Summary

Tirzepatide is a synthetic dual-action peptide that simultaneously activates the GIP and GLP-1 receptors, setting it apart from traditional incretin agonists through its superior efficacy in weight loss and glycaemic control. The SURMOUNT trials demonstrated weight reductions exceeding 20%, along with meaningful benefits in preventing progression to type 2 diabetes. Its safety profile is dominated by generally transient gastrointestinal effects, though gradual dose titration is essential to improve tolerability. Given the magnitude of its results, tirzepatide represents a new therapeutic standard in the treatment of obesity.

1

What Is Tirzepatide

Obesity is a chronic disease that affects hundreds of millions of people worldwide and is a direct risk factor for type 2 diabetes, cardiovascular disease and hepatic steatosis. For decades, pharmacological options for weight loss were limited and often disappointing. The arrival of GLP-1 receptor agonists changed that landscape, but tirzepatide took clinical efficacy a step further by combining, in a single molecule, the activation of both the GIP and GLP-1 receptors. (1,2)

Marketed as Mounjaro e Zepbound, tirzepatide is an acylated synthetic peptide developed by Eli Lilly. It was first approved for glycaemic control in type 2 diabetes in the SURPASS programme and, later, for the treatment of obesity in the SURMOUNT programme. Its half-life of approximately 120 hours (5 days) allows weekly subcutaneous administration, supporting treatment adherence. (1)

2

Mechanism of Action: The Advantage of Dual Agonism

Tirzepatide produces such striking results because it acts simultaneously on two distinct incretin receptors, creating an unprecedented pharmacological synergy. Its action on the GLP-1 receptor reduces appetite by acting on the hypothalamic satiety centres, delays gastric emptying prolonging post-meal fullness, and improves glycaemic control by stimulating insulin secretion in a glucose-dependent manner. (1,2)

Simultaneous activation of the GIP receptor adds a further dimension: it increases insulin sensitivity and enhances the insulin response, especially when glycaemic control is improved. Historically GIP was considered an unpromising target in type 2 diabetes owing to GIP resistance in these patients, but it was found that restoring glycaemic control reverses that resistance. (2)

Research published in JCI Insight demonstrated that tirzepatide is an “imbalanced and biased” agonist — it has greater affinity for the GIP receptor than for GLP-1, and favours cAMP signalling over beta-arrestin recruitment. This pharmacological particularity may explain its superior efficacy and distinct tolerability profile. (3) In addition, preclinical and clinical data suggest that tirzepatide reduces systemic inflammatory markers such as IL-6 and TNF-alpha, with beneficial implications beyond weight loss.

3

Proven Benefits: The SURMOUNT Trials

The SURMOUNT clinical trial programme constitutes the most robust body of evidence for tirzepatide in the treatment of obesity. The SURMOUNT-1 trial, published in the New England Journal of Medicine, evaluated 2,539 adults with obesity (without diabetes) over 72 weeks and revealed extraordinary results. (4) Participants treated with tirzepatide 5 mg lost on average 15.0% of body weight, those on 10 mg lost 19.5%, and the 15 mg group reached a reduction of 20.9%, compared with only 3.1% on placebo. Notably, 57% of participants in the 15 mg group lost 20% or more of body weight — figures approaching the results of bariatric surgery.

The long-term analysis of SURMOUNT-1, also published in the NEJM, followed participants with obesity and prediabetes over 176 weeks (3 years). The results confirmed the sustainability of weight loss and revealed an extraordinary finding: only 1.3% of participants treated with tirzepatide progressed to type 2 diabetes, versus 13.3% in the placebo group — a risk reduction of 93%. Weight loss remained sustained at -12.3% (5 mg), -18.7% (10 mg) and -19.7% (15 mg). (5)

SURMOUNT-4, published in JAMA, demonstrated the critical importance of continued treatment. Discontinuing tirzepatide after 36 weeks resulted in substantial regain of the weight lost. Participants who continued treatment through 88 weeks maintained a total weight loss of 25.3%, whereas those switched to placebo regained weight, ending with only 9.9% reduction. This finding underscores that tirzepatide, like other anti-obesity drugs, should be regarded as chronic treatment. (6)

SURMOUNT-5, the first head-to-head comparison between tirzepatide and semaglutide, published in the NEJM in 2025, showed clear superiority of tirzepatide. While tirzepatide produced a weight loss of 20.2% at 72 weeks, semaglutide reached 13.7%. Tirzepatide was also superior in reducing waist circumference, with -18.4 cm versus -13.0 cm. (7)

4

Dosing, Protocol and Tolerability

The tirzepatide dosing schedule follows a gradual escalation that is fundamental to minimising gastrointestinal effects. The protocol starts with 2.5 mg weekly for 4 weeks, escalates to 5.0 mg at weeks 5-8, then to 7.5 mg (weeks 9-12 if tolerated), and finally to maintenance doses of 10–15 mg according to tolerance and clinical response. The route of administration is subcutaneous, once weekly, with a half-life of approximately 120 hours allowing this frequency.

Storage: keep between 2–8 °C (refrigerated). Do not freeze. Slow escalation is essential — most gastrointestinal adverse effects occur during the first 20 weeks of dose adjustment and tend to ease over time. (4,5)

The most common side effects are predominantly gastrointestinal and mostly mild to moderate: nausea (usually transient and less intense than with semaglutide), diarrhoea, constipation, vomiting (more frequent at higher doses) and decreased appetite. A meta-analysis of randomised clinical trials confirmed that, compared with placebo, tirzepatide 15 mg increased the risk of nausea (OR 4.2), vomiting (OR 7.0) and diarrhoea (OR 2.8), although discontinuation due to adverse effects was low (<5–7%). (4,8)

5

Safety, Limitations and Precautions

One important aspect to consider is the loss of lean mass. Recent meta-analyses have shown that, although tirzepatide markedly reduces fat mass, it also causes a reduction in lean mass — roughly 25% of total weight loss corresponds to lean mass. Including resistance exercise during treatment is strongly recommended to mitigate this loss. (8)

Contraindications and precautions: Tirzepatide is contraindicated in individuals with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2. It should be used with caution in patients with a history of pancreatitis. Long-term cardiovascular safety is still being evaluated, although available data show no increased risk (MACE-4 with a hazard ratio below 1.0 in available studies). If discontinued, follow-up is warranted, as weight regain is expected. (1,6)

6

Conclusion

Tirzepatide represents a qualitative leap in the therapeutic arsenal against obesity. By combining GIP and GLP-1 receptor agonism, it delivers weight loss consistently above 20% — results that, until recently, were only achievable with bariatric surgery. The SURMOUNT trials demonstrated not only efficacy in weight reduction, but also in preventing progression to type 2 diabetes, with an acceptable safety profile and better gastrointestinal tolerability than semaglutide.

That said, it is essential to keep realistic expectations: tirzepatide is not a magic solution. It should be integrated into a plan that includes proper nutrition and physical exercise — especially resistance training to preserve muscle mass. Its use requires ongoing medical supervision, and discontinuation is associated with regain of the weight lost.