Semaglutide vs Tirzepatide: Comparing Two Leading Weight Loss Medications | Weight Loss Knox Blog

Two medications have dominated the conversation around medical weight loss in recent years: semaglutide and tirzepatide. Both are injectable GLP-1 based therapies that have shown remarkable results in clinical trials, and both are now widely prescribed by weight loss clinics across the country — including here at Weight Loss Knox in Knoxville, TN.

But how do these two medications actually compare? Which one produces better results? Are the side effects different? And most importantly, how do you decide which is right for you?

In this comprehensive guide, we break down the key differences and similarities between semaglutide and tirzepatide so you can have an informed conversation with your medical provider.

The Basics: What Are These Medications?

Semaglutide

Semaglutide is a GLP-1 receptor agonist. It mimics the naturally occurring hormone GLP-1, which your body releases after eating. Brand names include Ozempic (approved for type 2 diabetes) and Wegovy (approved for chronic weight management). Semaglutide was the first GLP-1 medication to gain widespread attention for its weight loss benefits, and it remains one of the most prescribed weight loss medications in the United States.

Tirzepatide

Tirzepatide is a dual GLP-1 and GIP receptor agonist. It targets the same GLP-1 pathway as semaglutide but adds activation of the GIP receptor, creating what researchers call a “twincretin” effect. Brand names include Mounjaro (for type 2 diabetes) and Zepbound (for weight management). Tirzepatide is the newer of the two medications and entered the weight loss space with clinical trial results that exceeded those of semaglutide.

How They Work: Mechanism of Action

Semaglutide — Single Receptor Agonism

Semaglutide works by binding to GLP-1 receptors in the brain, gut, and pancreas. Its primary effects include:

Reduced appetite: Signals to the hypothalamus to suppress hunger
Slowed gastric emptying: Food stays in the stomach longer, promoting fullness
Improved blood sugar regulation: Enhances insulin secretion and reduces glucagon release
Potential effects on food reward pathways: Some patients report reduced cravings for high-calorie foods

Tirzepatide — Dual Receptor Agonism

Tirzepatide does everything semaglutide does through the GLP-1 pathway, but also activates GIP receptors. This additional mechanism is believed to:

Enhance the satiety signal beyond what GLP-1 alone provides
Improve fat metabolism through GIP receptors present in adipose tissue
Further improve insulin sensitivity, which can reduce fat storage driven by insulin resistance
Provide complementary metabolic benefits that amplify weight loss outcomes

The dual mechanism is widely believed to be the primary reason tirzepatide has produced greater average weight loss in clinical trials.

Head-to-Head Efficacy: What the Studies Show

Semaglutide Clinical Results (STEP Trials)

The STEP (Semaglutide Treatment Effect in People with Obesity) trial program demonstrated impressive outcomes:

STEP 1: Participants lost an average of 14.9% of their body weight on semaglutide 2.4 mg over 68 weeks, compared to 2.4% with placebo.
STEP 2 (patients with type 2 diabetes): Average weight loss of 9.6% with semaglutide.
Approximately one-third of participants in STEP 1 lost 20% or more of their body weight.

These were groundbreaking results at the time, establishing semaglutide as a major advancement in obesity treatment.

Tirzepatide Clinical Results (SURMOUNT Trials)

The SURMOUNT trial program showed even greater weight loss:

SURMOUNT-1: Average weight loss of 15%, 19.5%, and 20.9% at the 5 mg, 10 mg, and 15 mg doses respectively, compared to 3.1% with placebo over 72 weeks.
SURMOUNT-2 (patients with type 2 diabetes): Up to 14.7% average weight loss.
Over half of participants on the highest dose lost 20% or more of their body weight, and over a third lost 25% or more.

Direct Comparison

While SURMOUNT and STEP were separate trials and direct head-to-head comparisons should be interpreted cautiously, the numbers speak clearly:

Metric	Semaglutide (2.4 mg)	Tirzepatide (15 mg)
Average weight loss	~15%	~21%
Participants losing ≥20%	~33%	~57%
Trial duration	68 weeks	72 weeks

The SURPASS-2 trial did directly compare tirzepatide to semaglutide 1 mg in patients with type 2 diabetes, and tirzepatide outperformed semaglutide at all three dose levels for both weight loss and blood sugar control.

Side Effect Profiles

Both medications share a similar side effect profile because they both act on the GLP-1 pathway. The most common side effects for both include:

Nausea
Vomiting
Diarrhea
Constipation
Abdominal pain
Decreased appetite
Injection site reactions

Key Differences in Tolerability

Semaglutide tends to cause nausea that is most prominent during the initial dose and during dose escalations. Many patients find that nausea subsides within the first few weeks at each dose level.

Tirzepatide has a comparable gastrointestinal side effect rate in clinical trials. Some providers and patients have reported anecdotally that tirzepatide may be slightly better tolerated at equivalent efficacy levels, possibly because the GIP receptor activation modulates some of the GLP-1-related gut effects. However, this has not been conclusively established in controlled studies.

Serious Side Effects

Both medications carry similar warnings regarding:

Pancreatitis
Gallbladder disease
Thyroid C-cell tumors (contraindicated in patients with a history of medullary thyroid carcinoma or MEN 2)
Potential kidney complications from dehydration

The risk profiles are similar enough that the choice between medications rarely comes down to safety alone. Medical monitoring is equally important with either option.

Dosing and Administration

Semaglutide (Wegovy)

Once-weekly subcutaneous injection
Starting dose: 0.25 mg, titrated over 16–20 weeks
Maintenance dose: 2.4 mg
Available in prefilled, single-dose pens

Tirzepatide (Zepbound)

Once-weekly subcutaneous injection
Starting dose: 2.5 mg, titrated over several months
Maintenance dose: 5 mg, 10 mg, or 15 mg (individualized)
Available in prefilled, single-dose pens

Both medications use a gradual dose escalation to minimize side effects. Your provider at Weight Loss Knox will customize your titration schedule based on how your body responds.

Cost and Insurance Considerations

Cost is a significant factor for many patients, and the landscape is complex:

Semaglutide (Wegovy) has been on the market longer and has broader insurance coverage in some cases. The list price is approximately $1,300–$1,400 per month without insurance.

Tirzepatide (Zepbound) is newer, and insurance coverage is still catching up. The list price is comparable, ranging from approximately $1,000–$1,100 per month without insurance. However, the manufacturer has offered savings programs that can reduce out-of-pocket costs for eligible patients.

At Weight Loss Knox, we work with patients to navigate insurance coverage and explore all available options to make treatment as affordable as possible. We also offer competitive self-pay pricing for patients who do not have insurance coverage for weight loss medications.

Which Medication Is Right for You?

There is no single “best” medication — the right choice depends on your individual health profile, goals, and circumstances. Here are some general considerations:

Tirzepatide May Be Preferred If:

You are looking for the maximum possible weight loss
You have type 2 diabetes alongside obesity (dual benefit)
You have significant insulin resistance
You have not achieved desired results with semaglutide
Your insurance covers it or you are comfortable with the cost

Semaglutide May Be Preferred If:

You have better insurance coverage for Wegovy
You have a track record of tolerating GLP-1 medications well
Your weight loss goals are more moderate
Your provider recommends it based on your specific health profile
You prefer a medication with a longer track record of real-world use

Factors Your Provider Will Consider

When you come to Weight Loss Knox for a consultation, our medical team evaluates:

Your BMI and weight loss goals
Existing medical conditions (diabetes, cardiovascular disease, etc.)
Current medications and potential interactions
Prior weight loss attempts and medication history
Insurance coverage and cost considerations
Your personal preferences and comfort level

The Bottom Line

Both semaglutide and tirzepatide are highly effective, evidence-based weight loss medications that represent a major advancement in obesity treatment. Tirzepatide’s dual mechanism gives it an edge in average weight loss outcomes, but semaglutide remains a powerful and well-established option.

The most important factor is not which medication you take — it is that you work with a qualified medical team that can guide your treatment, monitor your progress, and integrate medication with the lifestyle changes necessary for lasting success.

At Weight Loss Knox, we prescribe both semaglutide and tirzepatide and will help you determine which option aligns best with your health, goals, and budget. Weight loss is personal, and your treatment plan should be too.

Schedule a consultation with our Knoxville medical weight loss team to discuss which medication may be right for you.