Dual GIP/GLP-1 Receptor Agonism in Diabetes and Obesity: A Review of Tirzepatide’s Efficacy and Safety

Abstract

The increasing prevalence of obesity and type 2 diabetes mellitus (T2DM) worldwide has prompted researchers to look for treatments that address both glycemic dysfunction and excess body weight. Tirzepatide, a first-in-class dual GIP/GLP-1 receptor agonist that targets two incretin pathways at once, is a significant improvement in the treatment of metabolic diseases. Its special mechanism improves insulin production, inhibits glucagon release, delays the emptying of the stomach, and decreases hunger, all of which contribute to better metabolic results. Tirzepatide yields weight loss equal to various bariatric surgeries, with typical reductions of 10–20%, depending on dose and demographic, and achieves exceptional reductions in HbA1c, frequently reaching 2%, according to data from significant clinical studies like SURPASS and SURMOUNT. Beyond glycaemia and weight, tirzepatide provides additional cardiometabolic benefits, including improvements in blood pressure, lipid profile, insulin sensitivity, and inflammatory markers. Its safety profile aligns with other incretin-based therapies, with gastrointestinal symptoms being the most frequent and typically mild. While long-term cardiovascular outcome data and real-world evidence are still emerging, current findings highlight tirzepatide as a powerful and versatile option for T2DM, obesity, and metabolic syndrome. Continued research will further define its role, durability of benefits, and impact across diverse patient populations.

Keywords

Introduction

Treatments that target the complex pathophysiology of metabolic disease, going beyond glucose reduction to full metabolic improvement, are desperately needed in light of the global increase in type 2 diabetes mellitus (T2DM) and obesity. Metformin, insulin, and GLP-1 receptor agonists are examples of traditional medications that have provided significant advantages, but many patients still need extra help to meet glycaemic and weight-related objectives. ^[1][2][3]

As a dual agonist of the glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, tirzepatide has become a significant therapeutic advancement in this regard. This dual-incretin strategy is based on physiological data that both hormones independently regulate energy balance, hunger, and glucose, and that their combined activation may have synergistic metabolic effects. ^[4][5]

Tirzepatide's molecular structure enables it to take advantage of GIP's strong insulinotropic activity while maintaining the known advantages of GLP-1 receptor stimulation, including decreased glucagon release, delayed stomach emptying, appetite suppression, and improved β-cell function. The vast SURPASS and SURMOUNT trial programs, which continuously demonstrate that tirzepatide offers improved glycemic control and body-weight loss when compared to current antidiabetic treatments, including semaglutide, provide clinical validation. HbA1c reductions exceeding 2.3% and body weight losses ranging from 10% to over 20% have been reported in trials; these results are comparable to those of metabolic bariatric surgeries. ^[6]

Tirzepatide is now a prominent treatment possibility for obesity, metabolic syndrome, cardiovascular risk reduction, and non-alcoholic fatty liver disease (NAFLD) due to its strong efficacy. Its safety profile is similar to that of GLP-1 receptor agonists, with the most frequent adverse effects being gastrointestinal symptoms such nausea, vomiting, and diarrhoea. Nevertheless, the majority of these side effects are minor, temporary, and controllable with dose escalation techniques. The medication's position as a comprehensive metabolic therapy has been reinforced by positive trends in blood pressure reduction, lipid profile improvement, and inflammatory marker modulation. Tirzepatide is at the forefront of a paradigm change in the treatment of obesity and diabetes, giving hitherto unheard-of potential for disease modification and long-term cardiometabolic health, as dual GIP/GLP-1 receptor agonism marks the next frontier in incretin pharmacology. ^[7]

INCRETIN PHYSIOLOGY & METABOLIC REGULATION

The term "incretin" refers to hormones that are released from the gut in reaction to the consumption of nutrients. These hormones increase insulin production in a glucose-dependent manner, which helps the body better control post-meal hyperglycaemia.  Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two of the most significant incretins in humans.  These hormones are secreted by specialized enteroendocrine cells (K-cells for GIP, L-cells for GLP-1) in a normal postprandial state. They act on the pancreas to increase the release of insulin from β-cells while also suppressing glucagon from α-cells, decreasing the production of glucose in the liver, and encouraging effective glucose disposal. Additionally, GLP-1 (and to some extent GIP) affects other organs and tissues: in the brain, GLP-1 mediates satiety and decreases food intake; in the liver and adipose tissue, it modifies lipid metabolism; in the kidney, it may affect natriuresis; and in systemic activities, it may modify inflammation.   Crucially, GIP and GLP-1 play a major role in the "incretin effect," which is the increase in insulin secretion after oral (as opposed to intravenous) glucose.  According to some investigations, under normal mixed-meal conditions, GIP may contribute most of the post-meal C-peptide (a proxy for insulin production), with GLP-1's relative contribution increasing when gastric emptying or digestive kinetics are changed ^[8].

The incretin system is therefore a potent "metabolic regulation" axis that is not only essential to postprandial glycaemic control but also closely related to energy balance, hunger, and lipid metabolism.  In order to improve glycaemic control and body-weight/energy balance in metabolic illnesses including type 2 diabetes (T2DM) and obesity, therapeutic targeting of incretin receptors attempts to take advantage of this natural physiology ^[9]

PHARMACOLOGICAL OVERVIEW OF TIRZEPATIDE

Tirzepatide is a once-weekly, synthesized, acylated peptide designed to act as a dual agonist at the GLP-1 receptor (GLP-1R) and the GIP receptor.  It has a lengthy half-life appropriate for weekly dosage and a fatty-diacid side chain that facilitates albumin binding.  In comparison to selective GLP-1 receptor agonists, tirzepatide functions by engaging both receptors to generate a synergistic insulinotropic action (increased glucose-dependent insulin production), larger reductions in glucagon, and noticeable effects on satiety and calorie intake.  The significant weight loss and glycaemic effects seen in clinical trials are probably explained by co-activation, which alters peripheral metabolism and central hunger circuits in ways not possible with GLP-1 agonism alone, according to preclinical and mechanistic human investigations.  Phase-3 evidence has led to the drug's regulatory approval for the treatment of type 2 diabetes in several nations. ^[10]‌

CLINICAL EFFICACY OF TIRZEPATIDE IN TYPE 2 DIABETES (T2DM)

The "SURPASS" program (Phase 3 studies) spearheaded the clinical development of tirzepatide in type 2 diabetes. These trials collectively showed significant improvements in body weight and glycaemic control, coupled with acceptable safety and tolerability.  Once-weekly tirzepatide (at 5, 10, or 15 mg) decreased HbA?c by –1.87% (5 mg), –1.89% (10 mg), and –2.07% (15 mg) at 40 weeks in the foundational trial SURPASS 1 (478 participants with T2DM, mean baseline HbA?c ≈ 7.9%, BMI ≈ 31.9 kg/m²). The placebo group saw a negligible +0.04% change.  Additionally, a significant percentage of tirzepatide users met the suggested glycemic targets: 87–92% had HbA?c <7.0% (compared to 20% with a placebo), and 81–86% had HbA?c ≤6.5%. Interestingly, 31–52% of tirzepatide users had HbA?c levels as low as 5.7%.   Tirzepatide caused significant, dose-dependent weight loss in addition to glycemic benefits; in SURPASS-1, the average body weight loss over 40 weeks varied from around 7.0 to 9.5 kg.  First. ^[11]

Beyond SURPASS-1, pooled analyses and meta-analyses encompassing several trials (in some, over 11,000 patients) verified that tirzepatide consistently lowers body weight, fasting serum glucose, HbA?c, and improves aspects of glycolipid metabolism (e.g., lower triglycerides, higher HDL cholesterol) when compared to placebo or different comparators (insulin, GLP-1 receptor agonists). ^[12]

Mechanistic research sheds light on potential benefits of dual receptor agonism that go beyond simple weight loss.  In a study evaluating insulin sensitivity and β-cell function, tirzepatide improved markers of insulin sensitivity (HOMA2-IR) and β-cell function more than a selective GLP-1R agonist (Dulaglutide). Crucially, weight loss only accounted for ~13–21% of the improvement in insulin sensitivity in the 10 mg and 15 mg tirzepatide groups, suggesting that receptor-mediated mechanisms (beyond decreased adiposity) play a major role. In terms of safety, tirzepatide's adverse-event profile is similar to that of GLP-1 receptor agonists in that the most frequent side effects are gastrointestinal (nausea, diarrhea, vomiting), particularly during dose escalation, and are usually mild to moderate and temporary.  Because of its glucose-dependent mode of insulin secretion, the risk of hypoglycemia is minimal when administered without concurrent insulin or sulfonylureas. ^[13]

EFFICACY OF TIRZEPATIDE IN OBESITY AND WEIGHT MANAGEMENT ^[14][15]

Tirzepatide has emerged as one of the most effective pharmacological options for obesity management, owing to its dual activation of GIP and GLP-1 receptors. This combined mechanism not only reduces appetite and caloric intake but also enhances metabolic efficiency, resulting in significant and sustained weight reduction.

Clinical evidence from large phase-3 trials demonstrates that tirzepatide produces weight loss outcomes comparable to, and in some cases approaching, metabolic bariatric procedures. In individuals without diabetes, weight reductions exceeding 15% to 20% of baseline body weight have been consistently reported with higher doses. Importantly, this effect appears to be dose-dependent, with greater weight loss observed at 10 mg and 15 mg weekly regimens.

Beyond reducing weight, tirzepatide contributes to meaningful improvements in obesity-related metabolic parameters, including waist circumference, insulin sensitivity, blood pressure, and lipid profile. These secondary benefits are clinically relevant, as they help lower overall cardiometabolic risk. The durability of weight loss has also been demonstrated, with participants maintaining substantial reductions during long-term follow-up periods.

The safety profile is largely consistent with GLP-1–based therapies, with gastrointestinal symptoms being the most common adverse effects. These typically appear early in treatment and decrease with gradual dose escalation. Overall, tirzepatide provides a powerful and well-tolerated therapeutic option for individuals struggling with obesity, particularly those who have not achieved adequate results through lifestyle interventions alone.

CARDIOMETABOLIC BENEFITS OF TIRZEPATIDE ^[16][17]

Tirzepatide provides a broad spectrum of cardiometabolic advantages that go well beyond glucose control and weight reduction. Its dual GIP/GLP-1 agonistic action results in a coordinated improvement in several metabolic pathways that directly influence cardiovascular risk.

One of the most significant benefits is the consistent reduction in blood pressure, observed across multiple clinical trials. Both systolic and diastolic pressures tend to fall as body weight decreases and vascular function improves. This effect is complemented by favourable shifts in lipid parameters, including reductions in triglycerides, improvements in HDL cholesterol, and modest decreases in LDL cholesterol. Together, these changes contribute to a meaningful lowering of overall atherogenic burden.

Tirzepatide also demonstrates beneficial effects on insulin sensitivity, reducing fasting insulin levels and improving HOMA-IR scores. Improved glycaemic stability helps limit endothelial stress and chronic inflammation, both of which are major contributors to cardiovascular disease progression. In addition, the therapy has shown reductions in markers of systemic inflammation, such as CRP, suggesting a broader impact on metabolic health and vascular protection.

Emerging evidence indicates that tirzepatide may reduce hepatic fat content, supporting its role in improving metabolic dysfunction-associated steatotic liver disease (MASLD), which itself is linked to cardiometabolic risk. Collectively, these outcomes present tirzepatide as a therapy capable of comprehensive cardiometabolic optimisation, addressing not only glucose and weight but also core drivers of cardiovascular disease.

SAFETY AND TOLERABILITY PROFILE

Tirzepatide is generally well tolerated when titrated gradually, with most side effects being mild, predictable, and dose-related. Gastrointestinal symptoms—mainly nausea, vomiting, diarrhoea, and constipation—are the most common events. These usually appear early during dose escalation and tend to improve with time or slower titration.

Serious adverse events are uncommon. Isolated cases of pancreatitis and gallbladder disorders have been reported, similar to other incretin-based therapies, so any persistent or severe abdominal pain warrants evaluation. Due to rodent data showing C-cell tumours, tirzepatide is contraindicated in individuals with a history of medullary thyroid carcinoma or MEN2.

The risk of hypoglycaemia is low unless used with insulin or sulfonylureas, in which case dose adjustments of those agents are recommended. Rare hypersensitivity and injection-site reactions may occur. Dehydration from prolonged vomiting or diarrhoea can affect renal function, so monitoring is advised if significant GI symptoms are present.

Overall, tirzepatide demonstrates a favourable safety profile with manageable adverse effects when used appropriately and titrated according to clinical need. ^[18]

Comparison with existing metabolic therapies:

Tirzepatide, a once-weekly dual GIP/GLP-1 receptor agonist, widens the therapeutic landscape by combining incretin pathways to treat both glycaemia and body weight. Its clinical profile must be compared with

1. selective GLP-1 receptor agonists (e.g., semaglutide, liraglutide),
2. basal insulin therapies,
3. other anti-obesity agents, and
4. non-incretin pharmacotherapies (SGLT2 inhibitors, DPP-4 inhibitors) with with respect to efficacy, safety, durability, and real-world applicability. ^[19]

Glycaemic efficacy:

Superior HbA1c reduction vs specific GLP-1 RAs and basal insulin. Randomized trials (SURPASS program) and pooled reviews consistently indicate higher mean reductions in HbA1c with tirzepatide compared with titrated basal insulin and with semaglutide 1.0 mg/week in patients with type 2 diabetes. These improvements were dose-responsive and clinically relevant. ^[20][21]

durability and time across the glycaemic target. Trial results indicate tirzepatide enhances the proportion of time spent at or below prespecified HbA1c objectives compared with comparator arms, supporting not just larger early reductions but also sustained glycaemic management during study durations. ^[22]

Weight-loss efficacy (obesity and overweight)
Markedly greater weight loss than most known regimens. In obesity trials (SURMOUNT-1) tirzepatide showed very considerable mean weight losses (up to ~22% with higher dosages over 72 weeks), exceeding usual results found with GLP-1 monotherapy (e.g., semaglutide 2.4 mg) and considerably above the mild weight effects of basal insulin or SGLT2 inhibitors. Head-to-head and pooled analyses indicated tirzepatide achieved bigger absolute and percentage weight decreases than semaglutide in comparable populations. ^[20][23][24]

Safety and tolerability

Gastrointestinal adverse effects dominate but are class-typical. Nausea, vomiting, and diarrhoea are the most frequent adverse effects and are comparable in character to GLP-1 RAs, typically dose-related and higher during uptitration. Overall tolerability is generally good but higher dosages increase discontinuation risk for GI intolerance. ^[21][23]

Hypoglycaemia and other metabolic concerns. The risk of hypoglycemia rises when concurrent insulin or sulfonylureas are used, while tirzepatide by itself has a low intrinsic hypoglycemia risk that is comparable to incretin-based medications. Some pooled safety signals (trial and observational) show the need to monitor for gallbladder events and, in some datasets, unique patterns of adverse events that merit additional surveillance. ^[25][26]

Renal and cardiovascular outcomes are new but promising. While definitive dedicated CV outcome studies and longer-term data are still developing, prespecified analyses and observational cohorts indicate neutral to favorable signals for major cardiovascular and renal endpoints when compared with GLP-1 RAs and other comparators. Real-world cohort analyses report decreased risks of composite CV and kidney events in users of tirzepatide versus GLP-1 RAs, although these observational results should be viewed cautiously. ^[27][28]

Special population

Impaired renal function : Renal impairment (including severe impairment and end-stage renal disease) has no clinically significant impact on tirzepatide exposure, according to pharmacokinetic analyses and regulatory product information; dose modification for renal impairment alone is not usually necessary. Nevertheless, vigilance is advised in advanced kidney illness due to comorbidity burden and hypovolaemia risk from GI adverse events; monitor renal function and volume status. ^[28][29]

Hepatic impairment: Studies and EMA/FDA product information reveal negligible impact of hepatic impairment on tirzepatide pharmacokinetics and no formal dose change is recommended for hepatic dysfunction. Clinical judgment is indicated in severe hepatic disease and for patients with decompensated liver dysfunction. ^[30]

Adults over 65: Although post-hoc analyses and subgroup data indicate that older adults experience glycaemic and weight benefits comparable to those of younger adults, frail older patients need a customized evaluation that takes into account comorbidities, polypharmacy, the risk of dehydration from vomiting or diarrhea, and the fall risk from hypoglycemia when tirzepatide is used with insulin or secretagogues. Start conservatively, employ careful titration, and increase monitoring frequency. ^[31][32]

Pregnancy, fertilization, and lactation: Tirzepatide is not indicated in pregnancy and should be discontinued in women contemplating conception or who become pregnant. Animal research and inadequate human exposure data have led to conservative guidelines; pregnancy registries and specialist consulting are indicated for exposed pregnancies. There is little advice on breastfeeding; avoid it during nursing unless the advantages outweigh the hazards, and talk about other options. Women of reproductive potential should use effective contraception during therapy and for a period after finishing following local recommendations. ^[33][34]

Pediatrics and adolescents: Tirzepatide is not approved for use in children or adolescents for diabetes or weight management at the time of current labels. Ongoing studies may define pediatric roles but until regulatory approvals exist, use in those <18 years should be restricted to clinical trials.

History of pancreatitis or gallbladder disease: Although causality remains uncertain, incretin-based therapies (including tirzepatide) have been associated with rare reports of pancreatitis and gallbladder events in trials. Avoid initiation in patients with active pancreatitis; if pancreatitis is suspected discontinue tirzepatide and investigate. Monitor for biliary colic or cholelithiasis in patients who develop rapid weight loss. ^[23][35]

Cardiovascular disease / high CV risk: Large RCT programs and recent CV outcome data (SURPASS-CVOT top-line results) indicate that tirzepatide is at least non-inferior to an established GLP-1 RA comparator (dulaglutide) for major adverse cardiovascular events in patients with type 2 diabetes and high CV risk; these results support cardiovascular safety and suggest preserved cardioprotective effects while delivering superior metabolic benefits. Ongoing publication of full trial data and subgroup analyses will clarify absolute CV benefit and effects in diverse populations. Continue to follow guideline updates and individualize therapy in patients with established CVD. ^[36][37]

CLINICAL APPLICATIONS

Tirzepatide, a first-in-class dual glucose-dependent insulinotropic polypeptide (GIP) / glucagon-like peptide-1 (GLP-1) receptor agonist, has rapidly extended from glycaemic management in type 2 diabetes mellitus (T2DM) into obesity and broader cardiometabolic care. In phase 3 trials, tirzepatide produced large, dose-dependent reductions in body weight (mean placebo-adjusted weight loss up to ≈15% at higher doses in the SURMOUNT program) and robust reductions in HbA1c compared with placebo and some GLP-1 RAs, supporting its use for both glucose lowering and weight management in adults with T2DM and/or obesity

Randomized cardiovascular outcomes trials specifically powered for hard endpoints are awaited to confirm causality, but emerging real-world and cohort analyses suggest potential reductions in major adverse cardiovascular and kidney events when compared with GLP-1 RAs beyond glycaemia and weight. Therefore, while acknowledging the need for conclusive long-term outcome data, clinicians should consider tirzepatide as a powerful alternative to manage coupled hyperglycemia and obesity when weight loss is a therapeutic objective and when broad cardiometabolic risk reduction is needed. ^[26][38]

LIMITATION OF CURRENT EVIDENCE ^[39][40][41]

In the SURPASS and SURMOUNT programs, tirzepatide has demonstrated remarkable glycaemic and weight-loss advantages; nevertheless, there are still a number of data gaps. The majority of the data that is now accessible comes from industry-sponsored phase-3 trials, which might not accurately represent long-term safety, tolerability, and real-world adherence. Although encouraging, there is currently a dearth of data on cardiovascular and renal outcomes; comprehensive findings from sizable, specialized CVOTs have only lately been available, necessitating additional subgroup research. Evidence on long-term stability of weight loss beyond 2–3 years, particularly after therapy termination, is lacking. There is still a dearth of information on certain populations, such as the elderly with frailty, teenagers, patients with advanced liver illness, or people with severe chronic renal disease. Furthermore, long-term safety issues pertaining to gastrointestinal intolerance, gallbladder disease, and uncommon events like pancreatitis necessitate further observation, and molecular insights into the relative impact of GIP vs GLP-1 receptor activation in humans are still developing. All things considered, although efficacy is strong, thorough long-term, practical, and population-specific evidence is still emerging.

FUTURE DIRECTION ^[42][43][44]

To ascertain whether tirzepatide offers additional protection beyond glycaemic and weight benefits, future research should concentrate on finishing and growing cardiovascular and renal outcome trials. Its relative significance in the management of metabolic diseases will be clarified by comparative effectiveness trials with other newly developed incretin-based medicines, such as triple agonists (GLP-1/GIP/glucagon). To evaluate the sustainability of weight loss, impact on the retention of lean mass, and metabolic remission of type 2 diabetes, long-term follow-up (>5–10 years) is required. How dual receptor agonism affects energy expenditure, fat oxidation, and beta-cell activity should be further clarified by mechanistic investigations. Real-world implementation studies with a variety of populations, including patients with metabolic fatty liver disease, older persons with multiple conditions, and adolescents, are also necessary. In order to improve widespread clinical adoption, next directions include refining customized dosing techniques, reviewing cost-effectiveness, and exploring combination therapy with SGLT2 inhibitors.

CONCLUSION

Through its dual GIP/GLP-1 receptor agonism, tirzepatide offers previously unheard-of advantages in glycaemic management, body weight reduction, and broader cardiometabolic parameters, making it a significant therapeutic development. Evidence from large randomized studies consistently demonstrates superiority over several existing diabetes and obesity therapies, with a safety profile essentially comparable to GLP-1 receptor agonists. Current findings indicate tirzepatide as a potent and adaptable choice for people with T2DM, obesity, and metabolic syndrome, even if long-term outcome data and more comprehensive real-world evidence are still developing. With continuous research and expanded indications, tirzepatide is positioned to play a prominent role in current metabolic disease management.

REFERENCES

1. Allocca S, Monda A, Messina A, Casillo M, Sapuppo W, Monda V, et al. Endocrine and metabolic mechanisms linking obesity to Type 2 diabetes: Implications for targeted therapy. Healthcare (Basel) [Internet]. 2025;13(12):1437. Available from: http://dx.doi.org/10.3390/healthcare13121437
2. Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Al Kaabi J. Epidemiology of type 2 diabetes - Global Burden of Disease and forecasted trends. J Epidemiol Glob Health [Internet]. 2020;10(1):107–11. Available from: http://dx.doi.org/10.2991/jegh.k.191028.001
3. Diabetesjournals.org. [cited 2025 Dec 5]. Available from: https://diabetesjournals.org/care/article/24/3/489/22940/Effect-of-Metformin-on-Glucagon-Like-Peptide-1-GLP
4. Ghaleb J, Khouzami KK, Nassif N, Attieh P, Ajlani MFA, Sleiman JB, et al. Unveiling tirzepatide’s therapeutic spectrum: A dual GIP/GLP-1 agonist targeting metabolic, neurological, and cardiovascular health. Int J Endocrinol [Internet]. 2025;2025(1):2876156. Available from: http://dx.doi.org/10.1155/ije/2876156
5. Bergmann NC, Lund A, Gasbjerg LS, Meessen ECE, Andersen MM, Bergmann S, et al. Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study. Diabetologia [Internet]. 2019;62(4):665–75. Available from: http://dx.doi.org/10.1007/s00125-018-4810-0
6. Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight [Internet]. 9 2020;5(17). Available from: https://insight.jci.org/articles/view/140532
7. Ravussin E, Sanchez-Delgado G, Martin CK, Beyl RA, Greenway FL, O’Farrell LS, et al. Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation. Cell Metab [Internet]. 2025;37(5):1060-1074.e4. Available from: http://dx.doi.org/10.1016/j.cmet.2025.03.011
8. Sweta, Gupta S, Bansal S, Devi S, Sharma S, Laxmi, et al. Tirzepatide a novel anti diabetic molecule unfold dual action. Discov Public Health [Internet]. 2024;21(1). Available from: http://dx.doi.org/10.1186/s12982-024-00200-2
9. Mdpi.com. [cited 2025 Dec 5]. Available from: https://www.mdpi.com/2076-3271/13/4/269
10. Nauck MA, D’Alessio DA. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Cardiovasc Diabetol [Internet]. 2022;21(1):169. Available from: http://dx.doi.org/10.1186/s12933-022-01604-7
11. Rosenstock J, Wysham C, Frías JP, Kaneko S, Lee CJ, Fernández Landó L, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet [Internet]. 2021;398(10295):143–55. Available from: http://dx.doi.org/10.1016/S0140-6736(21)01324-6
12. Zhou Q, Lei X, Fu S, Liu P, Long C, Wang Y, et al. Efficacy and safety of tirzepatide, dual GLP-1/GIP receptor agonists, in the management of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetol Metab Syndr [Internet]. 2023;15(1):222. Available from: http://dx.doi.org/10.1186/s13098-023-01198-4
13. Thomas MK, Nikooienejad A, Bray R, Cui X, Wilson J, Duffin K, et al. Dual GIP and GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes. J Clin Endocrinol Metab [Internet]. 2021;106(2):388–96. Available from: http://dx.doi.org/10.1210/clinem/dgaa863
14. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med [Internet]. 2022;387(3):205–16. Available from: http://dx.doi.org/10.1056/NEJMoa2206038’
15. Gudzune KA, Stefanski A, Cao D, Mojdami D, Wang F, Ahmad N, et al. Association between weight reduction achieved with tirzepatide and quality of life in adults with obesity: Results from the SURMOUNT-1 study. Diabetes Obes Metab [Internet]. 2025;27(2):539–50. Available from: http://dx.doi.org/10.1111/dom.16046
16. Singh M. In type 2 diabetes with increased CV risk, tirzepatide reduced HbA1c vs. glargine at 52 wk. Ann Intern Med [Internet]. 2022;175(3):JC34. Available from: http://dx.doi.org/10.7326/J22-0009
17. Oup.com. [cited 2025 Dec 5]. Available from: https://academic.oup.com/jcem/article/109/7/1745/7585180
18. Corrao S, Pollicino C, Maggio D, Torres A, Argano C. Tirzepatide against obesity and insulin-resistance: pathophysiological aspects and clinical evidence. Front Endocrinol (Lausanne) [Internet]. 2024;15:1402583. Available from: http://dx.doi.org/10.3389/fendo.2024.1402583
19. Fda.gov. [cited 2025 Dec 5]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/217806Orig1s020lbl.pdf
20. Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med [Internet]. 2021;385(6):503–15. Available from: http://dx.doi.org/10.1056/nejmoa2107519
21. Vilsbøll T, Malecki MT, Sharma P, Thieu VT, Chivukula KK, Kiljanski J. HbA1c reduction with tirzepatide in people with type 2 diabetes: The contribution of weight loss assessed by a mediation analysis. Diabetes Obes Metab [Internet]. 2025;27(10):5498–505. Available from: http://dx.doi.org/10.1111/dom.16592
22. Bergman BK, Rosenstock J, Garvey WT, Batterham RL, Chen Y, Liu M, et al. Time spent in glycaemic control with sustained body weight reduction with tirzepatide: A post hoc analysis of the SURPASS clinical trial programme. Diabetes Obes Metab [Internet]. 2025;27(6):3223–32. Available from: http://dx.doi.org/10.1111/dom.16337
23. Diabetesjournals.org. [cited 2025 Dec 5]. Available from: https://diabetesjournals.org/care/article/48/9/1622/163002/Tirzepatide-Treatment-and-Associated-Changes-in
24. Aamir AB, Latif R, Alqoofi JF, Almarzoq FA, Fallatah JO, Hassan GA, et al. Comparative efficacy of tirzepatide vs. Semaglutide in reducing body weight in humans: A systematic review and meta-analysis of clinical trials and real-world data. J Clin Med Res [Internet]. 2025;17(5):285–96. Available from: http://dx.doi.org/10.14740/jocmr6231
25. Xie Z, Liang Z, Xie Y, Zheng G, Cao W. Comparative safety of GLP-1/GIP co-agonists versus GLP-1 receptor agonists for weight loss in patients with obesity or overweight: A systematic review. Diabetes Metab Syndr Obes [Internet]. 2025 [cited 2025 Dec 5];18:2837–49. Available from: https://www.dovepress.com/comparative-safety-of-glp-1gip-co-agonists-versus-glp-1-receptor-agoni-peer-reviewed-fulltext-article-DMSO
26. Chuang M-H, Chen J-Y, Wang H-Y, Jiang Z-H, Wu V-C. Clinical outcomes of tirzepatide or GLP-1 receptor agonists in individuals with type 2 diabetes. JAMA Netw Open [Internet]. 2024;7(8):e2427258. Available from: http://dx.doi.org/10.1001/jamanetworkopen.2024.27258
27. Dani SS, Makwana B, Khadke S, Kumar A, Jhund P, Nasir K, et al. An observational study of cardiovascular outcomes of tirzepatide vs glucagon-like peptide-1 receptor agonists. JACC Adv [Internet]. 2025;4(5):101740. Available from: http://dx.doi.org/10.1016/j.jacadv.2025.101740
28. Bosch C, Carriazo S, Soler MJ, Ortiz A, Fernandez-Fernandez B. Tirzepatide and prevention of chronic kidney disease. Clin Kidney J [Internet]. 2023;16(5):797–808. Available from: http://dx.doi.org/10.1093/ckj/sfac274
29. Europa.eu. [cited 2025 Dec 5]. Available from: https://www.ema.europa.eu/en/documents/product-information/mounjaro-epar-product-information_en.pdf?utm_source
30. Urva S, Quinlan T, Landry J, Ma X, Martin JA, Benson CT. Effects of hepatic impairment on the pharmacokinetics of the dual GIP and GLP-1 receptor agonist tirzepatide. Clin Pharmacokinet [Internet]. 2022;61(7):1057–67. Available from: http://dx.doi.org/10.1007/s40262-022-01140-3
31. Heise T, Mari A, DeVries JH, Urva S, Li J, Pratt EJ, et al. Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial. Lancet Diabetes Endocrinol [Internet]. 2022;10(6):418–29. Available from: http://dx.doi.org/10.1016/S2213-8587(22)00085-7
32. Farzam K, Patel P. Tirzepatide. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025.
33. Tirzepatide (mounjaro®, zepbound®). In: MotherToBaby | Fact Sheets. Brentwood (TN): Organization of Teratology Information Specialists (OTIS); 1994.
34. Drugs.com. [cited 2025 Dec 5]. Available from: https://www.drugs.com/pregnancy/tirzepatide.html?
35. Fda.gov. [cited 2025 Dec 5]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf?
36. O’Riordan M. Tirzepatide matches dulaglutide in large CV outcomes trial: SURPASS-CVOT [Internet]. Tctmd.com. 2025 [cited 2025 Dec 5]. Available from: https://www.tctmd.com/news/tirzepatide-matches-dulaglutide-large-cv-outcomes-trial-surpass-cvot?
37. Nicholls SJ, Bhatt DL, Buse JB, Prato SD, Kahn SE, Lincoff AM, et al. Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events in participants with type 2 diabetes and atherosclerotic cardiovascular disease: SURPASS-CVOT design and baseline characteristics. Am Heart J [Internet]. 2024;267:1–11. Available from: http://dx.doi.org/10.1016/j.ahj.2023.09.007
38. Researchgate.net. [cited 2025 Dec 5]. Available from: https://www.researchgate.net/publication/375088281_Efficacy_and_safety_of_tirzepatide_dual_GLP-1GIP_receptor_agonists_in_the_management_of_type_2_diabetes_a_systematic_review_and_meta-analysis_of_randomized_controlled_trials
39. Nasoufidou A, Stachteas P, Karakasis P, Fragakis N, Patoulias D. Cardiovascular efficacy of tirzepatide: what real-world evidence promises. Expert Rev Cardiovasc Ther [Internet]. 2025;(14779072.2025.2587294):1–4. Available from: http://dx.doi.org/10.1080/14779072.2025.2587294
40. Zile MR, Borlaug BA, Kramer CM, Baum SJ, Litwin SE, Menon V, et al. Effects of tirzepatide on the clinical trajectory of patients with heart failure, preserved ejection fraction, and obesity. Circulation [Internet]. 2025;151(10):656–68. Available from: http://dx.doi.org/10.1161/CIRCULATIONAHA.124.072679
41. Bhagavathula AS, Vidyasagar K, Tesfaye W. Efficacy and safety of tirzepatide in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized phase II/III trials. Pharmaceuticals (Basel) [Internet]. 2021;14(10):991. Available from: http://dx.doi.org/10.3390/ph14100991
42. Oup.com. [cited 2025 Dec 5]. Available from: https://academic.oup.com/ehjopen/article/5/5/oeaf117/8246115
43. Min T, Bain SC. The role of tirzepatide, dual GIP and GLP-1 receptor agonist, in the management of type 2 diabetes: The SURPASS clinical trials. Diabetes Ther [Internet]. 2021;12(1):143–57. Available from: http://dx.doi.org/10.1007/s13300-020-00981-0
44. Mdpi.com. [cited 2025 Dec 5]. Available from: https://www.mdpi.com/2076-3271/13/4/269/notes.