The escalating rates of obesity among American adults, reaching 41.9% in 2020, have amplified the need for effective weight loss solutions. With the overweight category included, an alarming 73% of Americans are facing weight-related health challenges. The COVID-19 pandemic may have further exacerbated these rates, according to a nationwide study. Semaglutide, originally a diabetes medication, has emerged as a promising therapeutic for weight loss, demonstrating benefits for both diabetes and heart disease. This article delves into the advantages and disadvantages of semaglutide for weight loss, providing a comprehensive overview for individuals considering this treatment option.
Semaglutide in the Spotlight
Semaglutide, the active ingredient in medications like Ozempic® and Wegovy®, initially gained FDA approval for diabetes treatment. However, its notable weight-loss properties have attracted individuals seeking to lose weight and improve their health. The internet quickly became a hub for information, with forums and guides detailing how individuals without diabetes could access off-label versions of these drugs.
Public awareness of semaglutide-based drugs surged, leading to global shortages due to high demand. This increased attention also sparked skepticism and raised concerns about the potential side effects of semaglutide treatment. It is crucial to carefully evaluate the benefits of semaglutide against the potential risks, including heart disease and other complications associated with obesity.
The Benefits of Semaglutide
Cardiologist Andrew Freeman, MD, offers valuable insights into the costs and benefits of semaglutide. He notes that many individuals are apprehensive about using these drugs, especially those without diabetes, recognizing their origin as diabetes medications. However, it's important to note that most diabetes drugs have minimal to no effect on weight, or even increase it, like insulin. Semaglutide, on the other hand, helps people lose weight, positively impacting various cardiovascular risk factors.
In 2020, the FDA expanded the medication’s approved usage after discovering that semaglutide reduced the risk of heart attack and stroke. Dr. Freeman expresses enthusiasm for these medications, highlighting their ability to target overall cardiometabolic risk by addressing diabetes, heart disease, and weight simultaneously. Weight loss achieved through semaglutide leads to improved heart health and a significantly better quality of life.
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The weight loss results reported by patients using semaglutide drugs are remarkable. Some patients have experienced a loss of approximately 30 to 40 pounds within two to three months, according to Dr. Freeman.
Semaglutide also has been studied in individuals with certain types of obesity-related heart failure, both with and without diabetes. Studies suggest that semaglutide may help improve heart failure-related symptoms, such as tiredness, shortness of breath and swelling. Multiple studies are in progress or being planned to examine if semaglutide will be helpful for other conditions.
Cardioprotective Effects
Semaglutide, a GLP-1 receptor agonist, has demonstrated superior cardioprotection for people with T2DM compared to other treatments. Clinical trials like SUSTAIN and PIONEER found that it reduced major adverse cardiovascular events (MACE) by approximately 26%, outperforming other diabetes drugs. Its benefits extend beyond glycemic control, including weight reduction and anti-inflammatory effects, which collectively lower cardiovascular risks. Additionally, in patients with Heart Failure With Preserved Ejection Fraction (HFpEF) and obesity, semaglutide produced large improvements in HFpEF related symptoms. Semaglutide treatment is also found to decrease myocardial diastolic stiffness and improve actin-myosin and muscle contraction pathways.
Semaglutide therapy also reduced incidence of any stroke when compared to a placebo through significant reductions in risk of small-vessel occlusion in a post hoc analysis of the SUSTAIN 6 and PIONEER 6 trials. Semaglutide therapy also seems to decrease incidence of stroke comparative to other therapies, specifically a dipeptidyl peptidase-4 inhibitor.
Potential Therapeutic Effects for Alzheimer’s Disease
Semaglutide therapy has also garnered attention for its potential therapeutic effects for Alzheimer’s Disease. Specifically, semaglutide therapy has been associated with associated with decreased amyloid-beta plaque deposition and neuroinflammation. It’s effects on the central and peripheral nervous system are thought to mediate these effects, party through ability to cross the blood-brain barrier.
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Pooled data from three randomized controlled trails and a nationwide registry-based cohort have consistent findings. Nørgaard et al. found that rates of dementia were lower in patients undergoing G1PR agonists compared to a placebo in both the randomized control trail patient data and nationwide cohort data. There is a need for more studies to explore the idea of repurposing semaglutide therapy for Alzheimer’s Disease treatment.
Reduction in HbA1c Levels to Improve Glycemic Control
One of the main goals of semaglutide therapy is a reduction in HbA1c levels to improve glycemic control. Subcutaneous semaglutide, administered once weekly, has shown a 1.5-1.8% reduction in HbA1c levels over 30-56 weeks in various SUSTAIN trials. In contrast, oral semaglutide, taken once daily, demonstrated HbA1c reductions ranging from 1.0-1.4% in the PIONEER trials, achieving a 1.4% reduction after 26 weeks in PIONEER 1 .
Weight Reduction
In SUSTAIN 1 and PIONEER 1 trials, with patients managing early-stage diabetes with diet and exercise alone, subcutaneous semaglutide 1.0 mg led to a mean weight reduction of 4.5 kg, whereas oral semaglutide 14 mg achieved a 3.7 kg reduction. In the SUSTAIN 2, PIONEER 3, and PIONEER 7 trials involving patients with established Type 2 Diabetes (T2D) on one or two oral antidiabetic drugs (OADs), both subcutaneous semaglutide (0.5 mg and 1.0 mg) and oral semaglutide (7 mg, 14 mg, and flexibly dosed) resulted in significantly greater body weight reductions compared to sitagliptin. Additionally, oral semaglutide 14 mg showed a significant reduction in body weight compared to liraglutide 1.8 mg in the PIONEER 4 trial.
Slowing the Progression of CKD in People with T2DM.
The FLOW clinical trial investigated whether semaglutide can slow the progression of CKD in people with T2DM. Participants were randomly assigned to receive either subcutaneous semaglutide or a placebo, administered weekly. Among 3533 randomized participants, the semaglutide group had demonstrated benefits for kidney-specific outcomes, cardiovascular death, and other secondary outcomes, including a slower decline in kidney function
Improves PCOS outcomes
The use of GLP-1R agonists in women with PCOS could provide weight loss effects, as well as improve hyperinsulinism, hyperandrogenism, normalize total testosterone, insulin resistance markers, and total cholesterol. A total of 176 participants from four RCTs were included in a systematic review study, where GLP1-R agonist use was associated with a significant reduction in waist circumference, BMI, serum triglycerides, and total testosterone levels compared to placebo. Another study also showed that semaglutide effectively reduces body weight in obese PCOS patients who did not respond to lifestyle changes. After three months of treatment, most patients lost weight, with 80% achieving a weight loss of at least 5%, and improvements in insulin resistance and fasting blood glucose were observed, with minimal side effects. Those who continued treatment for six months experienced further weight loss and normalization of menstrual cycles.
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The Costs of Semaglutide
The costs associated with semaglutide are a significant consideration. Dr. Freeman points out that it is a very expensive drug, with prices varying depending on insurance coverage. Some patients may pay as much as $1,400 a month for certain versions of the drug, and this cost is ongoing if they wish to maintain the weight loss. This makes semaglutide unaffordable for a substantial portion of the population, and even those who can initially afford it may struggle to sustain it long-term.
Dr. Freeman notes that many individuals either receive samples or have their insurance cover the drug initially, but coverage may cease or become too costly, leading them to discontinue use and regain the weight, often within a month or so.
Potential Side Effects and Risks
While rare, there are serious potential side effects associated with semaglutide use, including pancreatitis, gallbladder disease, kidney damage, and thyroid cancer. The long-term effects of taking semaglutide medications remain unknown, necessitating careful consideration and monitoring.
Semaglutide may cause some mild to moderate side effects, which often decrease over time, such as nausea, vomiting, diarrhea, constipation and abdominal pain. If using semaglutide with certain other medications for diabetes, low blood sugar also may result. In clinical trials, approximately 20% of people discontinued the medication due to side effects. Semaglutide is not recommended for people with type 1 diabetes, diabetic ketoacidosis, or a history of pancreatitis or a certain type of thyroid cancer.
Other side effects are cosmetic changes, including hair loss, muscle loss, loose or sagging skin, and more pronounced wrinkles and increased heart rate.
The Compromise: A Holistic Approach
Dr. Freeman advocates for a balanced approach to semaglutide use for weight loss. He suggests that these drugs should be used as a "running start" to kickstart the weight loss journey. While semaglutide can provide the initial momentum needed, it is crucial to adopt comprehensive lifestyle changes, including improved eating habits and regular exercise routines, to ensure long-term success.
Relying solely on semaglutide without making necessary lifestyle adjustments is not a sustainable approach. It is essential to view semaglutide as a tool to facilitate weight loss, rather than a standalone solution.
Semaglutide Injections for Weight Loss
Currently, semaglutide is only approved for weight loss under the brand name Wegovy. The typical dose for weight loss is 2.4 milligrams, administered weekly as subcutaneous (under the skin) self-injections.
As interest in semaglutide for weight loss continues to grow, health care professionals are finding ways to manage the demand. Many prescribe other brands of semaglutide, such as Ozempic and Rybelsus, off-label (using a drug that is FDA-approved for a different reason).
Effectiveness of Semaglutide for Weight Loss in Non-Diabetics
There have been several anti-obesity medications that help suppress appetite and achieve weight loss. But semaglutide performs on a new level.
An early study of 2,000 obese adults compared people using semaglutide plus a diet and exercise program with people who made the same lifestyle changes without semaglutide. After 68 weeks, half of the participants using semaglutide lost 15% of their body weight, and nearly a third lost 20%. Participants who incorporated only lifestyle changes lost about 2.4% of their weight.
Since then, additional studies have shown similar results. But they’ve also revealed that participants tend to regain the weight lost when they stop taking semaglutide.
Who Should (and Should Not) Take Semaglutide for Weight Loss?
The FDA recommends Wegovy for weight loss if you meet one of the following criteria:
- Have a body mass index (BMI) of 27kg/m2 or greater and at least one weight-related condition, such as high blood pressure, Type 2 diabetes or high cholesterol
- Have a BMI of 30kg/m2 or greater
Avoid semaglutide if you have:
- History of medullary thyroid cancer
- History of gallbladder disease
- History of pancreatitis
- Multiple endocrine neoplasia syndrome type 2 (MEN2)
If you’re considering semaglutide for weight loss, your first step should be consulting your primary care physician (PCP). They know your personal and family medical history and can guide you in the best treatment for your condition.
Semaglutide: Oral vs. Subcutaneous
Semaglutide is available in two formulations: oral and subcutaneous.
- Oral semaglutide therapy: should start at 3 mg once daily for a month before doses are increased to 7 mg once daily. If necessary, after a month of maintenance, dosage can be increased to 14 mg once daily. This formulation should be taken on an empty stomach, with a 30-minute wait before eating or taking other medications to optimize absorption, as food and increased fluid intake can affect bioavailability.
- Subcutaneous semaglutide therapy: should start at 0.25 mg once weekly and after 4 weeks, dosage can be increased to 0.5 mg once weekly. If necessary, dosage can be increased to 1 mg once weekly after another 4 weeks. This route offers a high bioavailability of 89%, with peak concentrations reached within 1-3 days and steady-state occurring after 4-5 weeks. The subcutaneous administration is flexible regarding meal timing, with injection sites rotated weekly among the abdomen, thigh, and upper arm.
Both formulations share an elimination half-life of about one week, remaining in circulation for around five weeks post-last dose, with clearance rates of 0.05 L/h for subcutaneous and 0.04 L/h for oral in healthy individuals. Elimination occurs primarily through the urine and feces.
Considerations and Precautions
Multiple Endocrine Neoplasia Syndrome (MEN2) is a rare, genetic disorder that affects the endocrine glands and can cause tumors. Semaglutide is not recommended for people with this condition.
Potential side effects:
Some common side effects of Semaglutide include nausea, diarrhea, constipation, and abdominal pain. These side effects are typically mild and improve over time.
Injections:
Semaglutide is administered via a once-weekly injection, which may be inconvenient for some individuals.
Cost:
Semaglutide can be expensive, and insurance coverage varies. It’s important to check with your insurance provider to determine your out-of-pocket costs.
Not a standalone solution:
Semaglutide should be used in conjunction with a reduced-calorie diet and increased physical activity to achieve the best results.
Long-Term Use:
As of now, the long-term effects of semaglutide use for weight loss are not well-known.
Semaglutide: Not a Cure-All
Semaglutide may offer potential benefits for many people; however, it is not a cure-all. It is important to remember that obesity is heterogenous, chronic and complex. There is no cure for obesity. It requires lifelong treatment that’s not one size fits all.