Introduction   

In 2017, the FDA approved the semaglutide injectable (Ozempic) for treating type 2 diabetes. The drug has experienced widespread acceptance due to its positive effects on weight loss and lowering chronic health risks. The drug has risen in popularity over the past few years, as many well-known actors/actresses/songwriters and others came forward, publicly sharing their weight loss journeys.

This rise in popularity has also resulted in significant shortages of this medication, negatively impacting the lives of the diabetic community, local pharmacies, and healthcare providers. The goal of this continuing education course is to educate and empower the healthcare provider in all aspects of this drug regimen: clinical indications, patient education, cost options, and benefit/risk analysis.

Diabetes Overview

Diabetes is a chronic medical condition. Despite advances in diet, medications, and monitoring devices, diabetes diagnoses continue to grow at staggering rates. The Institute for Health Metrics and Evaluation (IHME) reports that over 529 million people worldwide are currently living with diabetes. That number is expected to grow to 1.3 billion in only 30 years. While the risk factors for diabetes are vast in number (poor diet, inadequate activity, obesity, sedentary lifestyles, daily stressors, and more), the sad reality is that this chronic medical condition will most likely linger on for generations to come despite our efforts to contain this health epidemic (1).

According to the latest research on diabetes, there are over 37 million people in the United States with diabetes as of 2022. Statistically, approximately 28 million of them have a confirmed diagnosis, while another estimated 8 million are experiencing symptoms without an official diagnosis. Diabetes currently ranks as the 7^th leading cause of death in the United States (2).

Types of Diabetes

In basic terms, diabetes is an impairment in one’s ability to either adequately produce or utilize insulin, which results in elevated levels of circulating glucose. Chronically elevated glucose levels affect blood vessels at every level, causing chronic inflammation and raising the risk of heart disease, stroke, blindness, and atraumatic amputations.

There are three main types of diabetes:

1. Type 1 diabetes is thought to be an autoimmune disease. Approximately 5-10 percent of people with diabetes are diagnosed with type 1 diabetes. The diagnosis usually occurs in early childhood and results in a lifetime use of insulin to regulate blood glucose levels.
2. Type 2 diabetes is thought to be related to dietary and lifestyle choices. It accounts for nearly 90-95 percent of diabetes diagnoses. Usually occurring later in life (adult-elderly population), it is believed to be related to factors such as diet, activity, weight gain, and related factors. Type 2 diabetes is usually controlled by diet and exercise, in addition to oral medications, although injectable insulin may be included in the treatment plan.
3. Gestational diabetes refers to elevated glucose levels occurring during pregnancy for patients who are not diabetic at the onset of pregnancy. This version of diabetes usually resolves itself post-partum, although a woman may develop type 2 diabetes later in life, unrelated to pregnancy.

Type 2 diabetes in children: no longer a “later in life diagnosis”

Children are now being diagnosed with type 2 diabetes at an alarming rate. Despite widespread education and an increased awareness of diabetes, our up-and-coming generation is unhealthier than ever. Many families lack access to healthy food due to both general socioeconomic challenges and an increased rate of food insecurity. (19)

The CDC recommends that care providers have resources for diabetic patients and their families, such as food and nutrition programs, budget-friendly diabetes meal plans, information on how to save money on diabetes care, and coping strategies. (19)

Diabetes Signs and Symptoms, Diagnostic Testing

There are various ways to test for diabetes. A simple test is the fasting blood sugar (FBS)/ fasting glucose level.

The normal fasting glucose level is below 100mg/dl. The fasting glucose result of 100-125mg/dl indicates prediabetes, and results above 126mg/dl indicate diabetes.

The hemoglobin A1C blood test is another test used to confirm the diagnosis of diabetes. The patient does not need to be fasting for this test, so it is easier to order it regardless of the time of day. This blood test reflects the average glucose level over the period of 2-3 months.

The normal A1C level is below 5.7%. Test results between 5.7% and 6.4% indicate prediabetes and test results above 6.5% indicate diabetes.

A random glucose reading above 200mg/dl, done at any time of day, indicates diabetes.

Diabetes is diagnosed by blood tests, and for improved accuracy, it should be based on two separate readings, done (at least) a day apart. In the case of fasting and random blood tests, dietary intake (large amounts of carbohydrates in a single meal) may adversely affect test results. This is not the case when A1C testing is used for a confirmation diagnosis, as the results are an average of a 2-to 3-month span.

Target blood levels for a person with diabetes (3).

Target blood glucose levels for people with diabetes are as follows:

• Fasting glucose 80-130mg/dl.
• Postprandial blood glucose level- less than 180mg/dl
• A1C level 7-8%.

These target ranges are general guidelines. Patient-specific ranges will be dependent on a variety of factors, including preexisting comorbidities, overall health status, age, and activity levels.

The hallmark signs/symptoms of diabetes

1. Polyuria- increased urination
2. Polydipsia- increased thirst
3. Polyphagia-increased hunger/appetite

The truth is, as healthcare providers, you will have patients who have no hallmark signs and symptoms of diabetes; the diagnosis will be found during annual preventive examinations, often unrelated to any chronic disease. For this reason, many insurance companies now cover numerous preventive screenings, including diabetes screenings, as part of their wellness and prevention initiatives. These tests are often approved based on a patient’s age or preexisting conditions rather than outright signs and symptoms.

Lifestyle Interventions and the Diabetes Prevention Program

The initial diagnosis of diabetes can be managed in various ways, depending on the severity of the illness at the time of diagnosis. Lifestyle interventions (behavior modification education) are of utmost importance in the care and management of people with diabetes. Research over the past few decades has consistently shown that such interventions have immense positive effects on the successful long-term management of diabetes.

The official Diabetes Prevention Program was created in 2010 (4) and confirmed the effects of lifestyle interventions in managing diabetes:  Lifestyle interventions decreased the incidence of type 2 diabetes by 58% compared with 31% in the metformin-treated group. Thus, these findings now serve as the blueprint, if you will, for all-inclusive, patient-specific disease management guidelines. These lifestyle interventions will be discussed in detail later in the program.

Additional Resources on Diabetes Prevention

• Detailed History of the Diabetes Prevention Program
• Detailed on the National DPP Lifestyle Change Program

Semaglutide

Semaglutide is an injectable drug used in the treatment of type 2 diabetes. It was approved by the FDA in May of 2017.

It is a once-a-week injectable and belongs to the drug class known as glucagon-like peptide-1 receptor agonists (GLP-1RAs) (5). It has been referred to as a “miracle weight loss drug” among those who are living with obesity despite frequent side effects, unusually high out-of-pocket costs, drug shortages, and weight regain when attempting to stop using the medication.

GLP-1 receptor agonist: Hormone Review

GLP-1 RAs are a class of medications used to treat Type 2 diabetes and, in some cases, obesity treatment. They are also known as GLP-1 receptor agonists, incretin mimetics, and GLP-1 analogs.

Ghrelin and Leptin (6)

Ghrelin and Leptin are hormones that greatly influence appetite and the sensation of fullness. Ghrelin is often referred to as the “hunger hormone.” It is responsible for many functions, including playing a key role in metabolism through glucose and insulin regulation.

Ghrelin, produced in your stomach, signals your brain when hungry and increases food intake.

Leptin, conversely, is produced in your fat cells and signals to the brain when you have eaten enough (by decreasing your appetite).

Glucagon-like peptide-1 receptors

Known as GLP1 receptors, Glucagon-like peptide-1 receptor proteins are located in the beta cells of the pancreas as well as in the neurons in the brain. GLP-1 receptors are involved in the regulation of blood glucose levels and affect the secretion of insulin. These cells encourage insulin release from the pancreas, increase the volume of beta cells, and reduce the release of glucagon. In doing so, they increase the feeling of fullness during and between meals, suppressing the appetite and slowing gastric emptying.

What is meant by receptor agonist and antagonist?

The term agonist refers to any substance that mimics the actions of a hormone in producing a specific response: a receptor antagonist blocks a response from occurring.

Opioids are examples of receptor agonists in that they produce responses such as analgesia.

Naloxone/Narcan is an example of a receptor antagonist in that it binds to a receptor site and decreases/blocks a response from occurring.

Semaglutide mechanism of action (7)

GLP-1 agonists work in several ways to positively affect glucose levels. Their mechanism of action includes the following:

• Increasing (stimulating) insulin secretion by the pancreatic beta cells.
• Decreasing the production of glucagon, a hormone that raises blood glucose levels
• Decreasing (slowing) gastric emptying
• Decreasing appetite (and thereby reducing food intake) by creating a sensation of stomach fullness

Through these mechanisms of action, semaglutide results in a lowering of serum glucose/A1C levels, which lowers the risk of cardiovascular events. Studies have also shown that semaglutide resulted in weight loss (approximately 8-14 pounds on average {dose dependent results}.

Side Effects of Semaglutide

Common side effects of semaglutide (8)

Common side effects may include any of the following:

• Nausea and vomiting
• Headache
• Diarrhea and stomach pain
• Upset stomach, indigestion, constipation, flatulence

These side effects usually subside within a few weeks as the patient acclimates to the medication.

Serious side effects of semaglutide

• Hypoglycemia- enhanced/worsened when used in combination with other diabetes medication. Symptoms may include drowsiness, confusion, weakness, irritability, and headache.
• Symptoms may include abdominal pain and distension, nausea and vomiting, fever, and back pain.
• Diabetic retinopathy. Symptoms may include blurred vision, vision loss, and diminished night vision.
• Kidney damage/injury/failure. Symptoms may include fatigue, nausea, diminished urine output, confusion, and edema of extremities.
• Gallbladder disease. Symptoms may include gallstones, abdominal pain, nausea and vomiting, and poor appetite.

Black Box Warning (9)

Semaglutide has a Black Box Warning for thyroid cancer. This is the most serious warning from the Food and Drug Administration (FDA) and is intended to alert consumers to the potential risks of a medication.  This black box warning was issued when research found that the drug increased the risk of thyroid tumors in animals.

It is not known if semaglutide actually causes tumors in humans.

Contraindications

• Semaglutide is contraindicated in people with a personal or family history of MTC (medullary thyroid cancer) or in patients with multiple endocrine neoplasia syndrome type 2.
• Known hypersensitivity to semaglutide or any of the product components

Cautions

As noted under “serious side effects”, there have been reports of new illnesses or worsening of existing health conditions occurring “post-marketing”. Thus, healthcare providers are strongly encouraged to continue the ongoing surveillance of patients using semaglutide therapy. In addition, there is insufficient data available regarding the use of semaglutide by pregnant women. Women are, therefore, highly encouraged to stop any treatment with semaglutide for at least 2 months before a planned pregnancy.

Dosing

Semaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). It is also considered favorable for reducing the risk of cardiovascular events in adults with T2DM and a preexisting history of cardiovascular disease. This drug is FDA-approved for use in people with diabetes with a BMI of 27% or higher (a BMI of 25-29.9% is considered overweight).

Semaglutide (Ozempic) is an injectable prescription medication. It is available in 0.5mg, 1mg, or 2 mg doses once weekly.

The injection should be administered subcutaneously to the abdomen, thigh, or upper arm. Injection sites should be rotated and given as a single injection.

Start at 0.25 mg once weekly. After 4 weeks, increase the dose to 0.5 mg once weekly.

• If additional glycemic control is needed, increase the dose to 1 mg once weekly after at least 4 weeks on the 0.5 mg dose.
• If additional glycemic control is needed, increase the dose to 2 mg once weekly after at least 4 weeks on the 1 mg dose

Administer once weekly at any time of day, with or without meals.  The maximum dose recommendation is 2mg/weekly once weekly.

Note: The initial 0.25-mg dose is intended for treatment initiation and is not effective for glycemic control

Missing Dose Guidelines

• If the missed dose is ≤5 days: Administer dose as soon as possible
• If missed dose >5 days: Skip the missed dose and administer the next dose on the regularly scheduled day; patients can then resume their regular once-weekly dosing schedule

Administration Day Guidelines (10).

The administration day each week can be changed, if necessary, as long as the time between 2 doses is at least 2 days (>48 hours)

Dose Availability (packaging)

• 2mg/1.5mL (1.34mg/mL); delivers doses of 0.25mg or 0.5mg per injection or four to eight doses per injection pen
• 4mg/3mL (1.34mg/mL); delivers 1mg per injection or 4 doses per injection pen
• 8mg/3mL (2.68 mg/mL); delivers 2mg per injection or 4 doses per injection pen

Treatment Goals- Effects on A1C and Weight (11)

A majority of adults who were placed on injectable semaglutide for diabetes management achieved a target A1C under 7% and were able to maintain it.

• Dose specific effects on A1C were as follows:
• 0.5mg dose injection yielded a 1.4% decrease
• 1.0mg dose injection yielded a 1.6% decrease
• 2.0 mg dose injection, in combination with diabetes pills, yielded a 2.1% decrease in A1C.

Adults taking semifluid injectables for diabetes management also noted weight loss.

• 8-pound weight loss reported with 0.5mg dose injection
• 10 pounds weight loss reported with 1.0mg dose injection
• Up to 14 pounds of weight loss was reported with a 2.0mg dose injection

Prescribing insights: Long-Term therapy for a chronic condition?

Semaglutide is viewed favorably as a treatment option for Type 2 diabetes. It appears to lower A1C levels and body weight in the majority of patients, lowering their risk of future cardiovascular events.

The question of long-term medication use for a chronic health condition is being heavily discussed in the media. While a percentage of people can decrease or eliminate the need for chronic medications through significant lifestyle changes, there have been reports of weight gain in those who stopped taking this injectable medication.

Without intense lifestyle behavior modification education, there is a heightened risk of weight regain in the absence of such medications. Leaders in the treatment of obesity and related illnesses have commented that this drug is intended for long-term use.

Examples of this include the following:

“GLP-1 medications [like Ozempic] are designed to be taken long-term… They are chronic medications for the treatment of chronic conditions (both diabetes and obesity) (12)”. – Christopher McGowan, M.D., a gastroenterologist specializing in obesity medicine and endobariatrics

“As with many chronic conditions, most people who use the drugs for diabetes or weight loss will need to keep taking them to keep benefiting from them. Depending on your individual situation, and without sustained lifestyle changes, it is likely you would need to be on these medications indefinitely to maintain weight loss (13).” – Dr. Cecilia Low Wang, a UCHealth expert in endocrinology, diabetes and metabolism.

Cost Concerns

At this time, injectable semaglutide, FDA-approved for the treatment of Type 2 diabetes, has a self-pay price tag of $935.77 per month (4 injections). With FDA approval, many people with diabetes, insured under commercial plans, receive the drug for the cost of their copay. Those patients without coverage may use pharmacy discount cards that reduce the price, on average, to $814.55/month.

The following links are available to familiarize yourself with patient assistance programs related to semaglutide injectables.

Semaglutide Cost Savings Programs

The following links are provided to explore various semaglutide cost savings programs.

• Novo Care’s Ozempic Saving Offer
• How much does Ozempic (0.25 Or 0.5 Mg/Dose) cost?
• GoodRx

Emerging Concerns: Semaglutide and gastroparesis

In August 2023, a first-of-its-kind lawsuit was filed in Louisiana against the makers of semaglutide. The lawsuit states the makers of this injectable drug did not adequately warn patients about the risk of severe gastrointestinal issues/possible gastroparesis.

The plaintiff, in this case, had used both Ozempic and Mounjaro and experienced repeated episodes of severe gastrointestinal events, warranting trips to the emergency room and additional medications to alleviate her symptoms (14). While this lawsuit is in the developing stages, it bears mentioning in terms of concerns over long-term usage of the drug and possible complications.

While the drug labeling for semaglutide (Ozempic) does not specifically mention gastroparesis, the semaglutide/Mounjaro label does state that the drug has not been studied in patients with severe gastrointestinal disease and is, therefore, not recommended for these patients.

Up to 50% of people with diabetes have some degree of delayed gastric emptying, but most have no digestive symptoms or have only mild symptoms. For some people with diabetes, problems managing blood glucose levels may indicate delayed gastric emptying (15).

Healthcare providers should evaluate all patients with diabetes for possible symptoms of underlying gastroparesis, such as the feeling of fullness shortly after beginning a meal or the inability to finish a regular meal. Other symptoms of gastroparesis may include abdominal pain, nausea, bloating, vomiting, and anorexia.

Diabetes and gastroparesis

Uncontrolled or poorly controlled diabetes can affect nerve endings systemwide. Diabetes is a very common cause of gastroparesis. Although the condition is rare, it occurs more often in people with chronic conditions such as diabetes, autoimmune diseases, and nervous system disorders. Nerve endings are injured or damaged, cease to function properly, and result in delayed gastric emptying. The delay in gastric emptying can cause various symptoms, such as nausea, vomiting, bloating and distension, abdominal pain, and poor appetite.

In addition to underlying medical conditions, some medications may cause symptoms of gastroparesis (delays in gastric emptying and overall gastric motility. These medications include narcotics, antidepressants, and anticholinergics.

Left untreated, diabetic gastroparesis may lead to malnutrition, electrolyte imbalances, and poor glucose management and control.

Ozempic Case Study

• 52-year-old female
• Height 67 inches
• Weight 225 pounds
• B/P 138/84, Heart rate 76 NSR
• BMI 35.2%
• Nonsmoker, occasional social drinker
• Multiple attempts at dieting without success.
• Diagnosed T2DM approx. 6 months ago, current A1C 7.5%; initial medication Metformin 500mg BID tablets; tolerated well. No GI upsets.

Today’s appointment is for evaluation and additional medication consideration (the patient requested this appointment)

The patient was diagnosed with T2DM approximately 6 months ago. Initial A1C 8.0%. Current A1C 7.7%

Despite an improved diet and adherence to the medication regimen, the patient voiced frustration at the lack of weight loss. Requesting additional medication. I have a neighbor friend who began injectable Ozempic and is having “really great results with it. I want to start on it as well”.

The patient has expressed frustration that despite taking her medications and adjusting her diet, she has not lost any weight in the past 6 months. She has “heard from her neighbor friend that the weight just melts off immediately,” and she is ready to start this medication.

Your patient decides to go ahead with the semaglutide regimen, and your patient wants to know how long she will be taking this medication.