Contributor: Katrina Strand, PharmD Candidate Class of 2028, PCOM School of Pharmacy

Janice, a 47-year-old female with type 2 diabetes mellitus (T2DM), stops by her local pharmacy to refill her prescriptions. She currently takes metformin and injectable semaglutide, but she struggles with a fear of needles. While waiting, she asks the pharmacist about a new GLP-1 pill she recently heard about: orforglipron. “I’d love to be able to take a pill instead of giving myself a shot every week! Can you tell me more about it?”

Orforglipron is a once-daily oral GLP-1 receptor agonist currently in clinical trials to examine its safety and efficacy for patients with T2DM (ACHIEVE trials) and obesity (ATTAIN trials). It has reached Phase 3 and is projected to be approved for release in 2026. So far, Lilly has completed six Phase 3 clinical trials for the drug, and the results appear positive.

GLP-1 (glucagon-like peptide-1) receptor agonists are a common medication used to manage blood glucose in the treatment of T2DM. Most drugs in this class are injectable. In fact, there is only one oral GLP-1 currently available: oral semaglutide. One major difference between the novel oral GLP-1, orforglipron, and its predecessor, oral semaglutide, is its formulation. Oral semaglutide requires strict meal timing to be effective because peptides are more susceptible to breakdown in the stomach. Orforglipron, on the other hand, is a non-peptide small molecule, meaning it has no dietary restrictions and can be taken with or without a meal.

So far, orforglipron has been compared to at least two other medications used to treat T2DM. In Lilly’s ACHIEVE-2 trial, orforglipron was compared with dapagliflozin, an SGLT-2 inhibitor, in T2DM patients not adequately controlled on metformin. The results showed that orforglipron successfully lowered patients’ A1C by an average of 1.7%, whereas dapagliflozin only showed a 0.8% decrease.

In the ACHIEVE-3 trials, orforglipron went head-to-head against another common T2DM medication, oral semaglutide. This trial also showed orforglipron’s superiority in treating patients with T2DM not adequately controlled by metformin. Patients showed an average A1C decrease of 2.2% on orforglipron compared to 1.4% on oral semaglutide. Results also demonstrated that orforglipron more effectively promoted weight loss with an average reduction of 19.7 lbs compared to 11.0 lbs with oral semaglutide. Both trials consistently demonstrated orforglipron’s ability to lower A1C, achieve weight loss, and reduce cardiovascular risk factors.

Common adverse effects thus far are mild to moderate gastrointestinal distress, such as diarrhea, dyspepsia, and nausea. Most adverse effects were reported during the early stages of the trial while titrating to reach the desired dosage. These effects usually subsided over time.

Affordability plays a major role in treatment decisions and patient adherence. According to Lilly, the lowest dose of orforglipron, 3mg, is projected to cost $149 through LillyDirect self-pay, and higher doses will cost up to $399. The company does not specify the number of days that this estimate covers. For reference, these are the prices for a one-month supply of other popular GLP-1s as of November 2025: Ozempic® and Wegovy® – $199 for first two months then $349 thereafter ($499 for 2 mg Ozempic) (cash price from NovoCare® Pharmacy).

With this information, Janice feels more confident in her ability to make an informed decision about her diabetes treatment. Orforglipron could be an excellent alternative for patients who can benefit from GLP-1s but are uncomfortable with injections. This medication shows significant potential in managing diabetes and weight loss, and it appears to be even more effective than some treatment options currently available. She looks forward to discussing this option with her provider should orforglipron receive FDA approval in 2026.

References:

1. Eli Lilly and Company. (2025, November 20). What to know about orforglipron: An investigational oral GLP-1. Lilly News. https://www.lilly.com/news/stories/what-to-know-about-orforglipron
2. Eli Lilly and Company. (2025, September 17). Lilly’s oral GLP-1, Orforglipron, superior to oral semaglutide in head-to-head trial. Lilly Investors. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-superior-oral-semaglutide-head
3. Eli Lilly and Company. (2025, October 15). Lilly’s oral GLP-1, Orforglipron, demonstrated superior glycemic control in two successful phase 3 trials, reconfirming its potential as a foundational treatment in type 2 diabetes. Lilly Investors. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-demonstrated-superior-glycemic
4. Ma, X., Liu, R., Pratt, E. J., Benson, C. T., Bhattachar, S. N., & Sloop, K. W. (2024). Effect of food consumption on the pharmacokinetics, safety, and tolerability of once-daily orally administered orforglipron (LY3502970), a non-peptide GLP-1 receptor agonist. Diabetes Therapy, 15(4), 819-832.
5. Rosenstock, J., Hsia, S., Nevarez Ruiz, L., Eyde, S., Cox, D., Wu, W. S., … & Chen, Y. (2025). Orforglipron, an oral small-molecule GLP-1 receptor agonist, in early type 2 diabetes. New England Journal of Medicine.
6. Novo Nordisk. (2025). NovoCare. https://www.novocare.com/pharmacy.html. Accessed November 26, 2025.

Sally is a 70-year-old female who has been diagnosed with type 2 diabetes ten years ago and has been working hard to self-manage her diabetes through lifestyle and medications (semaglutide, insulin glargine, empagliflozin, metformin).   She survived a myocardial infarction a year ago.  She also has stage 3b CKD, osteoarthritis of the knee and obesity with a BMI of 30.   During Sally’s most recent office visit, she asked her provider about a novel triple incretin agonist that’s being studied for obesity and diabetes as she is interested in additional weight loss benefits.  Sally asked, “How is this triple incretin agonist different from semaglutide, and could it possibly help me in other ways too?”

Retatrutide is a triple agonist in that it is a receptor agonist of the glucose dependent insulinotrophic polypeptide (GIP), glucagon-like peptide 1(GLP-1)  and glucagon receptors. The potential mechanisms of action of retatrutide in obesity are maintaining energy expenditure, improved glucose, insulin and lipid metabolism, reduced inflammatory markers, and improved appetite regulation.  How exactly does this mechanism of action differ from tirzepatide and semaglutide?  Tirzepatide is a dual agonist that targets the GIP and GLP-1 receptors while semaglutide targets the GLP-1 receptor.  Retatrutide’s advantage is that it also targets the glucagon receptor. 

Retatrutide is currently being studied in persons with type 2 diabetes (TRANSCEND phase 3 clinical trial program), obesity (TRIUMPH phase 3 clinical trial programs) and with a substudy assessing benefit in metabolic dysfunction-associated steatotic liver disease.  The results from these trials are promising.  

TABLE 1. Select Phase 2 Trials

Trial Name	Population	Key Inclusion Criteria	Duration of Study	Primary Outcome	Results
Phase 2 Obesity Trial (1)	Obesity	Adults 18 – 75 years of ageBMI ≥ 30 and ≤ 50 kg/m2, or ≥ 27 to < 30 kg/m2 with at least one of the following:Hypertension      -Dyslipidemia      -CVD	48 weeks	Percentage change in weight from baseline to 24 weeks	−7.2% (1-mg group)−11.8% (4-mg group with an initial dose of 2 mg)−13.9% (4-mg group with an initial dose of 4 mg)−16.7% (8-mg group with an initial dose of 2 mg)−17.9% (8-mg group with an initial dose of 4 mg)−17.5% (12-mg group with an initial dose of 2 mg)−1.6% (placebo group)
A Substudy of Phase 2 Trial in Participants with Obesity without Diabetes (2)	Metabolic Dysfunction-Associated Steatotic Liver Disease	Metabolic dysfunction-associated steatotic liver disease  ≥10% of liver fat	48 weeks	Mean relative change from baseline in liver fat (LF) from baseline to at 24 weeks	-42.9% (1 mg group)-57.0% (4 mg group)-81.4% (8 mg group)-82.4% (12 mg group) +0.3% (placebo group)

Table 2. Overview of TRIUMPH Phase 3 Clinical Trial Program (in persons with obesity) (with focus on trials of retatrutide vs. placebo)

Trial Name	Population	Key Inclusion Criteria	Duration of Study	Primary Outcome
TRIUMPH-1 (3)	Adults with Overweight or Obesity	BMI ≥ 30 kg/m2 OR BMI ≤ 27 with ≥ 1 body weight related comorbidity (a) without T2D	80 weeks	Percent change in body weight from baseline
TRIUMPH-2 (4)	Adults with T2D and Overweight or Obesity	BMI ≥ 27 T2D	80 weeks	Percent change in body weight from baseline
TRIUMPH-3 (5)	Adults with Obesity and CV Disease	BMI ≥ 35Established CV disease with ≥ 1 of the following:Prior ischemic or hemorrhagic stroke,Prior MI, or Symptomatic PAD	80 weeks	Percent change in body weight from baseline
TRIUMPH-4 (6)	Adults with Overweight or Obesity with Knee Osteoarthritis	BMI ≥ 27Index knee pain for > 12 weeks prior to screening and for > 15 days over previous monthKnee x-ray with moderate radiographic changesMeets ACR criteria (clinical and radiological) for OA	68 weeks	Percent change in body weight from baselineChange from baseline in WOMAC Pain Subscale Score
TRIUMPH-6 (7)	Adults with obesity	BMI ≥ 30 kg/m2	116 weeks	Percent change in body weight from baseline
TRIUMPH-OUTCOMES (8)	People with Obesity and ASCVD and/or CKD	BMI ≥ 27With or without T2D (A1c ≤ 10%)Established ASCVD and/or CKD	248 weeks	Time to first occurrence of composite endpointsTime to first occurrence of composite endpoint of ESKD, >/= 40% sustained decline in eGFR, CV death or renal death

All studies are retatrutide versus placebo.

(a) Comorbidities include CV disease, dyslipidemia, hypertension or obstructive sleep apnea

What about side effects and cost? Based on the mechanism of action, the side effects will be similar to tirzepatide and semaglutide, particularly the gastrointestinal related in nature.   Cost is not available – however, it is reasonable to anticipate it will be similar to tirzepatide and semaglutide.

Back to Sally, retatrutide may benefit her over the semaglutide she is currently taking.  While there is not a head-to-head comparison of retatrutide vs. semaglutide, the triple action of retatrutide should result in more weight loss and better hemoglobin A1c reduction while possibly also reducing cardiovascular risk.  Sally feels this medication might be an option for her in the future after FDA approval.  She is excited to know that new novel medications are being developed that can address multiple chronic conditions with one medication.  

References:

1. Jastreboff AM, Kaplan LM, Frias JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial. New England Journal of Medicine. 2023;389(6):514-25. doi:10.1056/NEJMoa2301972
2. Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024;30(7):2037-2048. doi:10.1038/s41591-024-03018-2
3. A study of retatrutide (LY3437943) in participants who have obesity or overweight (TRIUMPH-1). ClinicalTrials.gov identifier: NCT05929066. Updated April 18, 2025. September 2, 2025. https://clinicaltrials.gov/study/NCT05929066
4. A study of retatrutide (LY3437943) in participants with type 2 diabetes mellitus who have obesity or overweight (TRIUMPH-2). Clinicaltrials.gov identifier: NCT05929079. Updated April 18, 2025. Accessed September 2, 2025. https://clinicaltrials.gov/study/NCT05929079
5. A study of retatrutide (LY3437943) in participants with obesity and cardiovascular disease (TRIUMPH-3). Clinicaltrials.gov identifier: NCT05882045. Updated July 23, 2025. Accessed September 2, 2025. https://clinicaltrials.gov/study/NCT05882045
6. A study of retatrutide (LY3437943) once weekly in participants who have obesity or overweight and osteoarthritis of the knee (TRIUMPH-4). Clinicaltrials.gov identifier: NCT05931367. Updated April 22, 2025. Accessed September 2, 2025. https://clinicaltrials.gov/study/NCT05931367
7. A Study of Retatrutide (LY3437943) in the Maintenance of Weight Reduction in Individuals With Obesity (TRIUMPH-6). Clinicaltrials.gov identifier: NCT06859268. Updated August 27, 2025. Accessed September 4, 2025.  https://clinicaltrials.gov/study/NCT06859268.
8. The effect of retatrutide once weekly on cardiovascular outcomes and kidney outcomes in adults living with obesity (TRIUMPH-Outcomes). Clinicaltrials.gov identifier: NCT06383390. Updated September 8, 2025. Accessed September 11, 2025. https://clinicaltrials.gov/study/NCT06383390

Contributor: Jalen Love, PharmD Candidate 2027, PCOM Georgia School of Pharmacy

        John is a 57-year-old man who was diagnosed with type 2 diabetes mellitus two years ago and has been actively managing his blood glucose with diet, exercise, and semaglutide. John was also diagnosed with coronary artery disease (CAD) five years ago, as well as chronic sleep apnea, and is clinically considered obese with a BMI of 35.7. At John’s most recent visit, his provider discussed with him a new option: tirzepatide, a once-weekly injection that works on both the GIP and GLP-1 pathways. Intrigued by the possibility of improved glycemic control and additional weight loss, John asked, “Is this only for diabetes and weight loss—or can it help me in other ways too?”

        In 2022, tirzepatide, under the brand name Mounjaro, was approved by the FDA as a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist for the treatment of type 2 diabetes. It gained further attention when clinical trials demonstrated significant weight reduction, leading to its 2023 approval under the name Zepboundfor chronic weight management in patients with obesity or overweight and associated comorbidities.

However, the scope of tirzepatide is rapidly expanding beyond glycemic control and weight loss. Current clinical trials and emerging evidence suggest promising roles in addressing a broad spectrum of metabolic and cardiovascular conditions.

Expanding Cardiometabolic Care 

1. Heart Failure with Preserved Ejection Fraction (HFpEF):

HfpEF is a common comorbidity among individuals with obesity and type 2 diabetes. The SURMOUNT and SURPASS-HF trials explore tirzepatide’s functional capacity and overall impact on quality of life in patients with HFpEF. Early data suggest improvements in symptoms and exercise tolerance. In the mentioned study, through a randomized(double-masked) trial, ~730 patients with class II-IV heart failure with EF greater than or equal to 50% with a concurrent BMI of greater than or equal to 30 kg/m2 were chosen to be given a placebo or tirzepatide. Tests to determine clinical variability included a 6-minute walk distance, ED-5D-5L health state index, and Patient Global Impression of Severity Overall Health score. Compared to placebo, tirzepatide produced a consistent improvement in worsening heart failure events and composites of death; they also improved Patient Global Impressional scores and required fewer heart failure medications after the study’s conclusion.

2. Atherosclerotic Cardiovascular Disease (ASCVD) Risk Reduction:

Similar to GLP-1 receptor agonists, tirzepatide may reduce major adverse cardiovascular events (MACE) in individuals at high risk. The ongoing SURPASS-CVOT trial states its primary outcome is determining the percentage of participants who achieve more than 5% body weight reduction within 72 weeks. Secondary outcomes include the following: with doses of tirzepatide 10 mg or 15 mg, they determined the rate of change in BMI, fasting glucose, fasting insulin, and body weight reductions of 5,15 and 20%.

        The study consists of two phases:  the primary phase and the extension phase; the main phase of the study will last a total of 72 weeks, and the extension will include patients who would continue the study beyond that point who were pre-diabetic to assess the progression to type 2 diabetes. This study concluded that with a dose of 15 mg of tirzepatide, patients achieved 20% of weight reduction. Among the extension phase group(with prediabetes), there was a reduction of progression to type 2 diabetes above 90%.

         Given John’s personal and family history of heart disease, his diagnosis of CAD, and chronic sleep apnea, his provider emphasized the potential benefits of tirzepatide beyond blood sugar control. It can potentially reduce cardiovascular risk and support weight loss. After discussion, John and his provider decided to initiate therapy with a comprehensive plan to monitor his glycemic status, cardiovascular markers, and sleep quality.

Three months later, John returned with encouraging updates: improved energy levels, notable weight loss, and normalization of liver function tests—demonstrating that the benefits of tirzepatide may extend well beyond diabetes management.

References

1. “Drug Approvals and Databases.” U.S. Food and Drug Administration, U.S. Department of Health and Human Services, www.fda.gov/drugs/drug-approvals-and-databases. Accessed 8 June 2025.
2. “Standards of Care in Diabetes—2025.” Diabetes Care, vol. 48, suppl. 1, 2025, pp. S1–S200, doi:10.2337/dc25-S001.
3. Jastreboff, Ania M., et al. “Tirzepatide Once Weekly for the Treatment of Obesity.” The New England Journal of Medicine, vol. 387, no. 3, 2022, pp. 205–216, doi:10.1056/NEJMoa2206038.
4. Sattar, Naveed, et al. “Dual GIP/GLP-1 Receptor Agonists in Cardiometabolic Disease.” The Lancet Diabetes & Endocrinology, vol. 11, no. 1, 2023, pp. 13–26, doi:10.1016/S2213-8587(22)00315-5.
5. “Tirzepatide – Clinical Trials.” ClinicalTrials.gov, U.S. National Library of Medicine, clinicaltrials.gov/ct2/results?cond=&term=tirzepatide&cntry=&state=&city=&dist=. Accessed 8 June 2025.
6. Zile, Michael R., et al. “Effects of Tirzepatide on the Clinical Trajectory of Patients with Heart Failure, Preserved Ejection Fraction, and Obesity.” Circulation, vol. 151, no. 10, 11 Mar. 2025, pp. 656–668. PubMed, doi:10.1161/CIRCULATIONAHA.124.072679.
7. Dominguez H., et al. “SURPASS‑CVOT Design and Baseline Characteristics: A Cardiovascular Outcomes Trial of Tirzepatide in Type 2 Diabetes.” American Heart Journal, vol. 268, 2023, p. 1, doi:10.1016/j.ahj.2023.09.007. PubMed, PMID 37758044.
8. Bastin, Marie, and Fabrizio Andreelli. “Dual GIP–GLP1-Receptor Agonists In The Treatment Of Type 2 Diabetes: A Short Review On Emerging Data And Therapeutic Potential.” Diabetes, Metabolic Syndrome and Obesity, vol. 12, no. , 2019, pp. 1973-1985.

Contributor: Airam Viennelu Aliwalas, PharmD Candidate 2027, PCOM Georgia School of Pharmacy

Helen, a 50-year-old woman, with a 3-year history of type 2 diabetes mellitus, presents to the clinic for her 3-month follow-up on therapy management. She is currently on insulin glargine (Lantus), a long-acting insulin, for the management of her type 2 diabetes mellitus. During her visit, she stated concern about the cost of her medications and inquired about alternatives that are as effective but more affordable than her current regimen.

Insulin is a hormone released by the pancreas to regulate the body’s blood sugar levels by allowing glucose to enter cells to be used as energy. Per the 2025 American Diabetes Association (ADA) Standards of Care in Diabetes, synthetic insulin therapy is required for type 1 diabetes mellitus, where the body does not produce enough insulin, and for specific parameters in type 2 diabetes mellitus, where the body does not use insulin effectively.

According to the National Institutes of Health (NIH), a biosimilar refers to a product that is clinically similar to an already approved reference biologic drug in terms of efficacy and safety. These products typically cost less than the reference drug, allowing the medication to be more affordable and accessible, especially for chronic conditions like diabetes mellitus. The approval process in the United States surrounding biosimilars requires preclinical and clinical studies to show that the proposed product to be equally effective as the reference product and are regulated by the Food and Drug Administration (FDA).

Approved Biosimilar and Follow-on Biologics in the United States

Reference Insulin	Biosimilar/Follow-on Insulin	Manufacturer	FDA Approval
Insulin Glargine	Insulin glargine (Basaglar)	Eli Lilly	2015 as follow-on insulin
	Insulin Glargine – yfgn (Semglee)	Viatris	2020 as follow-on insulin 2021 as biosimilar
Insulin Lispro	Insulin Lispro (Admelog)	Sanofi Aventis	2017 as follow-on insulin
Insulin Aspart	Insulin Aspart-szjj (Merilog)	Sanofi Aventis	2025 as biosimilar

With Helen’s concern regarding the price of her medication, insulin Glargine (Lantus), her healthcare team discussed possible alternatives while considering her insurance coverage. Her provider offered to switch her medication to the biosimilar, Semglee, to which Helen agreed. At her 3-month follow-up visit, her A1c remained stable and she expressed relief from financial stress.

References

Heinemann L, Davies M, Home P, Forst T, Vilsbøll T, Schnell O. Understanding biosimilar insulins – development, manufacturing, and clinical trials. Journal of diabetes science and technology. November 2023. Accessed April 18, 2025.

American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025 . Accessed April 18, 2025.

Marge, 68-year-old female with type 2 diabetes, presents for her 3 month follow up visit with her primary care provider (PCP).  She suspects that her hemoglobin A1c (A1c) is going to be up and is unsure of what exactly her goal A1c is after some particularly tough months emotionally and physically.   She is nervous that her provider may recommend insulin, and her sister said that insulin is not safe.  Marge is also curious whether one of these “GLP-1 agonists” might be good for her since her best friend (who also has type 2 diabetes) raves about her experience taking a GLP-1 agonist.  She bravely enters her PCP’s office determined to face her A1c regardless of what her number is, and advocates for herself in the treatment decision making process. The office visit begins well, then her provider enters the room and shares Marge has an A1c of 10%. 

Marge is not alone in her hesitation about insulin. Well-meaning friends and family weighing in on their opinion regarding the use of insulin can be a roadblock for providers.  The goal is for any treatment decision to incorporate shared decision making where both the person with diabetes and their provider have a voice in the final treatment selection.  The 2025 American Diabetes Association (ADA) Standards of Care in Standard 9 recommends GLP-1 agonist or dual GIP and GLP-1 agonist be considered in most individuals with type 2 diabetes prior to insulin.  These standards also recommend insulin use in type 2 diabetes when A1c is at or above 10% of glucose is at or above 300 mg/dL. Marge has A1c of 10%. So for Marge and her provider what are considerations beyond A1c that can help guide the selection of GLP-1 agonist or insulin?  What are the pros and cons of GLP-1 agonist versus?

Per the 2025 ADA Standards of Care, below are considerations when selecting therapy in type 2 diabetes.  Historically, the focus for treatment of type 2 diabetes was primarily glucose goal achievement and maintenance however those days are long gone.  The reduction of cardiovascular and kidney risk is now center stage as type 2 diabetes occurs on a cardiometabolic renal spectrum.

-Presence of or high risk for ASCVD

-Heart failure

-Chronic kidney disease

-Weight management

	Pros (Benefits)	Cons (Side Effects)
GLP-1 agonists	-Effectively lowers glucose and hemoglobin A1c-Cardiovascular (reduction in major adverse cardiovascular events (MACE) in those with or high risk of cardiovascular disease) ** -Renal (reduce persistent eGFR reduction and cardiovascular death in those with T2DM and chronic kidney disease) ** – Liver (potential benefit in MASLD or MASH) ** – Weight loss	-Constipation or diarrhea -Nausea -Risk of pancreatitis -Risk of gallbladder disease -Risk of thyroid C-cell disease
Insulin	-Effectively lowers glucose and hemoglobin A1c	-Weight gain -Hypoglycemia

**Benefit varies based on individual GLP-1 agonists

Back to Marge, a bit more about her clinical history as she has had NSTEMI (myocardial infarction in 2020), stage 3a chronic kidney disease and BMI of 28. She is also interested in trying out a continuous glucose monitor as she is tired of pricking her finger.  She is okay with injections but not any weight gain or low glucose values (as she lives alone).  She and her PCP spend about 10 minutes going through pros and cons of insulin versus non-insulin injectable.   They decide on a GLP-1 agonist in particular injectable semaglutide (Ozempic) due to the additional benefit considering her having CKD, established ASCVD and having elevated A1c. Oral semaglutide does not currently have the additional cardiometabolic renal indications.  Per the 2025 ADA Standards of Care Standard 6, an appropriate goal A1c for Marge considering her multiple co-morbidities would be < 8%.

References:

Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes – 2025. American Diabetes Association Professional Practice Committee. Diabetes Care. 2025; 48 (supplement 1):S181-S206.

Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes – 2025. American Diabetes Association Professional Practice Committee. Diabetes Care. 2025; 48 (supplement 1):S128-S145.

Contributor: Seana-Pierre Williams, PharmD Candidate 2025, PCOM Georgia School of Pharmacy

The use of insulin therapy to control elevated glucose levels in patients with diabetes adds a layer of complication in diabetes management due to the potential risk of over-treatment resulting in hypoglycemia. Hypoglycemia, in patients with diabetes, is typically characterized as having a blood glucose level below 70 mg/dL. This subsequent hypoglycemia can have a greater effect on morbidity and mortality for patients with type 1 diabetes, who are reliant on exogenous insulin, and extreme hypoglycemic events are directly associated with substantial overall health care costs.¹

Glucagon is a hormone produced by the pancreas that stimulates the liver to release glucose to replenish blood glucose therefore maintaining glucose homeostasis. Historically, exogenous glucagon was supplied as a powder that must be reconstituted into a solution before delivery due to glucagon’s instability in solution. One of the primary challenges in formulating exogenous glucagon is maintaining its stability over time. Glucagon is inherently unstable and can degrade when exposed to various conditions, such as temperature changes, pH fluctuations, and agitation.² The traditional reconstitution process of glucagon from powder to liquid has been a barrier to swift and efficient administration during emergencies.² Gvoke HypoPen is an autoinjector device developed by Xeris Pharmaceuticals that provides a convenient and user-friendly way to administer glucagon in cases of severe hypoglycemia and was approved by the FDA in 2019. The medication device is supplied as an auto-injector and prefilled syringe for subcutaneous injection only containing a freeze-dried powder glucagon, a surfactant, an antioxidant and chelating agent combined with a polar liquid to prevent instability. The formulations are available in two premeasured doses: a 0.5 mg/0.1 mL dose for pediatric administration and a 1 mg/0.2 mL dose for adolescent and adult administration. Gvoke (Glucagon) injection is an antihypoglycemic agent indicated for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes ages 2 years and above. Severe hypoglycemia is classified as a blood glucose level below 54 mg/dL and requires immediate treatment.

Potential advantages of Gvoke include the ease of use due to its auto-injection formulation, the absence of need for reconstitution and potentially the time to resolution of hypoglycemia in comparison to other delivery systems such as the Glucagon Emergency Kit (GEK). According to Cummins et al in a phase three comparison of a ready-to-use liquid glucagon rescue pen to glucagon emergency kit for the symptomatic relief of severe hypoglycemia, the auto-injector was shown to have a significantly higher success rate in delivering a full glucagon dose during simulated emergencies with both trained and untrained users. Additional advantages include the presence of a sheath protected needle that retracts into the auto-injector which reduces the incidence of needle sticks, the device can be stored for two years at room temperature and a reduction in injection site pain due to a smaller injected volume. A potential disadvantage of Gvoke is the potential for nausea and vomiting as the nonaqueous solution is delivered subcutaneously.¹ Drug interaction considerations include patients who are currently prescribed beta blockers, indomethacin and warfarin. Patients prescribed beta blockers may have a transient increase in pulse and blood pressure, Gvoke may may lose its ability to raise glucose or may produce hypoglycemia with use of indomethacin and risk of increased anticoagulant effects with warfarin.  

Key Counseling Points for Patients and Their Caregivers⁴:

• Be aware of signs and symptoms of hypoglycemia as severe hypoglycemia requires immediate treatment. Administer Gvoke as soon as severe hypoglycemia is recognized
• Signs and symptoms of hypoglycemia include but is not limited to shaking, sweating, fast heartbeat, extreme hunger, confusion, irritability, dizziness and blurred vision.
• Visually inspect the Gvoke product prior to administration. The solution should appear clear and colorless to pale yellow and be free of particles. If the solution is discolored or contains particulate matter, do not use.
• Store medication in its original sealed foil pouch until time of use
• Administer the injection in the lower abdomen, outer thigh, or outer upper arm according to printed instructions for use on packaging. Call for emergency assistance immediately after administering the dose.
• When the patient has responded to treatment, give oral carbohydrates to prevent recurrence of hypoglycemia.
•  Do not attempt to reuse Gvoke as each device contains a single dose of glucagon and cannot be reused.
• Allergic reactions can occur with Gvoke therefore seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions

Accessibility of Gvoke can be influenced by various factors including cost, insurance coverage and patient education. The future of glucagon delivery holds the promise of transforming hypoglycemia management, revolutionizing the way individuals with diabetes respond to low blood sugar episodes. Several avenues of innovation are shaping the future of glucagon administration, aiming to enhance its efficacy, ease of use, and overall patient experience.³

References:

1. Damianne Brand-Eubanks; Gvoke HypoPen: An Auto-Injector Containing an Innovative, Liquid-Stable Glucagon Formulation for Use in Severe Acute Hypoglycemia. Clin Diabetes 1 October 2019; 37 (4): 393–394.
2. Kumar, Samarth et al. “Glucagon: Delivery advancements for hypoglycemia management.” International journal of pharmaceutics vol. 652 (2024): 123785. doi: 10.1016/j.ijpharm.2024.123785
3. Christiansen M, Cummins M, Prestrelski S, Junaidi K. A phase 3 comparison of a ready-to-use liquid glucagon rescue pen to glucagon emergency kit for the symptomatic relief of severe hypoglycemia. Poster presented at the Diabetes Technology Society’s Diabetes Technology Meeting, 8–10 November 2018, Bethesda, Md
4. Gvoke-Accessdata.Fda.Gov, www.accessdata.fda.gov/drugsatfda_docs/label/2021/212097Orig1s007lbl.pdf. Accessed 12 Dec. 2024.

Contributor: Zuhal Saadut, PharmD Candidate 2025, PCOM Georgia School of Pharmacy

Meet Jana, a 48-year-old female that was recently diagnosed with prediabetes at her most recent primary care visit, with an A1c of 6.3%. She was upset when she found out about her diagnosis as her father had type 2 Diabetes. He had several incidences of extreme hyperglycemia, or high blood sugar, that required hospitalization. Her father also experienced vision loss due to many years of poor blood sugar control. Jana is afraid of these things potentially happening to her and wants to keep a close eye on her blood sugar levels without having to prick her finger every day and carry a blood glucose meter kit everywhere she goes. She is determined to gain control of her health again and signed up for nutrition classes and a gym membership to improve her dietary intake and physical activity. With these lifestyle changes, she wants to see how fast it will work. Jana is curious about the use of continuous glucose monitoring but does not want to go through the prescription process because her “insurance sucks anyways”.

As of March 5th, 2024, the U.S. Food and Drug Administration (FDA) has approved its first over the counter (OTC) continuous glucose monitoring (CGM), the Dexcom Stelo Glucose Biosensor. This product is intended for individuals ages 18 and older that either do not use insulin to treat their diabetes or want to check their blood glucose trends as they eat or exercise. This system does not have the ability to warn patients if they are experiencing hypoglycemia, or low blood sugar (<70 mg/dL), therefore is not meant for individuals with problematic hypoglycemia.

Dexcom Stelo is a sensor that is applied in a similar fashion as other CGM sensors, with wear time that can last up to 15 days. A study was conducted on the sensor wear time and showed that 77.9% of sensors last the full 15 days. The remaining sensors did not last for 15 days, with 10% of them lasting less than 12 days. The sensor must be paired with a smartphone device that is compatible with the Dexcom application to be downloaded. A Dexcom account must also be created before the sensor can be used. The readings of your blood sugar will appear on the app and updates every 15 minutes. Dexcom Stelo is currently not available in the market, but according to their manufacturers, it should be available Summer 2024 for online purchase.

Abbott has also obtained FDA approval for OTC CGMs (Lingo and Libre Rio) as of June 10th, 2024. Lingo is intended for individuals ages 18 and older that are looking to improve their overall health and wellness, with a sensor wear time of 14 days. Libre Rio is intended for individuals ages 18 and older with Type 2 Diabetes that do not use insulin therapy, with sensor wear time of up to 15 days, measuring blood sugars ranging from 40 to 400 mg/dL. Both of these sensors require smartphone devices compatible with their respective applications and an account must be created before use of the sensor. Neither product from Abbott is available on the market yet, however, Lingo is estimated to be available for purchase Summer 2024. As of right now, there is no estimated time of when Libre Rio will be available for purchase.

The OTC CGMs differ from the prescription CGM as they have an age restriction and are recommended to not be used in individuals with type 1 diabetes or those with type 2 Diabetes on insulin therapy or incidences of hypoglycemia. If you notice constant high or low readings of your blood sugar, be sure to consult your healthcare provider before taking any action of adjusting your medication doses. Adverse effects of sensor use include local infection, skin irritation and pain or discomfort.

Fast forward to 6 months later, she was looking forward to her follow up appointment with her doctor to find out what her new A1c would be after these lifestyle modifications. Results came back with an A1c of 5.3%! Her doctor applauded her for taking the initiative for her health. Jana is relieved that she was able to prevent herself from getting Diabetes before it was too late and will continue to do her best to stay healthy.  Jana is happy that she has the option to monitor her blood sugar levels without having to prick her finger daily and loves that the results are digital on her phone.

References:

• https://www.fda.gov/news-events/press-announcements/fda-clears-first-over-counter-continuous-glucose-monitor
• https://www.dexcom.com/stelo?sfc=7014y000000zbBPAAY&gad_source=1&gclid=CjwKCAjwm_SzBhAsEiwAXE2Cv2_hWxtpvxHKBeCsnM7QgiPMyrEyYy6GPT3gTJun9hBN2PF96-UH7RoCBmAQAvD_BwE

https://abbott.mediaroom.com/2024-06-10-Abbott-Receives-U-S-FDA-Clearance-for-Two-New-Over-the-Counter-Continuous-Glucose-Monitoring-Systems

Contributor: Seana-Pierre Williams, PharmD Candidate 2025, PCOM Georgia Campus School of Pharmacy

Earlier this year both Dexcom and Freestyle Libre stormed the Diabetes Technology market with an upgraded continuous glucose monitor (CGM). The new Freestyle Libre 3 and Dexcom G7 continuous glucose monitors will provide a significantly smaller device size and a highly anticipated enhancement in the devices’ features to improve the patient’s overall experience. Here’s what you should know about these new and improved versions of the CGM systems. 

Dexcom G7

The G7 is approximately 60% smaller than the previous G6 model and boasts a more circular shape. The sensor and transmitter have now been combined into one disposable device. The G7 now has a reduced warm up time from two hours with the G6 to now 30 minutes with the G7. Upon completion of the warmup period, the sensor will begin automatically. The wear time of the G7 remains the same as the previous G6 model, 10 days, with one major upgrade. The G7 sensors now carry a 12- hour grace period to replace an expiring sensor and new customizable alerts along with the ability to temporarily silence alarms. The mobile app for iOS and Android users- the Dexcom CGM app for the G7 is also redesigned to provide a “Clarity Card” which is a data summary of average glucose, Glycemic Management Indicator (GMI) and Time in Range (TIR) for the past 3, 7, 14, 30, or 90 days. The Dexcom G7 sends the glucose readings approximately every five minutes to the smartphone app or a receiver. The G7 reader or the smart phone being used can receive information from 20 feet away and stores up to 24 hours of data in case the phone or receiver is out of range. Once the receiving device is back in range, the data will be transmitted. The application of the G7 remains user friendly with the presence of a button on the applicator to press down to release the sensor.

Freestyle Libre 3

The Freestyle Libre 3 now provides real-time glucose readings sent to a compatible smartphone and can now be viewed with a quick glance without the need to scan. The sensor is now comparably smaller than the Libre 2 system, measuring at approximately 21mm in diameter with a new simple one piece applicator and optional real-time glucose alarms. The Libre 3 retains the 60-minute warmup period and the sensor starts upon first scan as with the Libre 2. The wear time for the Libre 3 remains the same as the previous Libre 2 model, 14 days. The Freestyle Libre 3 now sends the glucose readings automatically to the user’s smartphone every minute and can receive information from up to 33 feet away. The sensor stores 14 days of data in case the smartphone is out of range of the sensor. The Libre 3 now carries a new, simple one-piece applicator which requires a slight push down on the applicator to insert the sensor.

Affordability and Insurance

From an affordability and insurance standpoint, both the Dexcom and Libre 3 manufacturers offer programs to allow access to their respective CGM systems. Dexcom offers the “Dexcom G7 Simple Start” program for those with commercial insurance whose insurance plans have not yet added the G7 to their coverage. Under this program, the G7 sensors can be purchased for $89 a month at local pharmacies until coverage is added. Freestyle Libre offers a “Free Trial” program for eligible individuals to receive a free voucher for a trial of the system. This free trial comes with additional resources to help the new user get off to a good start. Commercially insured patients may pay up to $75 per month (depending on an individual’a coverage plan) for the sensors and is said to be more affordable than other CGM systems. Those who have questions regarding the Libre 3 sensors or are asked to pay over $75 can contact Freestyle Libre.  For those with Medicare coverage, both Dexcom G7 and the Freestyle Libre 3 are covered for eligible persons with diabetes.

What do these updates in both CGM systems mean for the person with diabetes?

Seana-Pierre Williams offered to give an insight on how the cutting edge CGM technology has impacted her overall management of diabetes. As a person with diabetes who has struggled with type 1 Diabetes for 15 years, continuous glucose monitoring has been pivotal in managing this chronic illness. Seeing my blood glucose in real time allows for more accurate treatment decisions which I have used to improve the overall control of my diabetes. Having alerts to keep me on track offers me peace of mind especially since I live a very active lifestyle.  I can feel confident and safe that my CGM will alert me in times when I am outside of my blood glucose target ranges. Hypoglycemia is a life-threatening risk when using blood glucose lowering treatments, especially insulin since I am insulin dependent. Smaller size sensors offer me more discretion and comfort since I am constantly wearing a sensor. There is also the additional benefit of not having to finger stick unless my symptoms do not match what my CGM is displaying. Having used multiple CGM systems over the years, there are pros and cons with both Dexcom and Freestyle Libre. With the upgrades in Freestyle Libre 3 and Dexcom G7, more patients, like me, are able to manage our Diabetes with more comfort and confidence and can focus on living a normal day to day life. Once Diabetes has entered the discussion, your world is turned upside down. From lifestyle modifications to pharmacological intervention, continuous glucose monitoring is a powerful tool helping me to stay on top of things! When choosing a continuous monitor, just remember that each patient’s experience is unique. There are several patient factors that should be considered when deciding what CGM is best for you.

https://www.diabeteseducator.org/danatech/glucose-monitoring/continuous-glucose-monitors-(cgm)/cgm-selection-training/dexcom-g7-libre-3-comparison

Contributor: Krishna Chavada, PharmD Candidate 2024, PCOM Georgia School of Pharmacy

Based on self-reported data, 1.3 million American adults have been diagnosed with Type 1 diabetes and use insulin. Maintaining blood glucose levels can become very difficult and it can become a burden to such patients’ lifestyle. To better manage such levels, automated insulin delivery systems were developed and have been lifesavers to persons with diabetes. Insulin pumps have become increasingly popular over time as a method to manage diabetes once placed under the skin. Throughout the day, the insulin the pump can give small doses of insulin as basal insulin, typically set up by your healthcare professional. The patient must enter in the amount of bolus, or mealtime, insulin is required based on their personal needs. The pump is typically the size of a deck of cards and typically doses are delivered more accurately with an insulin pump. Currently there are 6 insulin pumps that are recognized by the American Diabetes Association:

• Tandem T Slim X2 with Basal-IQ
• Tandem T Slim X2 with Control-IQ
• Omnipod 5
• Omnipod DASH
• Medtronic 770G/780G
• Medtronic 630G

Amongst these, you may find pumps that requires no calibrations throughout the day, such as the Omnipod 5, or insulin capacity up to 300 units, such as the Medtronic 770G/780G.

Boston University has brought a revolutionary device to the healthcare world, one that can be considered the “next-generation technology”. After completing long and successful clinical trial , the bionic pancreas, got approved for use in patients aged 6 years and older with Type 1 diabetes. It has been billed as the “first and only automated insulin-delivery system that delivers 100% of all insulin doses”. The iLet is an artificial device that can deliver personalized insulin doses every 5 minutes, dependent upon the glucose levels and the body’s reaction to previous insulin deliveries. Patients will have an easier time managing their diabetes without the stress of constantly having to calculate their insulin doses with adjustments. Patients will also be freed of having to monitor their glucose levels, optimizing their quality of life. One of the large benefits of the iLet system compared to insulin pumps is that it independently determines changes that are required for a patient in terms of basal rates, glucose correction factors, insulin correct factors, and other regimen parameters. Users must enter their body weight into the device’s software prior to initiating the regimen during the time of first use. Allowing patients to have this new level of ease in the management of Type 1 diabetes can be vital to transforming their day-to-day life. The most reported adverse effect with the use of the iLet was hyperglycemia (43%). Currently the iLet can be configured as an insulin only, glucagon only, or insulin-glucagon dual delivery system. The pocket-sized system is deemed to be a great breakthrough device. This fully automated bionic pancreas has shown improvement of HbA1c in persons with Type 1 diabetes, per the randomized, multicenter trial.

REFERENCES:

FDA Clears iLet Bionic Pancreas System for Type 1 Diabetes. www.medpagetoday.com. Published May 19, 2023. Accessed June 21, 2023. https://www.medpagetoday.com/endocrinology/type1diabetes/104599#:~:text=The%20pump%20can%20be%20configured

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FDA Clears Bionic Pancreas Developed in BU Lab for People with Type 1 Diabetes. Boston University. Published May 24, 2023. https://www.bu.edu/articles/2023/fda-clears-bionic-pancreas-for-type-1-diabetes/

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Commissioner O of the. FDA Clears New Insulin Pump and Algorithm-Based Software to Support Enhanced Automatic Insulin Delivery. FDA. Published May 22, 2023. Accessed June 21, 2023. https://www.fda.gov/news-events/press-announcements/fda-clears-new-insulin-pump-and-algorithm-based-software-support-enhanced-automatic-insulin-delivery

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Bionic Pancreas System Safe, Cuts HbA1c in Type 1 Diabetes. www.medpagetoday.com. Published September 28, 2022. Accessed June 21, 2023. https://www.medpagetoday.com/endocrinology/type1diabetes/100956

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After the recent release of the 2023 American Diabetes Association (ADA) Standards of Care, you may be wondering whether metformin is still the one size fits all for the first line treatment of all persons with newly diagnosed type 2 diabetes. Please check on the link below to learn more. Also, if you are a primary care provider, pharmacist or pharmacy or medical learner, please submit to my YouTube channel, ReecesPiecesDiabetes.

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