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GLP-1 Receptor Agonists: Ensuring Appropriate Use Amidst High Demand

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GLP-1 receptor agonists (GLP-1s) have become a hot topic in recent years. Celebrities, online influencers, and even multi-billionaires like Elon Musk use them, touting them as a quick fix weight loss solution. With about 70% of American adults being overweight or obese, and many dealing with related health complications, it’s no surprise that people seeking a slimmer figure are turning to GLP-1s for help. After all, the ability to lose upwards of 10-25 pounds just by taking a weekly injection sounds ideal and convenient.

However, GLP-1s are more than just a trend. It is a class of drugs used as a second-line add-on medication in type 2 diabetes management and as a first-line treatment in obesity management. This growing popularity, especially among those with obesity, has contributed to a nationwide drug shortage and raises concerns about ensuring that patients with diabetes still have access to these vital treatments. Therefore, understanding the appropriate use of GLP-1s for individuals is crucial.

How do GLP-1s work?

GLP-1s work by stimulating insulin secretion and suppressing glucagon secretion in hyperglycemic states. This delays gastric emptying and decreases appetite.

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What are GLP-1s used for?

  1. Diabetes Mellitus

GLP-1s are primarily used as a second-line treatment for type 2 diabetes. They are especially beneficial when used alongside metformin or combination therapy in the following situations:

  • Atherosclerotic cardiovascular disease (ASCVD)
  • Chronic kidney disease (if SGLT2 inhibitors are not tolerable or if additional glucose control is needed)
  • Existing combination therapy with need for additional weight loss or glycemic management
  1. Weight Loss

GLP-1s are also a first-line therapy for managing obesity in patients who have not achieved at least 5% total body weight loss in three to six months through lifestyle interventions. They are recommended for:

  • Individuals with a BMI >30 kg/m²
  • Individuals with a BMI of 27-29.9 kg/m² who have weight-related comorbidities such as hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea, or cardiovascular disease

See below for additional information regarding available GLP-1 medications:

What are some adverse reactions and warnings to be aware of?

When starting GLP-1 receptor agonists, patients typically undergo a titration period to help mitigate gastrointestinal side effects. It is recommended to prescribe a low dose initially and gradually increase it to minimize adverse effects like nausea and vomiting.

  • Gastrointestinal (nausea, vomiting, diarrhea)
  • Injection site reactions (redness, itching, swelling)
  • Acute kidney injury
  • Cholelithiasis (gallstones)

Black Box Warning

GLP-1s are not recommended in patients with or at risk of Thyroid C-Cell tumors. These drugs are also not recommended for pregnant patients and those with severe gastrointestinal diseases (ulcerative colitis, Crohn’s disease, irritable bowel syndrome, inflammatory bowel disease).

Challenges

Despite their effectiveness, GLP-1s face challenges regarding cost and availability. A one-month supply of these medications can cost over $1,000 without insurance, creating a financial barrier for many people. The demand for these drugs has also exceeded supply, causing major manufacturers to announce shortages. The Food and Drug Administration (FDA) manages a website that allows healthcare providers and patients to view drugs on shortage. To further assist patients, a telehealth company, Ro, has also developed a public tracker to provide real-time availability information submitted by consumers themselves. Another issue to note is the disparity in medication access, with the largest users being disproportionately non-Hispanic white females. Difficulty finding insurance coverage further exacerbates these inequities. Lastly, counterfeit versions of GLP-1s have also emerged in the market, posing risks to patient safety. Addressing these issues requires collaborative effort between insurers, healthcare professionals, and government entities to improve access, lower costs, and to ensure the authenticity and safety of medications.

Takeaway

GLP-1s offer significant benefits for diabetes and obesity management, but challenges such as high costs and shortages limit access to patients who need the drugs. People who are seeking these medications should always see a licensed medical professional to determine if the use of GLP-1s is the most appropriate option for them. Healthcare providers and pharmacists alike have a responsibility to stay informed about these medications, their availability, and cost to ensure they can offer the best guidance for patients.

Winnie Chu

RxPharmacist Team

Resources
  1. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. The New England Journal of Medicine. 2021;385(6):503-515. doi:10.1056/NEJMoa2107519. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2107519. Accessed August 3, 2024.
  2. FDA Approves New Medication for Chronic Weight Management. U.S. Food and Drug Administration. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-chronic-weight-management. Accessed August 3, 2024.
  3. Glucagon-like peptide-1 receptor agonists. Available at: https://www.ncbi.nlm.nih.gov/books/NBK551568/. Accessed August 3, 2024.
  4. Shifting Trends in the Indication of Glucagon-like Peptide-1 Receptor Agonist Prescriptions: A Nationwide Analysis. Available at: https://www.acpjournals.org/doi/10.7326/M24-0019. Accessed August 3, 2024.
  5. Are You Sure Your Ozempic Is Real? Fakes Are on the Rise. The New York Times. July 12, 2024. Available at: https://www.nytimes.com/2024/07/12/well/ozempic-fake-counterfeit-drugs.html. Accessed August 3, 2024.
  6. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2024. American Diabetes Association. 2024;26(4):501-510. doi:10.1111/dom.14535. Available at: https://pubmed.ncbi.nlm.nih.gov/38078590/. Accessed August 3, 2024.

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Five Varieties of Insulin and Why We Need Them

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An estimated 34.2 million people in the United States have some form of diabetes (⅕ of which are entirely unaware), and in the last 20 years the number of diagnosed adults has more than doubled in size.1 The significance of this disease state is paramount from a public health perspective, especially as diabetes has been identified as the number one cause of kidney failure, lower limb amputations and microvascular complications.1 You can think of diabetes as a metabolic disease which is generally broken down into four categories: type one diabetes, type two diabetes, gestational diabetes (onset during pregnancy) and prediabetes (elevated blood glucose levels which are yet to be considered entirely diagnostic of active disease).1

The following video is an excellent visual resource for understanding diabetes and its associated consequences on the human body.6 Both type one and type two diabetes cause an accumulation of glucose in the bloodstream, however, it is the etiology that differentiates them. Type one diabetics essentially experience autoimmune destruction of their pancreatic beta cells which diminishes endogenous insulin production (type one is usually diagnosed in younger people and makes up 5-10% of diabetics).1 In comparison, type two diabetics can produce insulin just fine but their body is unresponsive due to built up insulin resistance over time (type two is usually diagnosed in adults and makes up 90-95% of diabetics).1

The tricky thing about insulin is it must be injected because it is easily broken down and digested in an oral form.2 All patients with type one diabetes will be dependent on exogenous insulin for survival, and some type two diabetics may also require insulin for adequate control. There is a highly interesting concern in type two diabetes management surrounding a delay in insulin initiation, typically dubbed clinical inertia. You can read more about clinical inertia in the following literature review: Clinical inertia is the enemy of therapeutic success in the management of diabetes and its complications: a narrative literature review.

Insulins can be deadly when used inappropriately. It is important to understand and be familiar with the onset, peak and duration of insulins as seen in the figures above so an appropriate personalized regimen or adjustment can be made for each patient’s needs and goals. Generally, rapid and short acting insulins are intended for bolus purposes, whereas intermediate and long acting insulins are intended for basal purposes. We can also categorize and identify insulins via the five categories above. Note that Afrezza is inhaled as opposed to injected and can be given at the start of each meal which may be a great option if a patient is looking for something non-injectable.

As an aside, one important public health issue as it relates to insulins is actually affordability. Supposedly one in four diabetic patients cannot afford their insulin altogether.4 The issue is complex and significant enough to have its own dedicated gofundme page as for many patients insulins are a non-negotiable lifeline. You can read more about the black market dedicated to the insulin trade here, but remember there are resources for patients who need them should you ever directly encounter this issue in the community. Some patients may also obtain over the counter insulin from Walmart’s ReliOn insulin program.

References

  1. Centers for Disease Control and Prevention. What is Diabetes? Accessed April 6, 2021. https://www.cdc.gov/diabetes/basics/diabetes.html.
  2. American Diabetes Association. Insulin Basics. Accessed April 6, 2021. https://www.diabetes.org/healthy-living/medication-treatments/insulin-other-injectables/insulin-basics.
  3. Insulin and diabetes. Accessed April 6, 2021. https://www.diabetes.org.uk/guide-to-diabetes/managing-your-diabetes/treating-your-diabetes/insulin.
  4. About Mealtime Insulin. Accessed April 6, 2021. https://www.humalog.com/fast-acting-mealtime-insulin.
  5. Teare, K. One in four patients say they’ve skimped on insulin because of high cost. Accessed April 6, 2021. https://news.yale.edu/2018/12/03/one-four-patients-say-theyve-skimped-insulin-because-high-cost.
  6. Diabetes UK. Diabetes and the body | Diabetes UK. Published September 3, 2013. Accessed April 6, 2021. https://www.youtube.com/watch?v=X9ivR4y03DE.

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What Pharmacists Need to know about Diabetes

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As per the Centers for Disease Control and Prevention (CDC), 34.2 million people, or 1 in every 10, in the United States have diabetes. Diabetes is 7th on the list of leading causes of death while the total estimated medical costs and costs associated with lost work and wages equates to an estimated $327 billion.

Diabetes, otherwise known as increased sugar levels (hyperglycemia) may be a result of decreased insulin secretion, decreased insulin sensitivity, or both. It can present itself in one of two forms of the following:

  • Type 1
    • Autoimmune destruction of beta cells
    • Loss of insulin production
    • Must use insulin injections
  • Type 2
    • Insulin resistance
    • Decreased insulin production over time
    • Associated with obesity, physical inactivity, family history
  • Signs and symptoms of diabetes include:
Signs and Symptoms of Diabetes
  • Risk factors:
Risk Factors for Diabetes
  • General Screening Criteria:
    • All patients with BMI greater than or equal to 25 kg/m2 + 1 risk factor
    • Children/adolescents with obesity + 1 risk factor
    • 45 years old if no risk factors are present
    • Pregnant women at 24-48 weeks
PrediabetesDiabetes
->Fasting plasma glucose (FPG) 100-125 mg/dL; or
->2-hour glucose after glucose tolerance test 140-199 mg/dL; or
->A1c 5.7-6.4%  		->Symptoms + random plasma glucose > 200 mg/dL; or
->2-hour glucose after glucose tolerance test > 200 mg/dL; or
->FPG > 126 mg/dL; or
->A1c > 6.5%  
  • Glycemic targets (per ADA guidelines):
    • A1c < 7%
    • 80-130 mg/dL pre-prandial plasma glucose
    • < 180 mg/dL post-prandial plasma glucose
    • A1c should be measured quarterly if not at goal
      • Or twice yearly if at goal
      • (A1c – 2) x 30 = average blood glucose
  • Drugs that may increase blood glucose levels:
Drugs that may increase blood glucose levels
  • Non-drug treatment options:
    • Smoking cessation
    • Weight loss
      • 3500 kcal weekly reduction = 1 lb weight loss
      • Waist circumference < 35 inches for females and < 40 inches for males
    • Nutrition
      • Carbs from vegetables, fruits, grains, and dairy
      • Omega-3 fatty acids and fiber
      • Limit saturated fat, cholesterol, and sodium
      • 15 g = 1 serving of carbohydrates
    • Physical activity
      • 150 min/week, moderate intensity
      • No more than 2 consecutive days off
      • Resistance training at least 2x/week
Drug treatments (oral medications)
  • Additional notes on oral drug classes:
    • Biguanides
      • Take with food
      • Use of alcohol increases the risk of lactic acidosis
      • Discontinue before any imaging with iodinated contrast; resume after 48 hrs
    • Meglitinides
      • Take 1-30 minutes before meals
      • If skipping a meal, skip dose as well
    • Sulfonylureas
      • Take with breakfast
        • Exception: Glipizide IR 30 minutes before breakfast
      • Glyburide – avoid in elderly and patients with renal impairment
    • Thiazolidinediones
      • Take with meals
      • May take weeks to take effect
      • Additional warnings:
        • Bladder cancer (pioglitazone only)
        • Risk of macular edema
        • Fracture risk
        • Hepatic failure
        • Resumption of ovulation
    • SGLT-2 Inhibitors
      • Caution when taking with diuretics and NSAIDs (due to risk of hypotension and acute kidney injury)
      • Additional warnings:
        • Genital infections
        • Hypotension
        • Increased LDL
        • Renal insufficiency
        • Ketoacidosis
      • Monitor K+ with Canagliflozin
    • DPP-4 Inhibitors
      • Take in the morning
Drug treatments (injectable medications)

Additional notes on injectable drug classes:

  • GLP-1 Agonists:
    • Exenatide and lixisenatide are administered 60 minutes before a meal
    • All others given without regard to food
  • Amylin Analog
    • Used in treatment of both type I and II diabetes
    • Reduce mealtime insulin by 50%

  • Drug treatments (Insulin)
    • For all insulins:
      • Side effects: weight gain
      • Warnings; hypoglycemia, hypokalemia
      • Never use pens for more than one individual
      • Most are 100 units/mL concentration
      • High risk medications
    • Dosing strategies
      • Basal insulin
        • Long or intermediate acting
        • Mainly affect fasting blood glucose
      • Bolus insulin
        • Rapid or short acting
        • Two purposes:
          • Prandial (mealtime) & correction (acute elevation)
Drug treatments (Insulin medications)
  • Insulins that do not require a prescription:
    • Regular insulin, NPH, and the premixed 70/30 combination
  • Insulin dosing for Type I diabetes:
    • Rapid-acting and basal insulin preferred
    • If using NPH and regular insulin
      • 2/3 NPH, 1/3 regular
    • Initiating basal/bolus insulin:
      • Calculate total daily dose (TDD)
        • 0.6 units/kg/day using TBW
      • Step 2: Divide TDD
        • 50% basal
        • 50% bolus
      • Step 3: Divide the bolus among 3 meals
    • Based on the amount of carbohydrates in a meal, meal-time insulin can be adjusted using rule of 500 (rapid-acting insulin) or rule of 450 (regular insulin)
      • (500 or 450)/TDD = g of carbs covered by 1 unit of insulin
  • Correction factor/dose
    • Factor:
      • Determines how much blood sugar will drop for every 1 unit of insulin. Uses the rule of 1800 (rapid-acting insulin) or rule of 1500 (regular insulin)
        • (1800 or 1500)/TDD = correction factor for 1 unit of insulin
  • Dose:
    • Amount of insulin required to bring blood glucose back to normal: [(blood glucose now) – (target blood glucose)]/   correction factor = correction dose
  • General treatment algorithm for Type II Diabetes:
General treatment algorithm for Type II Diabetes
  • For A1c greater than or equal to 8.5%: Jump straight to dual treatment
  • A1C > 10%: Think insulin
  • Cardiovascular benefit:
    • GLP1 agonists: liraglutide, semaglutide, exenatide
    • SGLT2 inhibitors: empagliflozin, canagliflozin
  • Patient-specific factors
    • Drugs that minimize hypoglycemia:
      • DPP4 inhibitor, GLP1 agonist, SGLT2 or TZD
    • Drugs that promote weight loss:
      • GLP1 agonist or SGLT2 inhibitors
    • Drugs with cost concerns:
      • Sulfonylurea or TZD
  • Combinations to avoid:
    • DPP4 inhibitors + GLP1
    • Sulfonylureas + insulin
  • Insulin dosing for Type II diabetes:
    • Initiate basal insulin after patient fails to reach or maintain goal on multiple oral therapies
    • Starting dose: 0.1-0.2 units/kg/day or 10 units/day
    • Titrate by 10-15% or 2-4 units once or twice weekly until fasting blood glucose at goal
    • If patient reaches fasting blood glucose goal but their A1c is still above goal:
      • Consider the addition of rapid acting mealtime insulin or GLP-1 agonist
  • Insulin administration:
    • Abdomen is the injection site (avoid belly button)
    • May also inject in thighs, buttocks, arms
      • Be consistent with administrations
    • Prime before each dose
    • Rotate sites
  • Hypoglycemia is common with insulin products, thus important to be aware of what to look out for and how to treat it
    • Defined as a blood glucose < 70 mg/dl
    • Symptoms: sweating, pallor, irritable, hunger, lack of coordination, sleepy
      • Beta blockers mask most except hunger and sweating
    • Treatment
      • Consume 15-20 g of glucose/simple carbohydrates
      • Recheck glucose levels after 15 minutes
      • Repeat if needed
      • Eat a small meal/snack to prevent recurrence
    • Glucagon is used only if patient is unconscious
  • Diabetes in pregnancy
    • Gestational diabetes: during pregnancy
      • Risks
        • Macrosomia
        • Hypoglycemia at birth
        • Obesity and type 2 diabetes
      • Management
        • Lifestyle modifications
        • Insulin added if needed (preferred)
        • Metformin and glyburide used
      • Goals:
        • Fasting < 95 mg/dL
        • 1-hour post-meal less than or equal to 140
        • 1-hour post-meal less than or equal to 120

We hope this review helped refresh your clinical knowledge on diabetes. Next up, we will take a look at dyslipidemia.

Best of luck,

Sam Tamjidi

RxPharmacist Team

References:

  1. National Diabetes Statistics Report, 2020. Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/data/statistics-report/index.html. Accessed October 26, 2020.
  2. Micromedex Solutions. Greenwood Village, CO: Truven Health Analytics. http://micromedex.com/. Accessed October 26, 2020.

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