned in relation to medications

Fetch the Right Tools

• Keep a laminated cheat sheet behind the counter with common pet-toxic medications
• Use stickers on vials to warn of danger to pets (e.g., "TOXIC TO PETS – KEEP OUT OF REACH")
• Partner with local veterinary clinics to distribute safety flyers

 

PAUSE AND PONDER: What would you say to a pet owner who asks you to help them “put their dog down” because they can’t afford treatment after a drug exposure incident?

 

PETS AND PENALTIES

Accidental drug exposure in pets presents legal and ethical concerns. Pet owners must ensure their pet’s safety, while veterinarians navigate ethical obligations when treating drug-related poisonings.³²

 

Laws regarding pet poisoning vary by state, but owners can face legal consequences if their negligence results in harm. Unintentionally or intentionally exposing pets to drugs may lead to negligence claims, with owners remaining civilly liable for preventable injuries. In some states, reckless or intentional poisoning is classified as animal cruelty and can result in misdemeanor or felony charges.³² Recreational drug-related poisonings, especially those involving THC, have also brought increased legal scrutiny to pet owners in states where cannabis is legal.¹²

 

In several states, veterinary professionals are classified as mandatory reporters of suspected neglect or abuse. In cases of drug toxicity, ethical dilemmas often arise. Veterinarians must weigh client confidentiality against their duty to report suspected drug-related neglect. Some pet owners request euthanasia instead of pursuing costly treatment, raising additional ethical concerns. Legal protections for veterinarians who report drug-related neglect, such as immunity laws, are continuing to evolve.³²

Understanding the Pharmacy Boundaries

Pet poisoning incidents that stem from human medication exposure often raise legal and ethical questions for pharmacy professionals. Pharmacists and pharmacy technicians must understand their scope of practice and operate within it, while still providing meaningful support to pet-owning patients.³³

 

Pharmacists are legally bound to avoid giving direct medical advice about animal-specific treatment unless they are licensed veterinarians or have specialized training in veterinary pharmacy. Examples that are out of the pharmacist’s scope of practice include suggesting a dosage of activated charcoal or recommending OTC human medications for a pet without a veterinarian’s guidance. Doing so may open the door to legal liability, even if intentions are good.³³ Pharmacists should document counseling as they do with any human consultation when possible. The pet owner is ultimately responsible for storing their medications safely. However, pharmacy staff may bear ethical responsibility if they miss clear opportunities to prevent harm. For example, pharmacy staff must check that the medication strength and instructions align with veterinary guidance. It's a pharmacist’s duty to promote medication safety.³¹

 

With the rise in pet prescriptions being filled at human pharmacies, another legal concern has emerged. Medications like amoxicillin, gabapentin, prednisone, and levothyroxine are commonly prescribed to both humans and animals. However, the dosages, formulations, and routes of administration can differ. It is unsafe to give dogs human‑formulated gabapentin liquid—these often contain xylitol. Gabapentin for pets should only be used under veterinary supervision with a weight‑based dose.³⁴ Pharmacists must exercise due diligence in checking drug references that include veterinary considerations, such as VetMedux and Plumb’s Veterinary Pharmacy, especially when unfamiliar with a prescription’s purpose.

 

While legal boundaries are clear, ethical considerations require pharmacy staff to act with compassion, respect, and clarity. Pet owners in crisis may arrive at the counter distraught, panicked, or angry. Some may be grieving a pet’s death. If that happens, pharmacy staff must acknowledge the emotional distress and not minimize or dismiss the concerns. They can say, “We’re not veterinarians, but here’s what I can do to help.” The staff should refer owners clearly and quickly, providing poison control numbers, emergency vet locations, or printouts.

 

In cases where a pet owner requests euthanasia due to financial constraints after a drug exposure, veterinary and pharmacy professionals must respond with empathy but remain ethically grounded. A compassionate response might be: “I’m sorry you’re going through this. While I can’t give treatment advice, I urge you to contact an emergency veterinarian—there may be lower-cost options or payment plans available.” This approach balances empathy, defers clinical decisions to appropriate professionals, and reinforces that a pet’s life may still be saved with timely care.

A PET-SAFE FUTURE

In the evolving landscape of pharmacy practice and public health, one area rapidly gaining attention is the intersection of human medications and companion animal safety. The COVID-19 pandemic increased pet adoption rates and work-from-home opportunities. The overall shift in household routines has created new opportunities—and new risks—for pet exposures to toxic substances.

 

Ongoing research continues to improve diagnostic tools and treatment options for pets exposed to human medications. Future innovations include the development of rapid toxicology screening kits that allow faster, in-clinic detection of opioids, amphetamines, and antidepressants. Additionally, genetic studies on drug metabolism aim to identify species-specific sensitivities, helping to advance more personalized approaches in veterinary care.⁸

 

Many states now require cannabis products to be sold in child-resistant, often opaque, packaging to reduce the risk of accidental ingestion, particularly in children.³⁵ These measures may also help limit accidental exposures in pets. As telehealth and online pharmacy services expand, fewer patients are interacting face-to-face with pharmacists.³⁶ This limits opportunities to reinforce safe medication storage. As a result, it becomes essential for pharmacists and technicians to include safety messaging on prescription labels, auxiliary stickers, or digital communications.

Digital Defenses

Advances in technology are improving awareness, prevention, and emergency response for pet poisoning cases. Future tools include AI-powered toxicology apps that provide instant poisoning risk assessments and smart storage systems like electronic pill dispensers to prevent accidental exposures.^37,38 Wearable pet monitors may also detect toxicity through changes in heart rate or body temperature.³⁹ These innovations aim to support pet owners and veterinarians in managing drug-related emergencies more effectively.

 

Other tools are being developed to assist in identifying potential poison risks. These include the ASPCA APCC app, offering a searchable database of common toxins, and ASPCA AnTox database—a veterinary database system to help identify and characterize toxic exposure data. In the future, pharmacy software may integrate pet-safety alerts when filling medications known to be high risk. Until then, it falls on pharmacy professionals to stay educated and vigilant.

CONCLUSION

The rising incidence of pet poisonings due to human medications is more than an unfortunate trend—it’s a public health concern extending beyond species lines. Pharmacy professionals are often the first point of contact for patients navigating their own medications and their households’ safety practices. Future research will continue improving diagnosis, treatment, and toxicology education. Collaboration between veterinarians, policymakers, and pet owners remains essential to reducing risks. Let’s increase awareness and protect all members of the household—on two legs and four.

 

 

 

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INTRODUCTION

We often refer to cortisol as the “stress hormone” for good reason. The body releases it during acute, chronic, or traumatic stress as part of a fight-or-flight response. To keep the body on high alert during stressful situations, it decreases insulin and increases glucagon for quick energy, suppresses inflammation, increases blood pressure, and encourages wakefulness.¹ While this whole-body reaction can be quite useful in scenarios like running from an axe murderer or trying a new HIIT workout class, we don’t need our cortisol levels running high all the time.

 

Having excess or insufficient cortisol can cause significant damage to the body over time. Table 1 describes how high and low cortisol cause quite opposite effects.

 

Table 1. Opposing High vs. Low Cortisol Symptoms^1,2

High Cortisol	Low Cortisol
Weight gain	Unintentional weight loss & loss of appetite
Hyperglycemia	Hypoglycemia
Hypertension	Hypotension
Hirsutism	Body hair loss

 

Unraveling the HPA Axis

The adrenal glands produce cortisol and are a part of the hypothalamic-pituitary-adrenal (HPA) axis. Understanding the axis is key to knowing how the body makes and regulates cortisol.³

 

The HPA axis is a system made up of three parts named in its title: the hypothalamus, the pituitary gland, and the adrenal glands.

• When a person is stressed, the sympathetic nervous system (SNS) acts as a gas pedal to rev up the HPA axis.
• When the SNS signals the hypothalamus, it releases corticotropin-releasing hormone (CRH).
• CRH signals the pituitary gland to release adrenocorticotropic hormone (ACTH).
• ACTH signals the adrenal glands to release cortisol.
• Cortisol signals the whole body to respond to the stressful trigger.
• When the stressful event is over, the parasympathetic nervous system (PNS) acts as a brake, slowing the flow of hormones in the HPA axis.³

 

Stress upregulates a properly responsive HPA axis and rest downregulates it. Both improper upregulation and downregulation can cause health issues, manifesting as Cushing’s syndrome (CS) and Addison’s disease (AD), respectively.

 

THE “CORTISOL CRAZE”

Despite the relative rarity of diagnosed cortisol abnormalities, related hashtags on social media have racked up millions of views.⁴

 

NOTE: About 6 people in a million are diagnosed with AD and 49 people in a million are diagnosed with CS in the U.S. each year.⁵

 

The major concern for most people sharing online is chronic stress, leading to high cortisol. Low cortisol can be just as debilitating, but the Cushingoid appearance seems to be the highlight in advertising. A Cushingoid appearance is a catch-all term for the physical signs and symptoms of high cortisol, including excess weight in the face, abdomen, back of the neck, and chest, excess body hair, limb atrophy, acne, and easy bruising.^6-8 Users selling supplements and diet plans often refer to the product reducing “cortisol face” and “cortisol belly.”^9-11 “Cortisol detoxing” is another trend focused on weight loss and improved mood by reducing stress, thus reducing cortisol.¹²

 

The question is whether symptoms are severe enough to require intervention. It seems that urgent concern about cortisol itself is unproductive, but focusing on lowering daily stress may be beneficial for those in this scenario. A wide gap exists between being stressed and being diagnosed with CS (discussed in more detail below).

 

Safety and Efficacy of Select Supplements and Natural Remedies

So, if a patient comes to the pharmacy counter saying she wants to lower her cortisol, are any common supplements safe and effective? Let’s dig further into a couple of supplements touted for their ability to lower cortisol.

 

Supplement companies advertise ashwagandha for improving sleep and reducing stress and anxiety. Influencers sometimes include it on posts listing supplements to lower cortisol. Per NatMed Pro, tolerability in adults is established for a maximum dose of 1,250 mg daily when used for up to six months, and adverse effects are generally mild, including gastrointestinal (GI) upset, nausea, and drowsiness. Notably, ashwagandha should not be taken during pregnancy due to potential abortifacient effects.^13,14 Weak evidence suggests that ashwagandha may lower cortisol by reducing stress response. Small studies suggest that it may be effective for stress, anxiety, and poor sleep quality.^13,14 One meta-analysis and a small randomized control trial (RCT) found a statistically significant reduction in perceived stress, Hamilton Anxiety score, and serum cortisol levels.^15,16 However, the authors of the meta-analysis admit that it is difficult to apply these results clinically due to major differences between included studies, and the RCT only including 60 patients.^15,16

 

L-theanine is another supplement advertised as a cortisol-lowering agent. L-theanine is an amino acid found in tea leaves. Advertisements mainly highlight increased relaxation, lower stress and anxiety, and improved sleep. It is considered fairly safe, but evidence of efficacy is weak. Adult patients have tolerated doses of up to 900 mg daily used for up to eight weeks.¹⁷ It is unlikely to cause harm but the potential benefits remain murky.¹⁸

 

Lifestyle interventions promoted on social media often focus on reducing chronic stress. Things like good sleep, frequent exercise, and healthy eating can benefit everyone.¹⁹ Chronic stress can heighten cortisol levels, but this type of cortisol elevation is significantly different than having CS. Most lifestyle changes will benefit patients to some extent. (Note that although stress-reducing lifestyle changes have benefits, a patient with CS will need further medical intervention for the best outcomes.)

 

If a patient truly has symptoms of high cortisol, it is worthwhile to see a healthcare provider for a full workup. Over-the-counter supplements are not a substitute for prescription medications and monitoring by a licensed provider.

 

HIGH CORTISOL DUE TO CUSHING’S SYNDROME

Patient case: Eva is 38-year-old female patient with a past medical history of hypertension and prediabetes. She presents to the clinic reporting recent health changes. In particular, Eva says that her blood sugar and blood pressure, which she self-monitors at home, have been higher than usual lately. She also describes bruising with no known source or after events that would not have elicited a bruise in the past. When asked if there’s been any recent changes to her lifestyle or medications, Eva notes that she’s been gaining weight despite maintaining frequent exercise and a healthy diet. She feels that the weight gain is most visible in her face and abdomen.

 

PAUSE AND PONDER: Which of Eva’s symptoms are red flags? What stands out to you?

 

Pathophysiology of Cushing’s Syndrome

Patients with CS, or chronic high cortisol, either have an exogenous or endogenous cause of disease. The most common cause is several months of continuous exogenous exposure to glucocorticoids. Patients taking steroids for asthma, autoimmune disease, and other conditions may be at risk. Endogenous CS affects 2-3 people per million.⁶ About 80% of those rare cases result from an ACTH-dependent tumor, while the other 20% are associated with an ACTH-independent cause.⁶

 

The most common CS patient is a female in her 20s or 30s, although men and people of other ages can have CS.⁶ Seventy percent of patients with CS are women, and most are under the age of 50.⁷

 

Presentation and Complications

Table 2 lists common signs and symptoms that may be present in patients with CS. Encourage patients experiencing several of these symptoms to speak with a provider, especially if they are on a corticosteroid.

 

Table 2. Signs and Symptoms of CS^6-8

Rapid weight accumulation in the face (moon face), abdomen, back of the neck (buffalo hump), and chest	Red, round face
Poor wound healing	Hypertension
Hirsutism	Diabetes
Purple striae	Easy bruising
Fatigue	Blurry vision and dizziness
Muscle weakness and atrophy of limbs	Libido changes and/or erectile dysfunction
Irritability	Acne

 

NOTE: Hirsutism is excessive dark hair growth, especially on the face and body. Patients may also experience balding on their head. Striae are stretch marks, which are large, purple, and often seen on the abdomen in CS patients.⁷

 

CS can significantly reduce patients’ quality of life. Physical changes, like weight gain and excess body hair, may be embarrassing to some.⁷ Some recent studies associate psychiatric symptoms, especially depression, with the onset of CS. Most patients who experience depression with CS improve with correction of high cortisol, but depression may not completely resolve.²⁰ Untreated CS has consequences beyond the list of signs and symptoms. Table 3 lists high-risk complications that patients with active CS are at risk of developing. While they are at highest risk with active CS, some risk factors may persist after remission and require further treatment.²¹

 

Table 3. Complications of Active CS^6,21

Cardiovascular Complications	Metabolic Complications	Other
Arterial hypertension Atherosclerosis Heart failure Hyperlipidemia Thrombosis	Insulin resistance Glucose impairment Visceral obesity	Higher infection risk Myopathy Neuropsychiatric disorders Osteoporosis

 

NOTE: Due to the increased risk of infection, CS patients benefit from age-appropriate vaccines like influenza, Herpes zoster, and pneumonia.²⁰

 

Testing Cortisol Levels for CS

Clinicians have several ways to determine if a patient’s cortisol levels are above normal limits. Common test strategies include a 24-hour urinary free cortisol test, midnight plasma cortisol/late-night salivary cortisol, and dexamethasone suppression tests.²² Of note, two of the options include specific times of day for measurement. Cortisol is usually lower at night, so abnormally high measurements at night are notable. Table 4 highlights the differences between testing options.

 

Table 4. Cortisol Testing^8,22

Testing Method	Description
24-hour urinary free cortisol	Multiple urine collections over 24 hours tested
Midnight plasma/ late-night salivary	Blood or saliva level taken at night for ≥ 2 nights Saliva samples can be done at home
Overnight dexamethasone suppression test	The patient receives 1 mg of dexamethasone late at night Cortisol measured the next morning
Low-dose dexamethasone suppression test	The patient receives low-dose dexamethasone by mouth every six hours for two days Multiple urine collections starting before the first dose and continuing through the test

 

Treatment

Treatment of CS depends on the cause. For those with an exogenous source of cortisol causing the issue, tapering down or completely off the causative glucocorticoid will return cortisol to normal limits.⁷ For those with an ACTH-dependent tumor causing CS, the 2015 Endocrine Society Clinical Practice Guidelines recommend surgical removal of the tumor, if possible.²³ After surgery, a patient may have hypocortisolism, hypercortisolism, or eucortisolism. Eucortisolism does not need further treatment.²³

 

If patients experience hypocortisolism after surgery, they will require glucocorticoid replacement. Patients must be monitored every six hours for 24-72 hours after pituitary surgery for ACTH abnormalities. Use of glucocorticoids intraoperatively and postoperatively varies by institution. Providers may start glucocorticoids during surgery or wait to see if the patient starts displaying signs of adrenal insufficiency before starting glucocorticoids. All patients with a cortisol level less than 5 mcg/dL, and some with a level 10 to 15 mcg/dL, will require replacement. The recommend dosing of hydrocortisone to a physiologic level is 10 to 12 mg/m²/day in divided doses. Some institutions may use supraphysiologic replacement up to 20 mg of hydrocortisone two to three times daily with a 2- to 4-week taper.²⁴

 

Several options are available for those who don’t qualify for surgery or who continue to experience hypercortisolism after surgery. These include repeat surgery, radiation therapy, or pharmacological treatment. This continuing education (CE) will mainly focus on the pharmacologic options.

 

Three types of medications can treat CS²⁵:

• Steroidogenesis inhibitors, which block the enzymes that make cortisol.
• Glucocorticoid antagonists, which block cortisol’s action by preventing it from binding to its receptor.
• ACTH neuromodulators, which inhibit pituitary action and block the signal to the adrenals to release cortisol.

 

Table 5 provides a complete list of medications in each class.

 

Table 5. Medications Used to Treat CS²⁵

Steroidogenesis inhibitors	Glucocorticoid antagonist	ACTH neuromodulators
Etomidate Ketoconazole Levoketoconazole Mitotane Metyrapone Osilodrostat	Mifepristone	Cabergoline Pasireotide

 

Steroidogenesis inhibitors are the most commonly used medications for CS. They can be used on their own or as an adjunct treatment. See pros and cons to consider for each medication in Table 6.^23,25

 

The glucocorticoid antagonist mifepristone is used as primary therapy or after a failed surgery in patients with diabetes and/or uncontrolled high blood sugar in CS.^23,26 However, mifepristone can also be used in medical abortions. Prescribing and dispensing mifepristone can be complicated in the U.S. as a result of the indication for terminating pregnancy. More than 10 states restrict mifepristone’s use. Some ban its use entirely, while others only allow mifepristone prescriptions from certified providers and dispensing from authorized pharmacies.^26,27 Despite the controversy, mifepristone remains a highly effective treatment option for CS.^25-27 See Table 6 for more information.

 

Providers may use ACTH neuromodulators as monotherapy or an adjunct option. Cabergoline is an off-label medication for CS, but both formulations of pasireotide are FDA-approved. Pasireotide offers convenient dosing as an intramuscular injection every four weeks but comes with a high risk of hyperglycemia. Three quarters of patients managed with pasireotide require other medication for glucose management.²⁸

 

Table 6. Clinical Pearls for Common CS Medications^25,27-32

Medication	Dosing	Clinical Pearls
Steroidogenesis Inhibitors
Etomidate	0.03 mg/kg IV bolus 0.1–0.3 mg/kg/h	Off-label for CS Administered parenterally Rapid maximum effect, around 11 hours Requires intensive inpatient monitoring (not for long-term use)
Ketoconazole	TDD of 200 to 1,200 mg, split 2-3 times daily	Off-label for CS Rapid onset but can take weeks for full effect Decreases testosterone Boxed warning: liver toxicity Adverse effects include GI symptoms, gynecomastia, skin rash, edema, transient LFT elevations and rarely hepatotoxicity Monitor EKG (QT prolongation) and LFTs Requires low gastric pH for absorption Major CYP3A4 substrate and strong inhibitor, potential for significant drug interactions
Levoketoconazole	TDD of 300 mg to 1.2 g, split BID	Monitor EKG (QT prolongation) and LFTs Most common adverse events include GI symptoms, headache, arthralgias, myalgias, and fatigue Major CYP3A4 substrate and strong inhibitor, potential for significant drug interactions
Mitotane	TDD of 500 mg to 8 g, split TID	Off-label for CS Teratogenic Maximum effect after 2-3 months of treatment Adverse effects include GI symptoms, impaired mentation and dizziness, gynecomastia, rash, elevated LFTs, and hypercholesterolemia Almost 30% of patients discontinue treatment due to adverse effects Give largest dose in the evening
Metyrapone	TDD 500 mg to 6 g, split up to 4 times daily	Off-label for CS Cortisol levels decrease within two hours of administration May be used with caution in pregnancy Take with food Adverse effects include GI symptoms, hirsutism, hypertension, and hypokalemia
Osilodrostat	TDD 2 to 14 mg, split BID Max maintenance TDD is 60 to 80 mg	Monitor EKG for QTc prolongation Initial dose adjustments for moderate-severe renal impairment Effective in hours-days Note drug interactions Adverse effects include GI symptoms, arthralgia, dizziness, hypertension
Glucocorticoid Antagonist
Mifepristone	300 to 1,200 mg once daily	FDA approved to control hyperglycemia due to hypercortisolism Also used to terminate pregnancy, providers must confirm negative pregnancy status in patients of childbearing potential prior to starting this medication Has a REMS program Monitor thyroid function Major CYP3A4 interactions Adverse effects include nausea, fatigue, headache, hypokalemia, hypertension, abnormal vaginal bleeding
ACTH Neuromodulators
Cabergoline	0.5 to 4 mg total per week, split twice weekly	Off-label for CS Requires cardiac valve monitoring Adverse events include GI symptoms and dizziness May cause psychiatric effects; not recommended with history of bipolar or impulse disorder
Pasireotide	0.3 to 0.9 mg twice daily OR 10 to 40 mg per month	BID formulation given via subcutaneous injection, monthly formulation is via intramuscular injection Maximum dose of 0.6 mg BID or 20 mg monthly in moderate hepatic impairment Monitor glucose, LFTs, EKG Not recommended in diabetes
ABBREVIATIONS: BID (two times daily), CS (Cushing's syndrome), CYP3A4 (cytochrome P450 3A4), EKG (electrocardiogram), FDA (Food and Drug Administration), GI (gastrointestinal), LFTs (liver function tests), REMS (Risk Evaluation and Mitigation Strategy), TDD (total daily dose), TID (three times daily)

 

Only patients with an established diagnosis of CS and active signs and symptoms require treatment. Patients without an established diagnosis or borderline abnormalities with no signs and symptoms are unlikely to benefit from treatment.²³

 

NOTE: Metyrapone and mifepristone appear on the ISMP List of Look-Alike drug names. Be careful not to confuse metyraPONE with metyroSINE and miFEPRIStone with miSOPROStol.³³

 

Recently Approved Agents

The adverse effects from current CS medications are less than ideal. As a result, researchers are looking for new ways to treat the disease.

 

The FDA approved osilodrostat (Istrusia), an oral medication for CS, in March 2020. Patients start on 2 mg twice daily and titrate by 1 to 2 mg every two weeks based on tolerability and clinical response. Most patients can be maintained on 2 to 7 mg twice daily and the maximum dosage is 30 mg twice daily.³⁴ It works by preventing cortisol synthesis by inhibiting the 11-beta-hydroxylase enzyme.³⁵ Clinical trials included patients who were not cured by surgery or who were not surgical candidates. In a phase 3 trial, significantly more patients in the osilodrostat group had cortisol levels within normal limits (n = 37, 77.1%) than in the placebo group (n = 2, 8%) by week 12. By week 36, over 80% (n = 40) of patients in the osilodrostat group achieved normal cortisol. As a result, the drug improved signs of CS, like weight, fasting plasma glucose, blood pressure, and cholesterol.³⁶ Common adverse effects included adrenal insufficiency, headache, nausea and vomiting, fatigue, and edema. Rare but serious adverse effects include QTc prolongation and androgen elevation.³⁵

 

Levoketoconazole (Recorlev) is another recently approved medication for CS as of December 2021. Patients start on 150 mg twice daily and titrate up by 150 mg/day every two to three weeks based on tolerability and cortisol levels. The maximum dose is 600 mg twice daily.³⁷ It is a stereoisomer of ketoconazole, which is thought to be more potent than a racemic mix. A single-armed study of 94 patients found that 31% (n = 29) of patients in the intention-to-treat population responded to treatment with levoketoconazole. Despite the increased potency allowing for a lower dose compared to ketoconazole, almost all patients (n = 92, 98%) experienced an adverse event. The most common were nausea, headache, and peripheral edema. Rare but serious events included prolonged QT interval, abnormal liver function tests, and adrenal insufficiency.³⁸

 

It is important to note that CS is considered an orphan disease due to its rarity.³⁵ RCTs are often small, with fewer than 100 patients in the population of some phase 3 trials. These new medications are not incorporated into the most recent guidelines. This is reflective of the age of the most recent Endocrine Society guidelines, which came out in 2015, not the effectiveness or appropriateness of newer medications. Use of newer medications is likely to be reflected when new guidelines come out.

 

LOW CORTISOL DUE TO AD

Patient case: Liam is a 56-year-old man who arrives at the emergency department (ED) after three days of severe nausea and vomiting. He says his wife made him come in because she’s worried that he’s dehydrated. He reveals that he has new joint pain with this illness and it’s getting worse, up to a 7/10 on the pain scale. Liam reports that he spent most of the morning sitting on the floor of his bathroom because he feels lightheaded when he stands up and is afraid that he’ll fall. The ED physician completes a physical exam and notes that Liam’s skin is darker in some areas, like his gums, palm creases, and knuckles.

 

PAUSE AND PONDER: What testing is necessary to determine the cause of Liam’s condition? Do his symptoms sound like a run-of-the-mill virus? Something else?

 

Pathophysiology of AD

AD, named after Thomas Addison who discovered the disease, is adrenal insufficiency. AD occurs when a patient’s body does not produce enough cortisol. There are three different etiologies³⁹:

• Primary: destruction of the adrenal cortex
• Secondary: insufficient production of ACTH
• Tertiary: insufficient stimulation of the adrenal gland by CRH

 

Primary AD can be either congenital or acquired. Most cases of congenital AD are linked to a genetic mutation affecting cortisol and aldosterone synthesis. On the other hand, autoimmune adrenalitis is the main cause of acquired AD. Although they remain uncommon causes in the U.S., tuberculosis and human immunodeficiency virus infections can also trigger AD.³⁹

 

NOTE: Autoimmune adrenalitis is when the immune system attacks and destroys the adrenal glands with no known reason. It takes months to years of active autoimmune adrenalitis for symptoms of AD to show.⁴⁰

 

Secondary AD is due to a deficiency in ACTH secretion or a pituitary adenoma. Pituitary adenomas tend to cause deficiencies in all pituitary hormones.³⁹

 

Tertiary AD has an exogenous cause, usually sudden withdrawal from long-term corticosteroid use. This is why tapering corticosteroids matters; slowly reducing exogenous corticosteroids allows the body to adjust and helps prevent withdrawal. Providers should also warn patients not to self-discontinue corticosteroids. Sometimes chronic opioid use can cause tertiary AD by suppression of the entire HPA axis.³⁹

 

Presentation and Complications

Table 7 lists common signs and symptoms of AD. It is important to note that primary AD tends to present with more severe symptoms than secondary AD and has aldosterone abnormalities. Patients with secondary AD still have some cortisol and aldosterone may remain normal. These patients are unlikely to experience hyperpigmentation, dehydration, or hyperkalemia. Tertiary AD differs in that patients may experience a mix of Cushingoid appearance and AD symptoms.³⁹

 

Table 7. Signs and Symptoms of AD^2,39

Fatigue	Hyperpigmentation (scars, skin creases, gums)
Abdominal pain	Nausea and vomiting
Diarrhea	Loss of appetite, unintentional weight loss
Muscle and joint pain, muscle spasms	Dehydration
Hypotension	Irritability, depression, poor concentration
Craving salty food	Hypoglycemia
Hair loss	Abnormal menstruation
Hyperkalemia	Hyponatremia

 

Patients with AD may experience acute, life-threatening symptoms during severe injury, illness, or stress. This is known as an Addisonian crisis or acute adrenal failure. Hallmarks of the crisis include extreme pain and weakness, mental status changes, severe vomiting and diarrhea, hypotension, and possibly loss of consciousness.²

 

Testing Cortisol Levels for AD

Patients with signs and symptoms of AD should undergo a corticotropin stimulation test. In the test, patients receive 250 mcg of IV corticotropin. If the patient’s cortisol does not reach at least 500 nmol/L at 30 or 60 minutes, it indicates AD. Plasma ACTH is helpful to determine if a patient’s AD is primary in nature. High ACTH indicates primary AD.⁴¹

 

PAUSE AND PONDER: What medications are available to replace cortisol?

 

Treatment of AD

AD requires steroid replacement. Treatment for primary AD is lifelong. Patients with secondary and tertiary AD may require long-term treatment with a gradual taper or treatment for life. Appropriate choices for glucocorticoid replacement include 15 to 25 mg of oral hydrocortisone or 20 to 35 mg of cortisone acetate per day. If the hydrocortisone formulation is not modified-release, patients will need to take it two to three times per day. The first dose of the day should be the largest and no more than a maximum of 10 mg. Taking a steroid close to bedtime can disturb sleep and should be avoided.^39,41

 

When possible, providers should avoid prescribing prednisolone and dexamethasone. Prednisolone has a higher risk of dyslipidemia and bone weakening compared to other glucocorticoids. The advantage, however, is the lower dosing frequency of one to two times daily, which may increase adherence. Dexamethasone has an extremely long half-life, increasing the risk of Cushingoid adverse effects significantly.^39,41

 

Monitoring and adjusting glucocorticoid treatment should be based on patients’ signs and symptoms, not hormonal monitoring. In particular, providers must track body weight, postural blood pressure, energy levels, and Cushingoid symptoms at baseline and throughout treatment.⁴¹

 

Adjusting the dose of glucocorticoids is necessary in stressful situations, like surgery, severe illness, and pregnancy. More severe conditions, like major surgery and childbirth, require higher dosing than average illnesses. Patients may develop adrenal crisis if they take the same glucocorticoid dose during more stressful times.⁴¹

 

NOTE: Mineralocorticoid replacement in aldosterone deficiency is not the focus of this CE, but it is still important to mention. Patients with primary AD require mineralocorticoid replacement, while secondary and tertiary AD do not. Destruction of the adrenal gland in primary AD creates a deficiency in all hormones it produces. Secondary and tertiary AD are related to ACTH signaling, which does not affect aldosterone production. The treatment is 0.05 to 0.2 mg of fludrocortisone each morning. Monitoring blood pressure and electrolytes is necessary.³⁹

 

NOTE: Women with primary AD may also experience adrenal androgen deficiency. This manifests as low libido, depression, and low energy.⁴¹ Dehydroepiandrosterone (DHEA) treatment may be necessary if patients still have symptoms after appropriate glucocorticoid and mineralocorticoid management. The goal is to have a normal morning serum DHEAS (sulfate-bound, stored DHEA) level.^39,41

 

Emerging Treatments

New treatments for AD have focused more on modifying hydrocortisone release to improve patient satisfaction than on coming up with a brand new drug. The hydrocortisone modified-release hard capsule (Efmody) is a newer innovation to hydrocortisone that was approved by the European Commission in 2021. It is not yet available in the U.S..⁴²

 

Clinical trials are underway for a hydrocortisone subcutaneous pump, meant to closely mirror cortisol secretion. A small trial of 21 patients tested the pump. Over 6 weeks, the pump improved patients’ quality of life subjectively. Patients reported waking up more easily, better mood upon awakening, and an overall positive mood.⁴³ Larger studies are necessary to prove the objective benefits of a pulse pump, though improvement in mood may be significant considering AD’s link to irritability and depression.

 

One of the newest innovations under development in AD treatment is implantable cell therapy. Bioprinted tissue has the potential to replace the adrenal gland’s function in primary AD patients. At this time, research is in the preclinical stage. Researchers removed the adrenal glands of mice and replaced them with bioprinted tissue in one group. When researchers injected ACTH into the mice, those with bioprinted tissue replacement responded by producing cortisol, while those with no renal replacement showed no change.^44,45 In time, bioprinted tissue may offer a permanent treatment for primary AD.

 

NOTE: Bioprinted tissue is human tissue created in a lab. The new technology involves 3D printing bioink, a mixture of live cells and material to support cell growth, to create tissues and organs.⁴⁶

 

HANDLING MISINFORMATION AND DISINFORMATION

PAUSE AND PONDER: How would you speak to a patient that asks you about an article she saw online sharing incorrect information? What if she doesn’t believe you?

 

Misinformation is information that is false, but not shared to cause harm. Disinformation is information that is false and deliberately shared to cause harm.⁴⁷

 

People who spread misinformation and disinformation may use many strategies to distract from false claims. Tactics include⁴⁸

• Emotional triggering, especially sparking fear or anger
• Treating anecdotes like facts
• Sharing old or outdated information

 

People have access to a plethora of information with the Internet. With such an overwhelming amount of information available to consume online, it can be difficult to find factual medical advice. Additionally, social media companies are lax about false posts. For example, social media sites do not take action against 95% of posts reported for COVID-19 and vaccine misinformation.⁴⁷ As healthcare providers, pharmacists can offer patients an analysis of information they find and strategies for them to evaluate information on their own in the future.

 

One popular way to break down how to address disinformation and misinformation with patients is the “Three C” approach. This involves

• Compassion
• Connection
• Collaboration

 

It is important to recognize that being a trusted source of information requires mutual respect. Communicating in a nonjudgmental and compassionate way is important. If patients think pharmacy staff are judging them for believing something incorrect, they are more likely to get defensive and close off future opportunities for discussion. Pharmacy staff should make sure patients know their intent is to help them make the best health decisions and that the conversation is worthwhile. Staff should ask patients to share more of their point of view with open-ended questions and listen.^47,49 When patients explain their point of view, it will help to pick out what matters to the patient. Cultural, individual, and social values can play a part.⁴⁷

 

Connection directly links to compassion. Pharmacy staff should speak affirmatively to patients for seeking further information on a subject and acknowledge the parts of the patient’s narrative that are true. When it is necessary to correct false information, pharmacists and technicians should focus more on the evidence behind the correction than on the fact that the patient was wrong. Staff should continue to ask patients if they have further thoughts and questions. Pharmacists and technicians can also ask patients where they get their medical information and suggest reputable resources for them to use in the future.⁴⁷

 

At the end of the discussion, collaborate with the patient on the next steps. Trying to coerce or compel the patient to agree with everything you say often backfires. Remind patients that you’re on their side when you make recommendations. Allow them to share their thoughts and ask further questions about those recommendations.⁴⁷ To improve patient health literacy and confidence, consider sharing strategies to combat misinformation in the future. Online guides written in layman’s terms, like the ones posted by San Diego Circuit libraries (https://libguides.sdsu.edu/health/avoid-misinformation) and the Department of Health and Human Services (https://www.hhs.gov/surgeongeneral/reports-and-publications/health-misinformation/index.html), can help patients analyze other misinformation they come across.^50,51

 

Given the heavy discussion of cortisol on social media, pharmacists and technicians may run into situations where patients talk about false or overstated claims. Keep compassion, connection, and collaboration in mind when this happens.

 

CONCLUSION

The adrenal glands produce cortisol, which is necessary to respond to stress. However, when the adrenals release too much or too little cortisol, it can cause serious problems. Despite the rarity of adrenal diseases, people have been discussing cortisol, especially high cortisol, on online platforms. It has become a way to advertise supplements to reverse perceived symptoms of high stress. CS is treated first with surgery or cessation of exogenous steroids when possible. Medication therapy is still important and necessary for many CS patients. AD patients require long-term glucocorticoids, which may sometimes be for life. Pharmacists play an important role in educating patients on CS and AD medications. They can also break down expectations versus the low-evidence reality with “cortisol-lowering” supplements, while still validating patient concerns.

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INTRODUCTION

 

Did you know that the ketogenic diet was NOT initially created for weight loss? Recently, the “keto” diet has become another fad diet for people trying to lose weight. Since 2000, more researchers have started to study the ketogenic diet, causing an increase in dieters who are employing this diet.¹

 

For decades, various entities have promoted fad diets as a way to lose weight and accrue other health benefits, with no data to back them up. The ketogenic diet began to reach the public’s consciousness in the 1970s, gained popularity in the early 2010s, and by 2017, it was a frequent topic in national news media. Google searches for the ketogenic diet (sometimes called the paleo diet, which is similar but not identical) quadrupled that year; questions about this diet were in the top 10 health questions.² Many people started using the ketogenic diet without understanding how it works or its associated benefits and risks. In 2014, celebrities like Lebron James, Kim Kardashian, and Megan Fox started using the ketogenic diet during its fad weight loss phase. In 2020, around 6% of Americans were consuming a ketogenic, high fat diet.³

 

In the 1920s, researchers noticed that some patients with epilepsy experienced benefits during fasting, so they discovered a way to mimic fasting to treat the disease.¹ Soon, physicians began to use the ketogenic diet for its antiepileptic properties.¹ However, in the next decades, researchers introduced antiepileptic medications and the ketogenic diet’s popularity faded. Treatment for epilepsy still includes some of the first antiepileptic medications: phenobarbital and phenytoin.⁴ Although physicians began using phenobarbital in 1912 for epilepsy, the U.S. Food and Drug Administration did not approve phenytoin for use in epilepsy until 1938.⁵ In the 1940s, clinicians used troxidone, but its toxicity profile was unacceptable. Ethosuximide, approved in 1958, replaced it. Approval of carbamazepine and valproic acid in the 1960s made the ketogenic diet unnecessary and obsolete for the most part.⁵

 

Although pharmacists are the medication experts on the clinical team, they must understand all types of treatment, including nonpharmacologic interventions. During a ketogenic diet, patients eat a limited number of carbohydrates so the body will enter ketosis. Because of the diet’s intensity, pharmacists and technicians need to understand how the diet works to ensure patient safety. When patients start or are on the ketogenic diet, pharmacists need to counsel patients to ensure no drug interactions occur. Pharmacists also need to counsel patients who may have started the diet by themselves about its benefits and the risks. Also, remember interested dieters might embrace a New Year's resolution regarding ketogenic dieting, because National Keto Day is January 5th!

 

This continuing education activity summarizes knowledge of the ketogenic diet, the diet’s mechanism and its positive and negative effects, current medical uses for patients with epilepsy, diabetes, polycystic ovary syndrome (PCOS), and others, and recommendations for patient education and counseling.

 

KETOGENIC DIET

 

The ketogenic diet alters how the body burns energy, from carbohydrates to lipids. The traditional food pyramid places fats in the smallest section at the top, with carbohydrates in the largest bottom section. The ketogenic diet flips the pyramid, so most recommended foods are fats and very few are carbohydrates.

 

According to the Dietary Guidelines for Americans, 25% to 35% of an adult’s diet should come from fats, 45% to 65% from carbohydrates, and 10% to 30% from protein.⁶ In a 2000 calorie day for ketogenic diet patients, fat should account for 70% to 80% or 165 g of daily caloric intake.⁷

 

Although an exact timeframe is unknown, researchers believe that it can take the body up to four weeks to adapt to the ketogenic diet and ketosis.⁸ Patients initiating the diet could try daily exercise to force the body to break down fats, but its efficacy for reducing time to ketosis is unknown.⁸

 

Ketogenesis

 

The ketogenic diet uses ketosis and ketogenesis. When people eat carbohydrates, the body uses cellular respiration to produce energy from breaking down glucose molecules. However, if no carbohydrates are available, which would be the case during extended exercise or fasting periods, the body will naturally enter ketosis. Ketosis is a state of elevated ketone bodies, which include beta-hydroxybutyric acid, acetoacetic acid, and acetone in the blood.⁹ When the body needs energy, ketogenesis occurs to produce these ketone bodies, which can be used as an alternative energy source.

 

In normal cellular respiration, acetyl-CoA is condensed with oxaloacetate to begin the citric acid cycle. Beta-oxidation of fatty acids can produce acetyl-CoA, similar to the production of acetyl-CoA from glycolysis of glucose. In times of reduced glucose (i.e., fasting, extended exercise, ketogenic diet), the body diverts the acetyl-CoA produced from the fatty acids into ketogenesis.

 

Ketosis begins with fatty acid oxidation and the production of acetyl-CoA. Using the enzyme 3-ketothiolase, acetyl-CoA is converted into acetoacetyl-CoA. Then, the enzyme HMG-CoA synthase converts acetoacetyl-CoA to HMG-CoA.⁹ Low glucose levels during starvation or a high fat diet—a signal that the body needs to produce an alternative energy source for the brain—trigger this step of ketogenesis.¹⁰

 

The last step of energy production during ketosis is the conversion of HMG-CoA to the ketone bodies acetoacetate (AcAc) and 3-beta-hydroxybutyrate (3HB). Using HMG-CoA lyase, AcAc and 3HB are cleaved from HMG-CoA.⁹ By being in a constant state of ketogenesis from eating fatty foods, patients on the ketogenic diet change their natural fuel source from glucose to ketone bodies.

 

Ketone Bodies

 

The 3 main types of ketone bodies are AcAc, 3HB, and least commonly, acetone. The liver produces AcAc, 3HB, and acetone in a 78:20:2 ratio, respectively, during fatty acid oxidation.¹¹ Acetone is produced the least because it’s the byproduct of the uncommon and spontaneous decarboxylation of 3HB.¹¹ Ketone bodies are the only non-glucose derived energy source for the brain.¹⁰ The brain cannot process fatty acids, so they must be converted into ketone bodies first. They provide energy to the brain because both AcAc and 3HB can diffuse across blood brain barrier.⁹

 

During a normal day, ketone bodies account for only 2% to 6% of an individual's energy requirements. However, after a three- to four-day fast, ketone bodies account for 30% to 40% of the body's energy source.⁹ The liver can produce 185 grams of ketone bodies daily, which is enough to satisfy a person’s daily energy needs.⁹

 

By using ketone bodies, patients can avoid breaking down carbohydrates as an energy source, similar to how the body naturally functions during fasting. Ketone bodies are thought to have a direct beneficial mechanism, which will be discussed later, in disorders like epilepsy.

 

Effects of Insulin and Glucagon

 

Insulin and glucagon are important in ketosis and ketone bodies. Low insulin levels trigger steps in the ketosis process. Insulin, also called the antiketogenic hormone, decreases 3HB production, whereas glucagon, the ketogenic hormone, increases 3HB production.¹²

 

When humans consume carbohydrates and blood glucose levels rise, the pancreas releases insulin to absorb the blood sugar for energy storage.¹³ Insulin inhibits hormone-sensitive lipase and HMG-CoA synthase, enzymes that take part in fatty acid breakdown. It also stimulates acetyl-CoA carboxylase, causing the conversion of acetyl-CoA to malonyl-CoA, and blocking fatty acid transport into the mitochondria.¹⁰ As a result, insulin decreases the need for fatty acid oxidation and ketone bodies are decreased. The ketogenic diet requires patients to avoid carbohydrates to diminish insulin production and promote these mechanisms.

 

Glucagon does the opposite of insulin. The body uses epinephrine and glucagon to stimulate adipose (fat) tissue to produce more fatty acid.⁹ Glucagon triggers phosphorylation of hormone-sensitive lipase and HMG-CoA synthase, thus promoting ketogenesis.⁹ The body releases fatty acids from triglycerides, so they can be broken down by the newly activated enzymes.

 

A successful ketogenic diet requires a high glucagon/insulin ratio, similar to that experienced during fasting and by patients with diabetes. The high ratio increases fatty acid production and oxidation. Ketogenesis will follow.

 

Foods Consumed

 

Most foods for a ketogenic diet will have moderate amounts of proteins, no carbohydrates, with many fats. To prevent heart disease, physicians and pharmacists can counsel patients to eat healthy fats. Table 1 describes some examples of foods that are common in the ketogenic diet.

 

Table 1. Food Options Commonly Used in the Ketogenic Diet¹⁴

Fish and Seafood	-        Full of protein -        No carbs -        Associated with positive cardiovascular and health benefits
Poultry and Meat (Chicken, beef)	-        Rich in protein -        No carbs -        Limit processed meats
Nuts (Almonds, walnuts, pecans, cashews)	-        High in fiber, protein, and unsaturated fats -        Very low carbs -        Antioxidants
Non-starchy Vegetables (Broccoli, green beans, bell peppers)	-        Include other vitamins and nutrients -        Antioxidants
Cheese	-        No carbohydrates -        High in fats, protein, calcium -        Too many saturated fats
Avocados	-        Potassium, unsaturated fats -        Most carbohydrates in avocados are fiber

 

Patients on the ketogenic diet must understand how to track their nutrition to diet properly, calculating proteins, carbohydrates, and fats daily. Patients must calculate carbohydrates to account for dietary fiber because fiber is not digested with other carbohydrates.¹⁴ When tracking nutrition, patients on the ketogenic diet must track net carbohydrates, which can be found by subtracting the dietary fiber content from the total carbohydrates. The total carbohydrate level reported on nutrition labels does not accurately reflect the carbohydrate content the patient has consumed.

 

Most of the foods mentioned in Table 1 are high in fat. Fish, seafood, meat, poultry, and eggs are main staples. Processed meats, like bacon, should be eaten more sparingly compared to non-processed meats, like chicken and beef.¹⁴ Patients can eat chicken and fish more frequently because they promote cardiovascular health, unlike red meat. Many people believe that berries are not allowed on the ketogenic diet, but strawberries, raspberries, and blackberries have very low net carbohydrates. The total carbohydrates in berries may appear high, but their high fiber content allows berries to have a low net carbohydrate content.

 

A vegetarian ketogenic diet is a possibility, even though options are more limited. Vegetarian options with high protein and low carbohydrates include nuts, tofu, and seitan (a meat substitute made from the gluten in wheat).¹⁵ These dieters can also enjoy peanut butter-based desserts for more proteins. Seeds are high in fat and have high dietary fiber. For higher calorie meals, eggs and dairy (hard cheeses and plain yogurt) are an important fat option. Eggs have many fats, but essentially no carbohydrates.¹⁵

 

Any food that is high in net carbohydrates will disrupt the body's ketosis. These are foods like starchy vegetables, juices, syrup, chips, and crackers.¹⁴ Foods high in carbohydrates will give the body enough energy to not oxidize fatty acids and prevent the production of ketone bodies.¹⁴

 

PAUSE AND PONDER: Would a fasting patient reach ketosis quicker than a patient who is not fasting?

WHO BENEFITS FROM THE KETOGENIC DIET?

Obesity

Obesity, a leading risk factor for many chronic health conditions, continues to rise in the United States. According to the CDC, the prevalence of diabetes has increased to 41.9% from 2017 to 2020.¹⁶ Many have adopted low-carbohydrate, high fat lifestyles to lose weight. A 2016 meta-analysis of 11 randomized control trials assessed the efficacy of the ketogenic diet. Among the 1369 participants, those on the ketogenic diet experienced greater weight loss than those who participated in a low-fat diet.¹⁷ After six months to two years of intervention, patients experienced significant weight loss, HDL cholesterol increase, and triacylglycerol (TAG) reduction. The studies were limited by moderate to high heterogeneity and possible publication bias. A 2021 study evaluated the efficacy of the ketogenic diet using a mobile health application in comparison to a calorie restricted, low-fat application.¹⁸ Of the 155 participants, those using the ketogenic diet app experienced greater weight loss (12.3 pounds) at 12 weeks. Hemoglobin A1c (HbA1c) and liver enzymes also improved for the ketogenic diet group. This study was limited by operating fully remotely via the application. Patients could have benefited from in-person counseling or on-site visits to promote adherence.¹⁸

Another meta-analysis of 13 randomized controlled trials showed that participants on the ketogenic diet benefited from greater weight loss than those on a low-fat diet proving that the ketogenic diet can be used for obese patients. The low-fat diet group consisted of 787 patients while the ketogenic diet group consisted of 790. Patients that were part of the keto group lost approximately 3.6 pounds (1.6 kilograms) more than the low-fat group.¹⁹ Patients saw a greater increase in HDL and a more significant reduction in TAG in the keto group.

Type 2 Diabetes

Patients with type 2 diabetes (T2D) sometimes benefit from the ketogenic diet through improved glycemia and reduced insulin resistance. A study of 28 patients with T2D following a ketogenic diet showed that blood glucose and HbA1c improved. The ketogenic diet could potentially help patients with T2D reduce the number or dose of medications.²⁰ Another comparative study showed that obese patients with T2D had improvement in blood glucose profiles, insulin sensitivity, and HbA1c when adhering to the ketogenic diet for two consecutive weeks.²¹ However, the study was limited by short duration and small sample size.

Polycystic Ovary Syndrome

Similar benefits seem to apply to patients with polycystic ovarian syndrome (PCOS). Patients with PCOS experience hyperandrogenism, insulin resistance, and ovulatory dysfunction.²² Current treatment options include metformin, clomiphene, and letrozole; the ketogenic diet may provide good results for these women through insulin reduction.

In addition to the symptoms listed above, women with PCOS tend to gain weight, develop acne, and experience hirsutism.²³ Physicians recommend lifestyle modifications and hormonal contraceptives as first line interventions, but often, these interventions are insufficient, and symptoms persist.²³

Researchers have conducted many studies to evaluate the benefits of the ketogenic diet for women with PCOS, yet the studies are greatly limited by sample size. For example, a 2019 study consisting of 14 women with PCOS struggling with their weight assessed changes in body weight, BMI, fat body mass, lean body mass, HDL, and several other parameters. At 12 weeks, participants saw a 9.43-kilogram (20.7 pound) reduction in body weight, 3.35 reduction in BMI, and an 8.29-kilogram (18.2 pound) reduction in fat body mass.²³

A pilot study consisting of five women tested the ability of the ketogenic diet to reduce PCOS symptoms. Researchers provided the women with low-carbohydrate diet books and handouts alongside group meetings to test the ketogenic diet’s efficacy for PCOS. Participants consumed fewer than 20 grams of carbohydrates per day for six months. To test participants’ adherence, researchers measured ketones and body weight. Throughout the 24-week period, participants lost weight with a mean BMI decrease of four kilograms (approximately 8.8 pounds) which was a 14.3% total reduction in body weight.²⁴ The study resulted with clear reductions in testosterone, fasting serum insulin, and an overall improvement of PCOS symptoms.

Additionally, an eight-week crossover study involving 30 women with PCOS demonstrated various benefits. On average, weight loss ranged from 1.3 to 1.6 kg (2.8-3.5 pounds). When compared to baseline, the results of this study highlight the relationship between decreases in testosterone and fasting insulin.²⁵ Overall, improvements in insulin resistance, testosterone levels, and weight loss, the ketogenic diet may help patients with PCOS.

Epilepsy

The original use for the ketogenic diet was as an antiepileptic therapy in children.¹ After the discovery of antiepileptic medications, the need for the ketogenic diet diminished. However, researchers are bringing the ketogenic diet back to help treat patients who are refractory to modern antiepileptic medications.

In combination with medications, researchers have seen up to a 50% reduction in the number of seizures patients are having, with 10% to 15% becoming seizure free.²⁶ Co-administration with antiepileptics is possible for some medications. However, most patients are children and maintaining this strict diet is difficult.

During a retrospective study, researchers compared the effects of the ketogenic diet to modern anticonvulsant medications in 150 children. At one year, 55% of patients remained on the diet, and 27% of the patients who remained in the trial had a greater than 90% decrease in seizure frequency.²⁷ The diet allowed children to reduce their medication burden (patients averaged having 6.2 anticonvulsant medications before the trial), and proved to be more effective than many medications. More studies in larger patient populations are needed over longer periods of time to make stronger conclusions.

Research attributes the ketogenic diet’s anticonvulsant properties to an increased seizure threshold. Mitochondria in the brain have healthier biogenesis and density, leading to increased resistance to metabolic stress.²⁸ Another way the diet increases seizure threshold is through decreased glucose consumption and production of glycolytic ATP.²⁸ Subsequently, potassium channels remain open and hyperpolarize the neuronal membrane.²⁸

Researchers have found that ketone bodies produced from fatty acid oxidation have their own anticonvulsant effects. Although different ketone bodies have different effects, researchers have found that they can alter various neuronal membrane transporters to decrease excitability. Ketone bodies can inhibit transporters like the vesicular glutamate transporter and neuronal potassium channels. Inhibition of these transporters prevents signal transmission and causes decreased excitability of neuronal cells.²⁹

Other Neurodegenerative Disorders

In addition to epilepsy, promising evidence shows that the ketogenic diet has favorable effects for other neurodegenerative disorders. As the incidence of Alzheimer’s disease (AD) increases, few treatment options are available. The ketogenic diet may reduce deposition of amyloid beta (Aβ) plaques in patients with AD. With the addition of D-β-hydroxybutyrate (an enantiomer of the ketone body 3HB) to the ketogenic diet, ketones were able to increase neuron survival by reversing Aβ (1-42) toxicity. ³⁰ By increasing ketone production in the liver, the ketogenic diet can reduce the production of reactive oxygen species.³¹ Ketone bodies also work to block histone hyper-acetylation initiated by histone deacetylases (HDACs), increasing antioxidant levels. The ketogenic diet can improve metabolic efficiency which improves ATP concentrations resulting in further protective effects.³¹

Ketones’ neuroprotective effects can potentially help patients with Parkinson’s disease by reducing oxidative stress, maintaining energy supply, and modulating deacetylation and inflammatory responses.^31,32 Because they can reduce inflammation and inhibit the glutamate excitatory synapse, infusions of ketone bodies like 3HB may lead to small improvements in Parkinson’s symptoms.³² The use of the ketogenic diet for Parkinson’s is still controversial, thus further research is necessary.

Glaucoma

Glaucoma is the second leading cause of vision loss in the world.³³ Because ketone bodies are the major source of energy when participating in the ketogenic diet, mitochondrial dysfunction in the retina and optic nerves associated with glaucoma may be decreased.^32,34 A 2020 observational study assessed the benefit of the ketogenic diet in 185,638 adults with glaucoma from three studies between 1976 and 2017. Results showed that following a low carbohydrate diet was associated with 20% lower risk of developing primary open-angle glaucoma with initial paracentral visual field loss.³⁵ However, evidence is still lacking, and researchers need to investigate more to prove the ketogenic diet’s efficacy for glaucoma.

Colorectal Cancer

According to the American Cancer Society, colorectal cancer is the third leading cause of cancer-related deaths in men and women in the United States.³⁶ A 2022 study suggests that the ketone body, 3HB, can suppress colorectal cancer.³⁷ In one experiment, investigators evaluated the ability of the ketogenic diet to prevent tumor growth and development in mice.

They discovered that 3HB could suppress tumor growth by reducing proliferation of colonic crypt cells.³⁷ 3HB induced positive changes in tumor growth through the upregulation of the homeodomain-only protein X (HOPX). The HOPX protein inhibits cancer organoid growth when overexpressed.³⁷ Mice fed the ketogenic diet showed elevated levels of HOPX specific to the colonic tissue.

Overall, mice assigned to the ketogenic diet experienced improved long-term survival rates. To test the efficacy of the ketogenic diet for existing tumors, after two cycles of dextran sodium sulfate, researchers introduced the diet to the mice. After exposure to the diet, tumor growth decreased. When researchers discontinued the ketogenic diet from the mice, tumor development proceeded.³⁷

This discovery led to further testing, this time in human organoids. Organoids are tissue cultures derived from stem cells.³⁸ In the right environment, they are used to replicate organs. They are an essential tool to monitor disease development. Findings mimicked the results from the mice in 41 patients with colorectal cancer. This suggests that the ketogenic diet may be used for the prevention and treatment of colorectal cancer in the future.³⁷

PAUSE AND PONDER: How do you think patients would feel using the ketogenic diet as a primary treatment for neurodegenerative diseases in the future?

Contraindications to the Ketogenic Diet

Some patients should not follow the ketogenic diet. It is contraindicated in patients with liver failure, pancreatitis, inborn disorders of fat metabolism, primary carnitine deficiency, carnitine palmitoyl transferase deficiency, carnitine translocase deficiency, porphyria, and pyruvate kinase deficiency.^39,40

Because of the high risk of developing diabetic ketoacidosis (DKA), patients with type 1 diabetes on SGLT2 inhibitors should not participate in the ketogenic diet.⁴¹ DKA occurs when the body produces a dangerously high level of ketones at a rapid pace. Feeling extremely thirsty and frequent urination are early symptoms of DKA. Later symptoms of DKA include dry skin and mouth, flushing, fatigue, stomach upset, and pain. Another notable warning sign of DKA is a fruity odor on the patient’s breath. Acetone is responsible for the sweet scent and indicates high levels of ketones in the body.⁴² If left untreated, DKA can further develop, ultimately leading to death.

Pregnancy is also a contraindication. The CDC recommends 340 additional calories per day during the second trimester of pregnancy and 450 additional calories per day during the third trimester.⁴³ The CDC also recommends a well-balanced diet for women who are expecting. Losing weight during pregnancy is not safe and can be harmful to a patient’s baby.⁴³ Folic acid and iron supplementation is pivotal in a fetus’ development. The World Health Organization recommends daily iron and folic acid supplements to reduce the risk of low birth weight.⁴⁴ If a pregnant woman were to go on the ketogenic diet, she would need to ensure she consumes the suggested dose of 120 mg elemental iron and 2800 µg (2.8 mg) folic acid daily.⁴⁴ Overall, no evidence indicates that the ketogenic diet is safe for pregnant women.

KETOGENIC DIET SAFETY AND COUNSELING

Although several studies suggest the ketogenic diet can be effective for weight loss, limited literature is available concerning its long-term effects. Long-term effects include hepatic steatosis, hypoproteinemia, kidney stones, and vitamin and mineral deficiencies.⁴⁰

Currently, no guidelines address the ketogenic diet specifically, and other guidelines do not include the ketogenic diet for the treatment of the previously mentioned diseases. Researchers must complete longer term studies with larger patient populations to prove the ketogenic diet’s benefits and elucidate any long-term risks. Pharmacists and other healthcare providers should keep this in mind when recommending the diet to patients.

The Keto-Flu

A common adverse effect of the ketogenic diet is the “keto-flu.” The symptoms are indicative of carbohydrate withdrawal that can create symptoms like brain fog, fatigue, nausea, vomiting, constipation, and muscle soreness.^{40, 39} Symptoms usually begin within one to two days and resolve within a week or less. Pharmacists can counsel patients on proper hydration, light exercise, rest, and starting the diet slowly to try to prevent the keto-flu.

Cardiovascular Effects

As research has previously shown, the ketogenic diet shows short-term benefits for obesity and cholesterol. Due to the overconsumption of fats, researchers wondered about the longer-term effects. In rodent studies, the ketogenic diet led to the development of hepatic inflammation and nonalcoholic fatty liver disease.⁴⁵ Limited research has been done for nonalcoholic fatty liver disease in humans and more study is needed.

Other Adverse Effects

While on the ketogenic diet, patients may experience constipation. The healthcare team should implement a bowel regimen for the patient including an agent like polyethylene glycol 3350 (MiraLAX^®) that’s sugar-free, meaning it adds no additional carbs. Other notable side effects are kidney stones and a decrease in bone density. To prevent kidney stone occurrence, pharmacists can counsel patients on drinking large amounts of liquids.. Patients can reach out to their providers to ensure they check bone health routinely. Several advisory groups recommend bone mineral density screening for women aged 65 and older and men aged 70 and older, and for other patients who are at high risk. Patients participating in the ketogenic diet are no exception, and could be considered high-risk if they do not consume enough calcium and vitamin D. Pharmacists can counsel patients to monitor their calcium and vitamin D intake and supplement it if necessary. Upon screening, providers may also recommend calcium and vitamin D supplementation for patients who experience a decline in bone mineral density.⁴⁶

What Can Health Professionals Do?

Pharmacists can counsel patients on ketone testing to prevent occurrences of DKA. When a patient’s blood glucose exceeds 240 mg/dL, testing ketone levels every four to six hours is warranted.⁴⁷ Ketones can be monitored through the urine and blood. A urine stick test is the most common and changes color depending on the ketone level. Although urine tests are convenient, blood ketone tests from finger sticks are more accurate because they measure 3HB and/or AcAc in the blood.⁴⁸ If ketone tests indicate high levels, the patient is at moderate or high risk for ketoacidosis and patients should seek medical attention. Table 2 shows normal ketone levels, the optimal state of nutritional ketosis, and the level for ketoacidosis.

Table 2. Ketone Levels48
Normal Ketone	≤ 0.5 mmol/L
Nutritional Ketosis	1 - 3 mmol/L
Ketoacidosis	≥ 20 mmol/L

Patient adherence to long-term regimens always becomes challenging. Counseling patients on the importance of sticking to their diet and other medications will increase the likelihood of desired results.

PAUSE AND PONDER: On average, how long do you think a patient can remain adherent to the ketogenic diet lifestyle?

Medication management is a vital component of patient safety. To ensure that starting the ketogenic diet is safe, a healthcare professional should perform a complete medication reconciliation. Pharmacists, with an interdisciplinary team, should then develop a plan for medication adjustments (including OTCs) and carbohydrate intake. The use of medication package inserts, institutional databases, and manufacturer helplines can assist the team in determining carbohydrate content of drugs to make the process more seamless.⁴⁶ The following oral suspensions contain high carbohydrate contents:⁴⁹    

• Amoxicillin
• Nystatin
• Levetiracetam
• Midazolam
• Phenobarbital
• Phenytoin
• Baclofen
• Ibuprofen

Making patients aware that they must inform the healthcare team of any new medications is equally as important.

Some medications are of concern with the ketogenic diet.

• Patients taking SGLT2 inhibitors should not participate in nutritional ketosis due to the increased risk of diabetic ketoacidosis.
• Clinicians need to monitor patients taking the anticonvulsant valproate (a fatty acid) and might need to adjust their doses since the ketogenic diet increases metabolic efficiency and valproate can be burned by cells for energy.⁵⁰ Patients may feel as though valproate is not as effective after starting the ketogenic The dose, in this case, may need to be increased temporarily.
• A case study showed that topiramate can increase blood pH, inducing metabolic acidosis and kidney stones.⁵¹ This may become hazardous if patients are already in nutritional ketosis.
• Patients may experience hypotension while taking antihypertensive agents and following the ketogenic They should monitor blood pressure frequently.

Pharmacists and other health professionals should inform patients to stay hydrated to reduce the risk for kidney stones and eat low salt food items.

MYTHS AND FACTS

The ketogenic diet has become increasingly popular over the years. Halle Berry, Vanessa Hudgens, Kourtney and Kim Kardashian are a few of many celebrities that have tried the ketogenic diet and have seen incredible results. MTV’s Jersey Shore star, Vinny Guadagnino, also known as the Keto Guido, is no stranger to the diet and has even written a keto cookbook. Seeing such drastic transformations all over tabloids and social media, without a doubt leaves people wondering “Why not? If they can do it, so can I,” while others think, “This can’t be real.”

 

Many misconceptions create skepticism among patients from the abundance of information available on the internet. Pharmacists can alleviate patient worries by staying informed and referring patients to reliable resources. Table 3 below dispels common myths.

 

Table 3. Myths and Facts About the Ketogenic Diet52
MYTH	FACT
The ketogenic diet is bad for your health.	The ketogenic diet has several health benefits including: ●      Weight loss ●      Improved brain function ●      Reduction of seizures ●      Blood sugar management ●      Improvement of PCOS symptoms Side effects may include nausea, vomiting, constipation, or other common side effects.
All I have to do is consume any type of fat while going keto.	Patients should eat healthy fats like avocados, nuts, seeds, and fish. Healthy fats lower LDL levels and raise HDL levels. Unhealthy fats saturated and trans fatty acids (e.g., fried foods, pastries, butter, and cream) raise LDL levels.
If I go keto, I will get ketoacidosis.	Ketosis and ketoacidosis are different conditions. The ketogenic diet induces ketosis. ●      In ketosis, the body burns fat since carbohydrates are unavailable. Nutritional ketosis is a normal response. ●      Ketoacidosis is a complication seen primarily in patients with T2D where the blood becomes acidic. It can be life-threatening.
I will have no energy if I start a ketogenic diet.	Some people may experience an adjustment period while beginning the ketogenic diet. They may experience temporary fatigue, brain fog, or the “keto-flu.” Eventual ketone production fuels the brain with energy and resolves symptoms.
The ketogenic diet is only useful for weight management.	The ketogenic diet has proven effective in patients with diabetes, PCOS, metabolic syndromes, Alzheimer’s disease, and obesity.
I can’t drink any alcohol while on the ketogenic diet.	Various low-carb alcoholic beverages can be substituted. Light beer, vodka, gin, and rum are a few examples, but patients should keep intake low-moderate. Patients should avoid sweet drinks and cocktails to prevent high sugar intake.

 

Another common misinterpretation is that any low-carbohydrate food is considered keto. No food item has the same benefit as the other. The healthcare team must work with patients to create dietary plans that are more feasible for them. With a tailored diet plan, patients are more likely to feel structured and reach their goals. Overall, providers should conclude that patient education is necessary to certify patient trust and safety.

 

PATIENT RESOURCES

 

Reliable resources for patients are hard to find. Table 4 describes some resources that pharmacists can provide to patients for more information.

 

Table 4. Resources About the Ketogenic Diet for Patients

Cleveland Health Clinic	-        Discusses what patients eat on the ketogenic diet -        Small tidbits on benefits and risks -        Includes information on populations that could benefit from the diet -        https://health.clevelandclinic.org/what-is-the-keto-diet-and-should-you-try-it/
Harvard University Health	-        Discusses key-takeaways from a ketogenic diet review -        Gives food examples -        Easy-to-understand -        Discusses health implications for certain patient populations -        https://www.health.harvard.edu/blog/ketogenic-diet-is-the-ultimate-low-carb-diet-good-for-you-2017072712089
Academy of Nutrition and Dietetics	-        Popular nutrition website that presents findings on various health topics -        Discusses populations that the ketogenic diet would not be safe in -        Gives background on the diet -        https://www.eatright.org/health/wellness/fad-diets/what-is-the-ketogenic-diet
Everyday Health	-        Discusses risks and benefits of the diet -        Provides food substitutions and daily meal plans -        Discussion potential supplements and vitamins that may be beneficial to dieters -        Discusses other nutrition techniques for other topics -        Articles are peer-reviewed -        https://www.everydayhealth.com/diet-nutrition/ketogenic-diet/comprehensive-ketogenic-diet-food-list-follow/
EatingWell	-        Brief explanation about the ketogenic diet -        Provides variety of food options for dieters -        Easy-to-understand and discusses other nutrition techniques -        Peer reviewed and gives background on all authors/editors -        https://www.eatingwell.com/article/290697/ketogenic-diet-101-a-beginners-guide/

 

 

CONCLUSION

Following a low-carbohydrate, high fat diet that uses ketone production to fuel the body requires a large selection of foods if patients are to maintain this diet. This is the challenge of the ketogenic diet. Pharmacists and technicians need a good understanding of what this diet is—and what it is not—so they know when prescribers are likely to use it for diseases. Pharmacists, as they screen for contraindications, should identify the signs of ketosis and counsel patients on managing safe ketone levels.

Patient education is the key to reaching patient goals. Pharmacists must be ready to address patient questions and concerns regarding the ketogenic diet in conjunction with current medications. When pharmacists are a part of the care process, outcomes improve.

 

Download CE Activity

INTRODUCTION

This continuing education (CE) activity aims to guide safe insulin dose adjustments when adding glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1-RAs), and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs (GIP/GLP-1 RAs) in those with type 2 diabetes (T2D). Clinical utilization of GLP-1 RAs and GIP/GLP-1 RAs in combination with insulin has been lagging despite their benefits.¹ This is due to a lack of clinician comfort with insulin adjustment despite Food and Drug Administration (FDA) approval and improved insurance coverage. Pharmacists can optimize a patient’s regimen by reducing the risk of hyperglycemia or hypoglycemia, adverse drug reactions (ADRs), and medication/injection burden.

 

Diabetes Basics

Diabetes is an endocrinological disorder characterized by metabolic imbalance (glucose utilization and insulin effect).² In patients who have diabetes, hyperglycemia occurs and could lead to long-term complications such as myocardial infarction, cerebrovascular accident, peripheral artery disease, retinopathy, nephropathy, and neuropathy.²

 

A glycated hemoglobin level (A1c) greater than or equal to 6.5% indicates a person has diabetes.³ When discussing how an A1c correlates to a patient’s self-monitored blood glucose (SMBG; home blood glucose testing using a glucometer or a continuous glucose monitor [CGM]), it can be helpful to consider an estimated average glucose (eAG).³ The complete equation and calculator can be found at https://professional.diabetes.org/glucose_calc. A simplification is remembering that an A1c of 7% equals an eAG of 154 mg/dL and that each A1c percentage represents about 30 mg/dL. Generally, for an A1c goal of less than 7%, fasting blood sugars (FBGs) should be between 80 and 130 mg/dL, and 2-hour post-prandial glucose (PPGs) values should be less than 180 mg/dL.³

 

Previously, mainstay treatment options for glycemic control included metformin, sulfonylureas (glimepiride, glipizide, and glyburide), thiazolidinediones (pioglitazone), and dipeptidyl peptidase-4 inhibitors (alogliptin (Nesina), linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). Newer treatment options that are focused on cardiorenal benefits, weight management, and glycemic control include⁴

• Sodium-glucose cotransporter 2 (SGLT-2) inhibitors: canagliflozin (Invokana), bexagliflozin (Brenzavvy), dapagliflozin (Farxiga), empagliflozin (Jardiance), and ertugliflozin (Steglatro)
• GLP-1-RAs: dulaglutide (Trulicity), exenatide ER (Bydureon), exenatide IR (Byetta), liraglutide (Victoza), lixisenatide (Adlyxin), and semaglutide (Ozempic)
• GIP/GLP-1 RA (tirzepatide [Mounjaro])

 

The diabetes management landscape is changing. Even if patients have appropriate glycemic control, their medication regimen may not be optimal based on co-morbidities. Please see the following link to the American Diabetes Association’s recommendations on medication selection: https://diabetesjournals.org/view-large/figure/5311673/dc25S009f3.tif.

 

Insulin

Insulin has been a cornerstone of diabetes management for decades. With the advent of newer medication classes, it can appear as though insulin’s importance in current practice is diminishing. Many individuals still benefit from the use of insulin, including those with type 1 diabetes (T1D), patients with newly diagnosed T2D with an elevated A1c, and those with access/cost concerns regarding branded medications.

 

Although treatment options for diabetes have advanced and include SGLT-2 inhibitors, GLP-1-RAs, and GIP/GLP-1 RAs, these drugs can be cost prohibitive depending on the situation.⁴ Insulin itself can also be cost-prohibitive depending on insurance coverage (or lack thereof) and patient-specific dosing needs. In certain situations where patients pay out-of-pocket, reducing the daily insulin dose can help reduce the cost.

 

Insulin’s onset of action, duration of action, and concentration help to categorize it.

• Patients use bolus insulins such as ultra rapid, short, or regular insulin prior to meals to manage blood glucose spikes. These insulin types generally help lower PPGs. Checking SMBGs two hours after a meal helps to understand the effect while checking prior to mealtimes ensures safety.
• Patients use basal insulins, injected once or twice daily, to provide constant insulin action throughout the day and night. Options include intermediate, long-acting, and ultra-long-acting. These insulin types generally help lower FBGs and patients who use these insulins should check their SMBGs when in a fasting state as well.
• Examples of concentrated insulins include insulin lispro U-200 (insulin lispro U-200), insulin degludec (Tresiba U-200), insulin glargine U-300 (Tuojeo U-300), and insulin regular U-500. Testing for insulin degludec U200 and insulin glargine U-300 would match basal insulin testing. Testing for insulin lispro U-200 and insulin regular U-500 would match bolus insulin testing.
• Mixed insulins contain a mix of a bolus/regular insulin and an intermediate insulin in pre-fixed percentages to reduce the injection burden. Examples include insulin aspart protamine/insulin aspart (Novolog 70/30), insulin lispro protamine/insulin lispro (Humalog 75/25 or Humalog 50/50), and insulin isophone (NPH)/insulin regular (Humulin 70/30 or Novolin 70/30). For safety, these require fixed meal timings and portions and thus testing is recommended two hours before and after breakfast and dinner.

 

Insulin Dosing

In practice, clinicians usually start patients on a basal insulin rather than a bolus insulin as it involves fewer injections and provides steadier coverage throughout the day. Generally, a starting basal insulin dose is calculated using 0.1 to 0.2 units/kg/day or 10 units daily.⁵ When insulin needs increase beyond 0.5 units/kg/day of basal insulin, providers (such as clinical pharmacists) can consider the addition of bolus insulin.⁶ Using greater than 0.5 units/kg/day of basal insulin is referred to as overbasalization (see SIDEBAR).

 

 

SIDEBAR: Overbasalization^6,7

Overbasalization describes the situation in which the patient’s bedtime glucose readings are significantly higher (greater than 50 points) than their fasting values. Ideally, bedtime and fasting readings should be in equilibrium. Overbasalization is common in patients whose basal insulins are titrated to a fasting goal without considering the patient’s end-of-day blood sugars. It also occurs if prescribers think adding a medication would increase the patient’s injection/medication burden. This generally occurs when the patient’s basal insulin dosing exceeds 0.5 units/kg/day. Ideally, the provider should consider a medication that helps lower PPGs.

 

Using GLP-1 RAs and GIP/GLP-1 RAs has increased the ability to minimize the need for bolus insulin, reduce the risk of hypoglycemia, and lower PPG. Using a collaborative practice agreement within an interprofessional collaborative team has significantly reduced overbasalization and A1c.

 

 

The total amount of insulin a patient takes in a day is their total daily dose (TDD). This TDD is a helpful starting point when making insulin adjustments. For example, if a patient is taking 100 units of insulin per day (this could be basal or basal + bolus) then generally 10% to 15% is a reasonable adjustment.⁵ This equates to an increase or decrease of 10 to 15 units. For a smaller TDD of 20 units the adjustment would be 2 to 3 units. Alternately, patients can self-adjust the dosing within specified parameters such as increasing a basal insulin by 2 units (up to a pre-specified maximum) every three days that the FBGs are above goal.⁵

 

Patient/situation specific parameters that additionally need to be considered are the patient specific glycemic goal, glycemic trends (variability vs. stability), planned lifestyle changes, hypo/hyperglycemia, and ADRs. The prior recommendations only account for medication changes while everything else remains constant. Realistically, dosing changes will likely need to be made at larger percentages to accommodate multiple changing factors.

 

If PPGs indicate a need for improvement of glycemic control, clinicians can consider either a GLP-1 RA (for T2D) or bolus insulin (T1D or T2D). Adding a GLP-1 RA can be more complex for those on a multiple daily injection (MDI) insulin regimen (basal + bolus). Guidance regarding basal + bolus insulin dose deprescribing varies.

 

Insulin Dose Adjustment with GLP-1 RAs and GIP/GLP-1 RAs

Three studies have reviewed the efficacy of adding liraglutide to an MDI insulin regimen in patients with T2D.^8-10 They documented a significant reduction in A1c from baseline in the GLP-1 RA group compared to the MDI control groups. Two studies—one conducted by researchers at the Mountain Diabetes and Endocrine Center, Asheville, North Carolina and a second conducted in Europe and Saudi Arabia called the MDI Liraglutide Trial—showed significantly reduced insulin dosing in the liraglutide groups.^8,9 In contrast, the third study (N = 71), conducted at the University of Texas Southwestern Medical Center (UTSMC), Dallas, did not show a significant reduction in insulin dosing.¹⁰

 

The Mountain Diabetes and Endocrine Center study made insulin dose adjustments based on A1c but included only 37 participants. The study protocol indicated that researchers should reduce the basal dose by 20% for those with an A1c less than or equal to 8%.⁸

 

In the MDI Liraglutide Trial (N = 124), the insulin adjustments were based on FBGs and PPGs . When fasting values were less than 90 mg/dL or participants had nocturnal hypoglycemia, the researchers reduced the basal dose by 20% to 40%. If the fasting values were 90 to 126 mg/dL, the researchers reduced the basal doses by 20% to 30%. The researchers did not adjust the basal insulin dose if fasting glucose levels were above 126 mg/dL. If they found the patient’s pre-meal glucose value to be less than 126 mg/dL, they reduced the bolus dose of the prior meal by 10% to 20%. If participants experienced daytime hypoglycemia, the researchers reduced the bolus dose of the preceding meal by more than 20%.⁹

 

The UTSMC study protocol reduced insulin doses by 20% if the A1c was less than or equal to 8%. The investigators did not adjust the insulin dose if the A1c was greater than 8%. They did not define the specific bolus and basal insulin dose adjustments.¹⁰

 

The TRANSITION2D study (N = 60) reviewed insulin deintensification with once weekly semaglutide.¹¹ These researchers transitioned patients who were reasonably well controlled (A1c 7.5% or less) from bolus insulin to a GLP-1 RA (semaglutide) in a one-step approach. They discontinued bolus insulin upon initiating semaglutide, then titrated the semaglutide dose.¹¹ A limitation to real-world applicability was that less than 25% of the participants were on 80 to 120 units of insulin per day.¹¹ Concerns in the real world would be a lack of tolerance to semaglutide or lack of follow-up on the patients’ behalf, as this would lead to hyperglycemia. Also, shared decision making between the patient/provider would first need to optimize glycemic control using insulin dose adjustments to reduce the risk of hyperglycemia/diabetic ketoacidosis (DKA)/hyperosmolar hyperglycemic state (HHS).

 

Traditional insulin dosing guidance and these studies show that insulin dose adjustments can vary widely from 10% to 40%. One path isn’t necessarily correct as adjusting insulin doses is an art of sorts.

 

HYPOGLYCEMIA TREATMENT

Accounting for and incorporating historical patient-specific parameters helps minimize the risk of hypoglycemia. Patient education regarding appropriate identification, treatment, and prevention of recurrence is paramount for safety. Common hypoglycemia symptoms are hunger, difficulty concentrating, headache, shakiness, sweating, and irritability. The 15-15 Rule advises patients with low blood sugar, defined as less than 70 mg/dL, to consume 15 g of carbohydrates and then wait 15 minutes to recheck the SMBG. Options to increase the blood sugar are 4 ounces of regular juice or non-diet soda, 1 tablespoon of sugar, honey, or syrup, 3 to 4 glucose tablets, or 1 dose glucose gel.¹² It is important to know that glucose tablets and gel are available without a prescription. Most patients know that if they experience hypoglycemia, they should eat something sweet. However, without following the treatment/prevention steps, patients may experience additional concerns. Table 1 describes appropriate action steps.

 

Table 1. Action Steps to Address Hypoglycemia¹³

Appropriate step	Assessment questions
Patients must check initial and subsequent glucose values to have objective data	What values did you see when you checked your blood sugar?
Initial treatment should consist of 15 grams of simple carbohydrates for the quickest improvement of hypoglycemia symptoms. Of note, treatment with complex carbohydrates or carbohydrates + protein/fat* will delay the improvement of hypoglycemia symptoms.	What food/drink/treatment option did you initially use to address the low blood sugar?
Overtreatment with more than 15 grams of carbohydrates leads to overcorrection (hyperglycemia)	How much of the food/drink/treatment option did you initially use to address the low blood sugar?
After consuming a simple carbohydrate, the patient should consume a complex carbohydrate + protein pairing, to prevent hypoglycemia from recurring within two hours	Once the blood sugar returned to a safe range, what did you eat to keep the blood sugar steady?

^*Examples of complex carbohydrates (wheat/corn/peas/potatoes/fruit) and carbohydrates + protein/fat (apple + peanut butter/pizza/candy bar)

 

NEWER THERAPIES

As this activity discusses newer therapies, new information is consistently being learned. To provide comprehensive and current or guideline-directed care, these must be a part of the patient assistance process. Some patients have strong feelings for or against newer therapies, so it is helpful to be able to provide the information in a non-biased manner.

 

SGLT-2 Inhibitors    

SGLT-2 inhibitors increase urinary excretion of excess glucose and thus can increase the risk of genitourinary infections such as yeast infections and urinary tract infections. This class of medications also has significant long-term cardiorenal benefits.¹⁴ Optimization of these medications would also be ideal, especially when affordable, to reduce the need for insulin.

 

Although this CE activity’s focus is to review insulin dosing adjustments when introducing concurrent GLP-1 RA and GIP/GLP-1 RA dose adjustments, clinicians can apply some of the same practices when adjusting other medications, such as SGLT2-inhibitors.

 

GLP-1 RAs

The FDA approved the first GLP-1 RA, exenatide, in 2005, and patients needed to inject it twice daily.¹⁵ Now, patients can inject GLP-1 RAs daily or weekly. In 2019, the FDA approved the first non-injectable GLP-1 RA, oral semaglutide (Rybelsus).¹⁵ Additionally, this group of medications provides cardiorenal protective effects and weight loss.¹⁶ Common ADRs are gastrointestinal intolerances such as nausea, upset stomach, constipation, and vomiting.¹⁶

 

Semaglutide is the most effective medication in this class from a glycemic management perspective.¹⁶ Dulaglutide, liraglutide, and exenatide are the most tolerated in this class; however, of these options dulaglutide is the most effective.¹⁶ Before these newer DM medications were available, the commonly utilized PPG-lowering options were metformin, sulfonylureas, bolus insulin, and mixed insulin. Of those, metformin is the only one that does not increase risk of hypoglycemia.

 

GIP/GLP-1 RAs

GIP/GLP-1 RAs have a dual hormonal activation that promotes satiety, slows digestion, and reduces hunger. Common ADRs are similar to that of GLP1-RAs but even though tirzepatide is more potent at improving glycemic control than semaglutide, it is also better tolerated.¹⁶ Currently, the FDA has approved tirzepatide as the only medication in this class. Additionally, despite the dual activation, patients tend to tolerate tirzepatide better than some GLP-1 RAs based on anecdotal experience. Tirzepatide also provides cardiorenal protective effects.¹⁷

 

Combination basal insulin + GLP-1 RA medications

Currently, the FDA has approved two fixed-ratio combinations (FRC) of basal insulin/GLP-1 RA: insulin degludec/liraglutide, also known as iDeglira (Xultophy), and insulin glargine/lixisenatide, also known as iGlarlixi (Suliqua).¹⁸ These medications have a fixed level of a basal insulin and a once daily GLP-1 RA combined into a single pre-filled pen. Insulin has no maximum daily limit but the GLP-1 RAs do. Thus (because these products are fixed ratios combinations) the maximum daily GLP-1 RA dose limits the daily insulin dose in FRCs.¹⁹ The dosing is based on units of the insulin component.

 

For example, each unit of iDeglira contains 1 unit of insulin and 0.036 units of liraglutide.²⁰ The maximum dose is 50 units, which contains 50 units of insulin degludec and 1.8 mg of liraglutide (liraglutide's maximum daily dose). The manufacturer advises patients who are insulin and GLP-1 RA naïve to start at 10 units daily, whereas those that are currently on basal insulin can start at 16 units daily.¹²

 

IGlarlixi is available in the United States as Soliqua 100/33, indicating that there is 0.33 mg of lixisenatide for every unit of insulin glargine. The maximum dosage of iGlarlixi is 60 units; however, this is based on the lixisenatide daily maximum of 20 mcg. Those transitioning from less than 30 units of basal insulin would be started on 15 units of iGlarlixi. For those between 30 to 60 units of basal insulin, the starting dose would be 30 units of iGlarlixi.²¹

 

A study completed at the Diabetes Center of the Békés County Central Hospital in Hungary (N = 62) sought to review the safety and efficacy of switching well-managed patients with T2DM (A1c less than 7.5%) from basal/bolus insulin (low TDD) to insulin degludec/liraglutide combination.²⁰ The study defined low TDD as less than or equal to 70 units of insulin per day. The transition method was to stop the prior basal/bolus insulin regimen and to start 16 units of iDeglira. Then the FBGs were titrated to 90 to 108 mg/dL by increasing the iDeglira dose by 2 units every 3 days. The study continued or initiated metformin and titrated it up to 3000 mg (the maximum daily dose of metformin is higher in Hungary than in the United States). The intervention reduced the TDD from 43.3 units to 22.55 units, which was significant.²⁰

 

Theoretically, this is a wonderful way to reduce injection burden and optimize adherence.⁶ These medications’ clinical utility depends on the patient’s lifestyle patterns, insurance coverage, medication availability, and out-of-pocket cost. Depending on the patient, the fixed ratio dosing and once-daily dosing could be a benefit or a drawback. Patients who would like to minimize injection burden and can safely delay insulin may prefer a once weekly GLP-1 RA or GIP/GLP-1 RA injection. Having the ability to titrate basal insulin and a GLP-1 RA separately allows more dosing individualization, which leads to more patients achieving goal FBGs.²²

 

INTRODUCTION TO THE CASES

The rest of this activity focuses on case-based learning. For these cases, learners should assume that any information not provided is within normal limits, there is no change from baseline, or any change has been addressed. These cases derive from patients in a primary care setting, but this information can help in various settings. Also, due to the focus on insulin dose adjustments, the healthcare provider does not discuss the use of GLP-1 RAs or GIP/GLP-1 RAs for an indication of obesity. As obesity can co-exist with T2D, healthcare providers should monitor weight during initiation and titration of GLP-1 RAs or GIP/GLP-1 RAs.

 

CGMs have been more accessible in recent years, and they provide excellent graphic review of glycemic control. This learning experience uses glycemic charts. The charts depicted here would be gathered from a patient’s glucometer or SMBG log and commonly depict the last 14 days of glycemic control. Clinicians should crosscheck values from a SMBG log with the patient’s glucometer if they have concerns about inaccuracy. Each column that lists a glucose value specifies the timing with regard to meals; acB is before breakfast, acL is before lunch, acD is before dinner, and HS is at bedtime. During the initial pharmacist visit, pharmacists need to manage patients expectations and urge frequent testing because it allows for the safest insulin dose adjustments. It also ideally decreases the testing needs moving forward by limiting the patient’s insulin doses and frequency.

 

PAUSE AND PONDER: Thought Questions

Safety:

• Is the patient tolerating the current regimen?
• Is the patient experiencing any hypoglycemia?

Efficacy:

• Is the current regimen helping the patient achieve glycemic goals?
• What medication adjustments would help move the current glycemic patterns towards the goal?

 

CASE 1: Arya Brown–pronouns: he/him/his

Arya is a patient who presents for his first pharmacist visit. First, the pharmacist reviews the electronic medical record for Arya’s recent history.

 

Visit 1

Arya reported that he was doing well with dulaglutide 0.75 mg weekly and his current insulin glargine dose of 18 units daily. He reported that his appetite was more controlled, and he felt more energetic since starting dulaglutide. The patient was excited to increase the dose of dulaglutide.

 

The patient’s current SMBG log shows he checks his FBGs only sporadically, and they fall between 128 and 154 (average = 143), no hypoglycemia, and consistent values above goal. Based on the anticipated improvement of glycemic control throughout the day by increasing the dulaglutide dose to 1.5 mg weekly, the pharmacist started shared decision making to continue the current insulin glargine for now. The pharmacist asked the patient to check his blood sugars in the evening, either before dinner or at bedtime, to allow for further assessment of glycemic trends throughout the day. Arya verbalized understanding of this request, but reports that he will likely only check blood sugars once a day and therefore asked to alternate testing times.

 

Visit 2

Arya presented for his second pharmacist visit after his third dose of dulaglutide 1.5 mg. He said that his blood sugars were at goal and that he had slight but tolerable nausea with the current dulaglutide dose. He reported that the nausea improved since the first injection at this dose. The pharmacist and Arya discussed the option of maintaining the dulaglutide dose for the next prescription to allow additional time for tolerance. However, Arya prefers to increase it to dulaglutide 3 mg weekly with the next prescription after four doses of 1.5 mg have been taken. He indicates the symptoms have improved over time and are barely noticeable.

 

His current SMBGs show FBGs ranging from 128 to 141 (average = 135). Since his glycemic control is now closer to goal than previously, he will need to adjust insulin glargine dosing to minimize the risk of hypoglycemia. The risk of causing temporary hypoglycemia is higher than that of causing temporary hyperglycemia. Thus, the pharmacist decides to reduce the insulin dose by 6 units. This is a 33% insulin reduction.

 

Visit 3

At Arya’s third visit, he reports feeling nauseous and vomiting after injecting the second dose of dulaglutide 3 mg weekly. He says he vomited after the first dose and thought it may have been related to a food choice at that time. The vomiting improved after a couple of days, but it recurred after the second dose of dulaglutide 3 mg. The patient shows his glucometer for SMBGs as noted in Table 3.

 

Table 3. Arya Visit 3

Date	AcB	HS	HS dose (insulin glargine)	comment
			12 units
	134		12 units
		147	12 units
	136		12 units
			12 units
	124	149	12 units
			12 units	Dulaglutide 3 mg (dose 1)
			12 units
	117	146	12 units
			12 units
		137	12 units
	120		12 units
		131	12 units
	116		12 units	Dulaglutide 3 mg (dose 2)
		127	12 units
Visit 3			12 units
Average	125	140

 

The SMBGs indicate improved glycemic control. The pharmacist suggested that Arya’s ADRs seem intolerable. Arya agrees. He was amenable to stopping the dulaglutide 3 mg weekly and resuming the lower 1.5 mg weekly dose when his symptoms abate (at least a week after the last dose). Now the discussion turned to what insulin dose the patient should take with the lower dose of dulaglutide.

 

The patient’s prior glycemic control is a blueprint for patient specific response to insulin dose adjustments. Since Arya is returning to the 1.5 mg of dulaglutide weekly, and he has taken that dose before, the glycemic control information presented during visit 2 is helpful. The general takeaway is that his glycemic control was close to goal while on dulaglutide 1.5 mg weekly and insulin glargine 18 units daily. The pharmacist and the patient make a shared decision to adjust the insulin glargine to 20 units daily to move the patient’s glycemic control closer to goal.

 

They agree to re-try dulaglutide 3 mg weekly in the future if he tolerates the 1.5 mg weekly dose better over time. They also discuss the possibility of using a different GLP-1 RA or a GIP/GLP-1 RA, as tolerance between medications can vary.

 

CASE 2: Alex Devi–pronouns: they/them/theirs

Visit 1

Alex presented to their first pharmacist visit and reports that their insurance now covers tirzepatide for diabetes at a reasonable cost, so they would like to minimize MDI insulin regimen. The patient denies any contraindications to GIP/GLP-1 RA. The pharmacist tells Alex that they can adjust their insulin doses based on tolerance to tirzepatide, but there is no guarantee that insulin can be stopped.

 

Based on the current optimized glycemic control (Table 4), starting and titrating tirzepatide will necessitate insulin dose adjustments. They are currently injecting insulin degludec 36 units daily and insulin lispro 8 units with breakfast, 10 units with lunch, and 14 units with dinner. To limit the risk of hypoglycemia, the pharmacist and Alex planned to decrease doses and assess this specific patient’s response. As tirzepatide will primarily impact post-prandial glycemic control, and the patient is on a medication (insulin lispro) that can cause post-prandial hypoglycemia, the goal was to focus on bolus insulin reduction. In this case, glycemic control appears steady throughout the day. The pharmacist planned to reduce all prandial doses equally to allow blood sugars to rise throughout the day and let the full effect of tirzepatide occur while limiting hypoglycemia due to insulin. Due to tirzepatide’s potency as a dual GIP/GLP-1 RA and Alex’s current glycemic control, they will reduce the insulin lispro dose by 4 units per meal. Thus, the patient’s total daily insulin dose was reduced by 12 units per day, an 18% reduction in TDD of insulin.

 

Table 4. Alex Visit 1

Date	acB	acB dose (insulin lispro)	acL	acL dose (insulin lispro)	acD	acD dose (insulin lispro)	HS	HS dose (insulin degludec U100)	Notes
	117	8	109	10	137	14	171	36 units
	93	8	129	10	128	14	161	36 units
	107	8	91	10	145	14	127	36 units
	126	8	79	10	141	14	152	36 units
	93	8	133	10	147	14	131	36 units
	82	8	121	10	124	14	170	36 units
	107	8	132	10	128	14	160	36 units
	112	8	125	10	111	14	165	36 units
	105	8	89	10	147	14	170	36 units
	77	8	96	10	133	14	130	36 units
	108	8	111	10	91	14	146	36 units
	92	8	103	10	113	14	164	36 units
	97	8	110	10	118	14	151	36 units
	101	8	89	10	97	14	132	36 units
	122	8	131	10	121	14	130	36 units
Visit 1	104	8	125	10				36 units	Start tirzepatide 2.5 mg
Average	103		111		125		151

 

Visit 2

Table 5 summarizes Alex’s glycemic control when they returned for their second appointment. The pharmacist looks for trends and sees that the blood sugar averages appear to be lowest pre-dinner and then highest at bedtime. A potential concern is that Alex may overeat at dinnertime as a response to rapidly decreasing blood sugars between lunch and dinner. Alex denies any hypoglycemia symptoms or adverse effects from tirzepatide. They just finished the fourth dose of tirzepatide 2.5 mg and are interested in increasing the dose. To increase tirzepatide, the pharmacist used the information gathered to minimize the patient’s insulin intake. Based on the response and current SMBGs, roughly 4 units is an appropriate dose reduction per meal. Logistically, this would eliminate the breakfast insulin, reduce the lunchtime dose to 2 units, and reduce the dinnertime insulin dose to 6 units. The pharmacist needs to evaluate the lunchtime dose of 2 units further. For someone with T2D, 2 units is a minimal dose of insulin. The actual effect is questionable, especially in this individual, where another medication is being titrated up.

 

Table 5. Alex Visit 2

Date	acB	acB dose (insulin lispro)	acL	acL dose (insulin lispro)	acD	acD dose (insulin lispro)	HS	HS dose (insulin degludec U-100)	Notes
	113	4	95	6	79	10	150	36 units
	79	4	122	6	91	10	139	36 units
	107	4	107	6	113	10	162	36 units
	102	4	125	6	91	10	172	36 units
	104	4	118	6	99	10	164	36 units	tirzepatide 2.5 mg (Dose 3)
	81	4	118	6	81	10	156	36 units
	120	4	102	6	101	10	158	36 units
	85	4	123	6	75	10	169	36 units
	77	4	127	6	79	10	168	36 units
	84	4	108	6	103	10	126	36 units
	111	4	89	6	79	10	139	36 units
	112	4	115	6	92	10	140	36 units	tirzepatide 2.5 mg (Dose 4)
	87	4	87	6	101	10	174	36 units
	73	4	102	6	76	10	139	36 units
	85	4	127	6	98	10	163	36 units
Visit 2	107	4						36 units
Average	95		111		91		155

 

Reviewing the pre-dinner glycemic values (the lowest throughout the day) and eliminating the lunchtime insulin dose would help reduce the risk of hypoglycemia. Thus, the consensus was to eliminate the breakfast and lunchtime insulin doses while reducing the dinner time dose to 6 units. Therefore, they decided to reduce the patient’s total daily insulin dose by 14 units, a 25% reduction in TDD of insulin. The pharmacist advised the patient that he can skip testing his SMBG before lunch as he is not injecting a bolus insulin at that time.

 

Visit 3

Alex presented for their third appointment and denies any adverse effects with tirzepatide 5 mg weekly. Alex was happy with reducing injection burden from four times a day to twice a day! They reported they have lost some weight. They have also increased activity slightly and are planning to make that a priority in the upcoming month. They would like to continue titrating tirzepatide when able. Looking at current glycemic values (Table 6), the adjustments made at the last visit stabilized control again.

 

Table 6. Alex Visit 3

Date	acB	acB dose (insulin lispro)	acD	acD dose (insulin lispro)	HS	HS dose (insulin degludec U100)	Notes
	110	0	111	6	115	36 units
	119	0	106	6	132	36 units
	133	0	129	6	96	36 units
	126	0	100	6	99	36 units
	126	0	99	6	151	36 units	tirzepatide  5 mg (Dose 2)
	118	0	111	6	97	36 units
	130	0	110	6	124	36 units
	112	0	131	6	149	36 units
	134	0	106	6	144	36 units
	99	0	105	6	103	36 units
	97	0	117	6	154	36 units
	98	0	111	6	153	36 units	tirzepatide 5 mg (Dose 3)
	115	0	121	6	141	36 units
	119	0	96	6	129	36 units
	122	0	98	6	154	36 units
Visit 3	102	0				36 units
Average	116		110		129

 

Based on this patient’s previous responses, it seems that the insulin dose should be reduced by about 12 to 14 units of insulin to accommodate the tirzepatide dose increase. Additionally, due to Alex’s anticipated activity change, they may need to reduce the total daily insulin dose further. The pharmacist can help reduce the injection burden by eliminating the dinnertime dose of insulin lispro. Next, the basal dose needs to be adjusted. There is room for discussion, based on the factors noted (current glycemic control, planned activity changes, and dose increase of tirzepatide). To limit the risk of hypoglycemia, they decide to reduce insulin degludec from 36 units to 26 units. This is a reduction of 16 units of insulin. They could have reduced the patient’s basal dose to accommodate everything except the activity change if it was unclear that they were planning to make a change soon.

 

All plans must be patient-specific, and with this discussion, the patient is reliable and was waiting to change their activity once this discussion occurred. For other patients who are not as clear that they are planning a change, the pharmacist could advise reducing the basal insulin dose to approximately 30 units daily for now and then communicate with the clinic when they make the change for review of SMBGs to allow for additional adjustments.

 

CASE 3: Zephyr Hernandez–pronouns: she/her/hers

Visit 1

Zephyr’s provider referred her to the pharmacist because her A1c was above goal and she was experiencing hypoglycemic episodes. From a complete assessment of the patient’s medication and lifestyle routine, it appeared that the patient’s mealtimes were inconsistent. Zephyr indicated her schedule dictates whether she can eat breakfast and/or lunch, but that she tries to eat dinner consistently. She injects insulin aspart protamine/insulin aspart 70/30 mix, 24 units in the morning and 30 units in the evening. Based on Zephyr’s readings (Table 7), she has hypoglycemia before dinner when she skips lunch. She treats the hypoglycemia with soda or candy. The patient says she skips her breakfast mixed insulin dose when she skips breakfast but then ends up with hyperglycemia pre-dinner.

 

Table 7. Zephyr Visit 1

Date	acB	acB dose (insulin aspart protamine/insulin aspart 70/30 mix)	acL	acD	acD dose (insulin aspart protamine/insulin aspart 70/30 mix)	HS	Notes
	123	24	122	113	30	137
	134	24	106	78	30	257	skipped lunch
	88	24	114	112	30	118
	159	24	109	76	30	188	skipped lunch
	76	24	121	111	30	123
	118	0	156	187	30	187	skipped breakfast
	123	0	164	190	30	128	skipped breakfast
	139	24	116	106	30	164
	95	24	96	68	30	196	skipped lunch
	113	24	107	102	30	141
	117	24	120	109	30	186
	159	0	145	189	30	145	skipped breakfast
	149	24	132	72	30	179	skipped lunch
	117	24	127	109	30	125
	107	24	114	79	30	212	skipped lunch
Visit 1	96	0	163				skipped breakfast
Average	120		126	113		166

 

During the visit, the pharmacist and Zephyr reviewed the 15-15 Rule for identifying and treating hypoglycemia. They also discussed the fact that mixed insulin, unfortunately, does not allow mealtime flexibility due to the fixed ratio. The patient says she will try to maintain steady mealtimes and portions. She also asked to try a medication like semaglutide and has no contraindications.

 

The pharmacist explained that the first dose of semaglutide is a tolerance dose and is not expected to have a significant clinical impact. Transitioning to an MDI insulin regimen would help stabilize blood sugars, minimize hypoglycemia, and provide insulin dosing flexibility. However, Zephyr preferred not to switch insulin to MDI insulin at this time. She stated she will focus on having consistent meals instead. Based on her preference, they adjusted the current insulin regimen to reduce the risk of hypoglycemia. The pharmacist advised her to reduce the insulin aspart protamine/insulin aspart 70/30 morning dose to 20 units, the evening dose to 26 units, and to start semaglutide 0.25 mg weekly.

 

Visit 2

At the second visit, Zephyr reported that she could not maintain steady meal times despite her efforts. She initially reduced her insulin doses as requested, but once she realized she couldn’t maintain steady mealtimes, she resumed her previous dosing. Therefore, her current SMBG values closely resemble her last visits' values (Table 7). The pharmacist advised Zephyr to communicate questions, concerns, and changes to the clinic in between appointments moving forward. As Zephyr was unable to maintain steady meal choices, she couldn’t safely remain on mixed insulin due to safety concerns.

 

Consequently, the pharmacist talked with Zephyr about two options based on her goal to increase the semaglutide dose to 0.5 mg weekly. One option would be to transition to basal/bolus insulin (administered TID or QID), but the patient previously rejected this option. An alternative option (dependent on the patient’s prandial insulin dose) would be to transition the patient to basal-only insulin and eliminate prandial insulin. This option creates a risk of hyperglycemia until the semaglutide doses can be titrated. Thus, periodic clinical assessment of hyperglycemia would be critical. DKA and HHS are a concern with significantly elevated blood sugars. Still, temporary elevations in the high 100s to low 200s may be acceptable if the patient is not safe or willing to take alternate recommended options.

 

After this review, Zephyr stated she cannot tolerate more than two insulin injections a day. They decided to transition Zephyr to once daily basal insulin and then a bolus insulin with dinner, as that is her largest and most consistent meal of the day. Based on her current regimen, she was injecting 37.8 units of basal insulin and 16.2 units of prandial insulin per day. She could transition to a bolus insulin dose of 4 to 8 units and a basal dose of 34 to 38 units with a goal of a total insulin dose of 42 units per day (~22% reduction from the prior TDD). Eliminating the prandial insulin would be risky. Dependent on Zephyr’s motivation, ability to tolerate semaglutide, and attention to portion sizes and SMBGs, she may do well without any prandial insulin.

 

Semaglutide does not require set mealtimes or portions for safety. The pharmacist believed that with time, the patient would do well on basal insulin + semaglutide at higher doses, if tolerated. Sometimes, this interim period is the toughest for clinical decision-making.

 

CASE 4: Sahar Kim–pronouns: they/them/theirs

Visit 1

Sahar presented for their first visit, reporting that despite their FBGs being at goal, their A1c has been above goal. The insurance company did not cover their CGM so the pharmacist asked Sahar to test SMBGs more frequently. They sporadically checked, when possible, at the day's beginning or end (Table 8).

 

They were currently prescribed insulin glargine-yfgn (Semglee), which is a biosimilar to insulin glargine (Lantus), and inject 52 units once daily. The SMBG chart indicates FBGs of 80 to 100 mg/dL, and bedtime values are in the high 100s to low 200s.

 

Table 8. Sahar Visit 1

Date	acB	HS	HS insulin (insulin glargine-yfgn)
	78	198	52
	89		52
		201	52
	123	188	52
	111		52
			52
	97	187	52
	79		52
		210	52
	83	218	52
	98		52
		189	52
	109		52
		186	52
	87	199	52
Visit 1	98		52
Average	96	197

 

PAUSE AND PONDER: What would be the appropriate term for this situation regarding glycemic control/treatment?

 

Sahar declined an oral medication, as they have trouble swallowing them. They were amenable to an alternate once daily injection, as they would prefer not to have more than one injection daily. Sahar and the pharmacist deemed that an FRC would be the preferred option due to overbasalization and the patient’s preference to minimize injections. After some investigation into insurance coverage and discussion, they determined that iGlarlixi would be reasonable.

 

The pharmacist started Sahar on 30 units of iGlarlixi daily, which equates to 30 units of insulin glargine and 10 mcg of lixisenatide. Additionally, they were previously injecting at bedtime, but the FDA-approved labeling recommends morning dosing of iGlarlixi.²¹ Sahar reported that they will not be able to attend the next appointment (intended to be in approximately 2 weeks) or speak on the phone for the next 6 weeks. As they have been reliable and this was a transitional period in their treatment, the pharmacist developed a self-adjustment dosing plan. The pharmacist advised Sahar to increase iGlarlixi by 2 units once a week (up to 42 units daily) for each week that all their FBGS are greater than 130 mg/dL.

 

Visit 2

Sahar returned 6 weeks later and indicates that they increased iGlarlixi to 42 units over time based on the guidance the pharmacist provided at the last visit. They denied any ADRs (including hypoglycemia) associated with the FRC. A review of SMBGs shows stabilization between morning and bedtime values, indicating that the bedtime values have come down and the FBGs have increased. Although the FBG average is above 136, the trend shows decreasing FBGs over the last week or so. Through shared decision-making, Sahar and the pharmacist decided to maintain the current dose. The pharmacist expects to see an improvement in the A1c based on this improved PPG control. This is because although FBG and HS readings are being tested for ease, the improvement in HS readings indicates an improvement in PPGs.

 

TAKEAWAYS

We’ve reviewed many situations where insulin still plays a significant role in diabetes care. The advent of newer medications and greater coverage and affordability require a balance between new and old therapies to maximize the benefits and minimize the risks of both. Many medications for diabetes or coexisting obesity and diabetes (diabesity) are in the pipeline. This balance of optimal medication management will continue to change as the FDA approves new medications for diabetes.

 

Patient safety, especially prevention of hypoglycemia, is paramount in insulin dose adjustments, but monitoring and education regarding side effects is a close second. The pharmacist will need to adjust the dose or medication if there is a safety risk. Especially with the positive benefits associated with GLP-1 RAs, some patients may want to tolerate the adverse effects or hope they improve.

 

While these cases are extrapolated from the ambulatory care perspective, this knowledge can be helpful in a variety of settings. For example, pharmacists can use the principles discussed here for people obtaining their medications in the retail setting or those in the process of being titrated who are then hospitalized.

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