Tirzepatide vs Semaglutide: Head-to-Head Comparison

The fundamental difference between tirzepatide and semaglutide lies in their receptor pharmacology, which directly impacts their efficacy and side effect profiles.

Semaglutide: GLP-1 Receptor Agonism

Semaglutide is a selective GLP-1 (glucagon-like peptide-1) receptor agonist. GLP-1 is an incretin hormone naturally released by the gut after eating. When semaglutide activates GLP-1 receptors, it produces several metabolic effects:^[1]

• Appetite suppression: GLP-1 receptor activation in the hypothalamus and brainstem reduces hunger signals and increases satiety, leading to reduced caloric intake.
• Delayed gastric emptying: Semaglutide slows the rate at which food leaves the stomach, prolonging the feeling of fullness after meals.
• Insulin secretion: In a glucose-dependent manner, GLP-1 stimulates pancreatic beta cells to release insulin, improving blood sugar control.
• Glucagon suppression: GLP-1 reduces glucagon secretion from alpha cells, further lowering blood glucose levels.

Semaglutide has been structurally modified with a C-18 fatty acid chain that enables albumin binding, giving it a half-life of approximately 7 days and allowing once-weekly dosing.

Tirzepatide: Dual GIP/GLP-1 Receptor Agonism

Tirzepatide is the first dual GIP/GLP-1 receptor agonist, activating both glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors simultaneously. This dual mechanism is what distinguishes it from semaglutide:^[2]

• GLP-1 effects: Tirzepatide activates the same GLP-1 pathways as semaglutide, producing appetite suppression, delayed gastric emptying, and improved glucose metabolism.
• GIP effects: GIP receptor activation adds complementary metabolic benefits. GIP signaling in adipose tissue may improve fat metabolism and insulin sensitivity. In the brain, GIP receptors appear to contribute to appetite regulation through pathways distinct from GLP-1.
• Synergistic action: The combination of GIP and GLP-1 receptor activation appears to produce greater metabolic effects than GLP-1 alone. This may explain tirzepatide’s superior weight loss results in clinical trials.

Tirzepatide is based on a modified GIP sequence with GLP-1 activity engineered in. Its C-20 fatty diacid side chain allows albumin binding and a half-life of approximately 5 days, also supporting once-weekly dosing.

Both tirzepatide and semaglutide have been evaluated in extensive Phase III clinical trial programs. These trials provide the strongest evidence for comparing their efficacy.

Semaglutide: The STEP Trial Program

The STEP (Semaglutide Treatment Effect in People with obesity) trials enrolled thousands of participants with overweight or obesity across multiple studies:^[1]

• STEP 1 (n=1,961): Participants without diabetes receiving semaglutide 2.4 mg achieved a mean weight loss of 14.9% vs 2.4% with placebo at 68 weeks. 86.4% of participants lost at least 5% of body weight, and 50.5% lost at least 15%.
• STEP 2 (n=1,210): In participants with type 2 diabetes, semaglutide 2.4 mg produced a mean weight loss of 9.6% vs 3.4% with placebo at 68 weeks.
• STEP 3 (n=611): Combined with intensive behavioral therapy, semaglutide 2.4 mg achieved 16.0% mean weight loss vs 5.7% with placebo.
• STEP 5 (n=304): Two-year data showed sustained 15.2% weight loss with semaglutide 2.4 mg vs 2.6% with placebo at 104 weeks.

Tirzepatide: The SURMOUNT Trial Program

The SURMOUNT trials evaluated tirzepatide at three dose levels (5 mg, 10 mg, and 15 mg) in individuals with obesity or overweight:^[3]

• SURMOUNT-1 (n=2,539): The flagship trial showed dose-dependent weight loss at 72 weeks: 16.0% (5 mg), 21.4% (10 mg), and 22.5% (15 mg) vs 3.1% with placebo. At the 15 mg dose, 63% of participants lost at least 20% of body weight.
• SURMOUNT-2 (n=938): In participants with type 2 diabetes, tirzepatide 15 mg achieved 14.7% mean weight loss vs 3.2% with placebo at 72 weeks.
• SURMOUNT-4 (n=670): Participants who achieved 20.9% weight loss during a 36-week lead-in continued to lose an additional 5.5% with continued treatment, while those switched to placebo regained 14.0%.

Head-to-Head: SURPASS-2 and SURMOUNT-5

Direct comparisons provide the most compelling evidence. The SURPASS-2 trial compared tirzepatide to semaglutide 1 mg (the diabetes dose, not the 2.4 mg obesity dose) in patients with type 2 diabetes:^[4]

• Tirzepatide produced greater weight loss at all dose levels: -7.6 kg (5 mg), -9.3 kg (10 mg), and -11.2 kg (15 mg) vs -5.7 kg with semaglutide 1 mg at 40 weeks.
• The highest tirzepatide dose produced nearly double the weight loss of semaglutide.

The more recent SURMOUNT-5 trial directly compared tirzepatide 15 mg to semaglutide 2.4 mg (both at their highest approved obesity doses) in adults with obesity without diabetes. At 72 weeks, tirzepatide achieved 20.2% mean weight loss versus 13.7% for semaglutide—a statistically significant 47% relative improvement.

Both medications share a similar side effect profile, largely driven by their GLP-1 receptor activity on the gastrointestinal tract. However, there are meaningful differences in frequency and severity.

Gastrointestinal Side Effects

The most common side effects for both drugs are GI-related:

• Nausea: Reported in approximately 24–33% of tirzepatide users and 44% of semaglutide users across clinical trials. The higher nausea rate with semaglutide may reflect its stronger GLP-1 receptor activation relative to GIP receptor activation.
• Diarrhea: Occurred in approximately 17–23% of tirzepatide users and 30% of semaglutide users.
• Vomiting: Reported in approximately 9–13% of tirzepatide users and 24% of semaglutide users.
• Constipation: Affected approximately 6–11% of tirzepatide users and 24% of semaglutide users.

For both medications, GI side effects are most common during dose escalation and tend to diminish over weeks of continued use at a stable dose. The gradual dose-titration schedules for both drugs are specifically designed to minimize these effects.

Discontinuation Rates

In SURMOUNT-1, the treatment discontinuation rate due to adverse events was 4.3–7.1% across tirzepatide dose groups. In STEP 1, the discontinuation rate for semaglutide 2.4 mg was approximately 7%. These rates are generally comparable, though tirzepatide’s lower GI side effect rates may translate to better tolerability for some individuals.

Other Side Effects

• Injection site reactions: Mild and generally comparable for both drugs.
• Hair thinning: Reported anecdotally with both medications, likely related to rapid weight loss rather than the drugs themselves.
• Pancreatitis risk: Both carry a precautionary warning for pancreatitis, though the incidence in clinical trials was very low for both.
• Thyroid concerns: Both drugs carry a boxed warning about thyroid C-cell tumors based on rodent studies. The clinical relevance in humans remains under investigation.
• Gallbladder events: Rapid weight loss with either drug may increase the risk of gallstones, consistent with any intervention producing significant weight reduction.

Real-world access to tirzepatide and semaglutide involves considerations beyond clinical efficacy, including cost, insurance coverage, supply availability, and prescribing patterns.

FDA Approval Status

• Semaglutide was first to market, receiving FDA approval for weight management (as Wegovy) in June 2021, and for type 2 diabetes (as Ozempic) in 2017.
• Tirzepatide received FDA approval for weight management (as Zepbound) in November 2023, and for type 2 diabetes (as Mounjaro) in May 2022.

Cost Comparison

Without insurance, both medications carry a high list price:

• Tirzepatide (Zepbound): Approximately $1,000–$1,100 per month at list price.
• Semaglutide (Wegovy): Approximately $1,300–$1,400 per month at list price.

Insurance coverage varies significantly by plan. Many insurers now cover GLP-1 agonists for weight management, though prior authorization and specific BMI thresholds are common requirements. Manufacturer savings programs and coupon cards can substantially reduce out-of-pocket costs for eligible patients.

Supply and Access

Both medications have experienced supply shortages due to unprecedented demand. Semaglutide shortages were particularly acute through 2023–2024, with certain doses frequently unavailable. Tirzepatide has also experienced intermittent shortages. Supply has generally improved but remains a practical consideration when choosing between the two.

Dosing Convenience

Both drugs are administered as once-weekly subcutaneous injections using pre-filled auto-injector pens. The injection process is similar for both, requiring no reconstitution or special preparation. Dose escalation schedules differ slightly:

• Semaglutide: Starts at 0.25 mg weekly, escalating monthly to the target dose of 2.4 mg over approximately 16–20 weeks.
• Tirzepatide: Starts at 2.5 mg weekly, escalating by 2.5 mg every 4 weeks to the target dose of 10 mg or 15 mg over approximately 16–20 weeks.

One of the most important considerations with any GLP-1 agonist is what happens when treatment stops. Clinical trial data show that both tirzepatide and semaglutide are associated with significant weight regain after discontinuation.

Semaglutide Discontinuation Data

The STEP 4 trial specifically examined this question. Participants who achieved weight loss on semaglutide 2.4 mg were randomized to continue treatment or switch to placebo. Those who discontinued semaglutide regained approximately two-thirds of their lost weight over the following 48 weeks, while those who continued treatment maintained their weight loss and lost additional weight.

Tirzepatide Discontinuation Data

The SURMOUNT-4 trial provided similar insights. After achieving approximately 21% weight loss on tirzepatide over 36 weeks, participants randomized to placebo regained 14 percentage points of body weight over the following year, while those continuing tirzepatide lost an additional 5.5%.^[3]

Implications

These data suggest that both medications may require long-term or indefinite use to maintain weight loss. This is consistent with the understanding of obesity as a chronic condition requiring ongoing management, similar to hypertension or diabetes. The weight regain pattern is comparable between the two drugs, indicating that this is a class effect of GLP-1 agonism rather than a differentiator between tirzepatide and semaglutide.