Tirzepatide and the Cardiovascular Continuum: Metabolic, Cardiorenal and Heart Failure Evidence

Abstract

Tirzepatide is a first-in-class, once-weekly dual GIP and GLP-1 receptor agonist approved for type 2 diabetes and obesity. Given the tight link between hyperglycemia, adiposity, and cardiovascular disease, tirzepatide has rapidly gained interest as a broader cardiometabolic intervention. This narrative review summarizes mechanistic rationale and clinical evidence on cardiovascular risk-factor modification, cardiorenal signals, and outcome data. Across the SURPASS program in type 2 diabetes, tirzepatide produces large, dose-dependent reductions in HbA1c and substantial weight loss, with consistent benefits versus active comparators. In obesity, the SURMOUNT trials showed marked and durable weight reduction over long follow-up, with clinically relevant improvements in waist circumference, blood pressure, triglycerides, and inflammatory biomarkers. Beyond weight and glycaemia, available data suggest favorable effects on lipids, ambulatory blood pressure, inflammatory markers, and kidney-related endpoints in exploratory analyses. Tirzepatide also improves obstructive sleep apnea severity in adults with obesity. Regarding cardiovascular outcomes, SURPASS-CVOT supports cardiovascular safety by demonstrating noninferiority versus dulaglutide for 3-point major adverse cardiovascular events in patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD). In obesity-related HFpEF, SUMMIT shows reductions in worsening heart failure (HF) events and improvements in health status, supporting a phenotype-specific role in HF. Overall, tirzepatide is emerging as a key therapeutic option for integrated cardiometabolic risk reduction, with ongoing research needed to define its incremental benefit versus established GLP-1 receptor agonists, long-term effectiveness in routine care, and optimal positioning across HF phenotypes.

1. Introduction

Tirzepatide is a clinically approved, single-molecule agonist that combines activity at the receptors for glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). ¹ This dual incretin strategy provides complementary metabolic effects that translate into marked reductions in glycated hemoglobin and body weight. Because obesity, insulin resistance, type 2 diabetes, and cardiovascular disease are closely intertwined, interest in tirzepatide has rapidly expanded beyond glucose lowering toward broader cardiometabolic risk reduction.^2-6 Accordingly, this narrative review focuses primarily on the clinical evidence relevant to cardiovascular risk-factor modification, cardiorenal outcomes, HF and safety, while limiting mechanistic discussion to concepts needed to contextualize the trial data. Clinically, tirzepatide is administered as a once-weekly subcutaneous injection, initiated at 2.5 mg weekly for 4 weeks, increased to 5 mg, and then up-titrated by 2.5 mg steps at ≥4-week intervals according to efficacy and tolerability up to 15 mg once weekly. ⁷

2. Methods

The reporting of this narrative review was guided by the SANRA (Scale for the Assessment of Narrative Review Articles) recommendations for narrative reviews (Supplemental File). ⁸ This narrative review is based on a selective overview of the major randomized clinical trials, cardiovascular outcome studies, and relevant mechanistic investigations on tirzepatide, with particular focus on the SURPASS, SURMOUNT, SURPASS-CVOT and SUMMIT programs. Relevant English-language peer-reviewed studies, meta-analyses, and clinically relevant investigations addressing the cardiometabolic, renal, and heart failure effects of tirzepatide were considered to provide an updated overview of the available evidence.

3. Tirzepatide and Cardiovascular Risk Factors/Disease

Building on the dual incretin biology outlined above, the following subsections synthesize mechanistic and clinical evidence on tirzepatide’s cardiovascular and cardiometabolic effects.

3.1. Diabetes Mellitus

Evidence for tirzepatide in type 2 diabetes is largely derived from the phase 3 SURPASS trial suite, in which weekly tirzepatide was tested against placebo, semaglutide, and basal insulin comparators. Across studies, glycated hemoglobin improvements were substantial, generally in the range of 1.5–2.5%, and accompanied by clinically meaningful, dose-dependent weight loss. In the placebo-controlled SURPASS-1 trial, tirzepatide 15 mg reduced HbA1c by approximately 2.07%. ⁹ In SURPASS-2, HbA1c decreased more with tirzepatide than with semaglutide 1 mg (2.46% vs 1.86%), and weight loss was also greater (11.2 kg vs 5.7 kg with tirzepatide 15 mg). ¹⁰ Consistent advantages were observed versus basal insulin strategies in SURPASS-3 and SURPASS-4 and when tirzepatide was added to titrated insulin glargine in SURPASS-5.^11-13 Design characteristics of the efficacy trials should, however, temper interpretation: follow-up was around one year in most studies, and these trials were optimized for metabolic endpoints rather than definitive cardiovascular event reduction. This limitation motivated the dedicated SURPASS-CVOT trial, which enrolled patients with type 2 diabetes and established atherosclerotic cardiovascular disease and randomized them to tirzepatide (up to 15 mg) or dulaglutide 1.5 mg. ¹⁴ The choice of dulaglutide as comparator is important for interpretation. Dulaglutide is not a neutral control; it is a GLP-1 receptor agonist with established cardiovascular benefit, making SURPASS-CVOT a stringent active-comparator trial rather than a placebo-controlled superiority study. In this context, the finding that tirzepatide achieved noninferiority for 3-point major adverse cardiovascular events (12.2% vs 13.1%; HR 0.92; 95.3% CI 0.83–1.01; P=0.003 for non inferiority) supports preservation of cardiovascular benefit relative to an evidence-based GLP-1 receptor agonist despite superiority not being demonstrated. ¹⁴ The failure to meet superiority should therefore not be overinterpreted as lack of cardiovascular efficacy; rather, it suggests that any incremental advantage over an already cardioprotective comparator may be modest, difficult to detect, or biologically constrained by a possible ceiling effect in contemporary secondary prevention. At the same time, not achieving superiority means that claims of cardiovascular advantage over established GLP-1 receptor agonists remain unproven, even if tirzepatide offers stronger glycaemic and weight effects. This distinction is clinically relevant when treatment goals prioritize proven event reduction versus maximal metabolic efficacy.

3.2. Obesity

Clinical evidence for tirzepatide as an anti-obesity therapy comes from the SURMOUNT phase 3 program, which evaluated once-weekly dosing (5/10/15 mg) over long follow-up in people with obesity, with and without type 2 diabetes. In adults without diabetes in SURMOUNT-1, which had a 72-week treatment period, mean weight loss reached approximately 16%, 21.4%, and 22.5% with 5, 10, and 15 mg respectively, versus about 2.4% with placebo. ¹ In participants with obesity and T2DM in SURMOUNT-2, also conducted over 72 weeks, the 15 mg dose produced roughly 15% mean weight reduction and was accompanied by major improvements in glycaemia, with HbA1c declining from around 8.0% to approximately 5.9% at week 72. ¹⁵ When tirzepatide was introduced after a structured lifestyle run-in in SURMOUNT-3, substantial additional weight loss was observed, commonly in the 20–25% range overall. ¹⁶ An important clinical issue is the trajectory of body weight after treatment discontinuation. SURMOUNT-4 addressed this by using an open-label lead-in period of 36 weeks on 10 or 15 mg, followed by randomization to continued tirzepatide or placebo for 52 weeks. ¹⁷ After randomization, participants switched to placebo showed substantial weight rebound, averaging about 14% of their initial body weight, whereas those who continued tirzepatide largely preserved the achieved reduction and in some cases extended it further, reaching a total mean reduction of 27.1%. The overall magnitude of weight loss achieved with tirzepatide is comparable to that typically reported after bariatric or metabolic surgery. ¹⁸ Beyond body weight, trials reported parallel improvements in waist circumference, blood pressure, triglycerides, and inflammatory biomarkers such as C-reactive protein.

3.3. Head-To-Head Comparison With GLP-1 Receptor Agonists

A direct comparison with GLP-1 receptor agonists is essential because these agents represent the current benchmark for both metabolic efficacy and, in some cases, cardiovascular risk reduction. The clearest randomized head-to-head evidence comes from SURPASS-2, in which tirzepatide produced greater reductions in HbA1c and body weight than semaglutide 1 mg in patients with type 2 diabetes. ¹⁰ However, interpretation requires attention to dose and indication: semaglutide 1 mg is a diabetes dose and is not equivalent to the 2.4 mg dose used for obesity management. Thus, SURPASS-2 shows superiority for metabolic endpoints against a commonly used diabetes-dose GLP-1 receptor agonist, but it does not fully resolve comparative efficacy against higher-dose semaglutide regimens used in obesity. Indirect comparisons across placebo-controlled programs suggest that tirzepatide may achieve greater average weight reduction than semaglutide, but such cross-trial comparisons should be interpreted cautiously because of differences in populations, baseline risk, background therapy, and trial design. From a cardiovascular perspective, semaglutide currently has the more mature dedicated outcomes evidence in obesity. In SELECT, ¹⁹ once-weekly semaglutide 2.4 mg reduced major adverse cardiovascular events by 20% versus placebo in patients with overweight or obesity and established cardiovascular disease but without diabetes, thereby establishing event reduction in a non-diabetic obesity population. By contrast, tirzepatide has shown cardiovascular noninferiority versus dulaglutide in type 2 diabetes with established ASCVD, but an unequivocal superiority signal over an established GLP-1 receptor agonist has not yet been demonstrated. ¹⁴ Taken together, the current evidence suggests that tirzepatide may offer stronger glycaemic and weight effects, whereas semaglutide currently has the most definitive placebo-controlled cardiovascular outcome evidence in obesity. Until additional direct or dedicated comparative outcome data mature, claims that one agent is categorically “better” should remain qualified and linked to the clinical objective under consideration: metabolic potency, obesity management, or proven cardiovascular event reduction.

3.4. Dyslipidemia

Tirzepatide has been associated with a directionally consistent improvement in circulating lipid parameters across clinical studies. Across studies, HDL-C shows a small but consistent upward shift, with increases of roughly 1–11%. Atherogenic fractions generally move in the opposite direction, total cholesterol usually declines by approximately 2–15%, and LDL-C usually falls by approximately 5–20%. ²⁰ Triglycerides also improve; in a network meta-analysis the estimated mean difference versus placebo was −0.89 mmol/L (95% CI −1.64 to −0.13). ²¹ Beyond plasma lipids, imaging data suggest an effect on ectopic fat. In an MRI substudy of SURPASS-3, participants with a fatty liver index ≥60 treated with pooled 10 mg/15 mg tirzepatide experienced a marked absolute reduction in liver fat compared with a smaller reduction in those receiving insulin degludec. ²² While these metabolic shifts are plausibly driven in part by weight loss and improved insulin sensitivity, additional mechanisms may contribute. Taken together, trials and meta-analyses describe a broadly beneficial lipid pattern with tirzepatide, lower total cholesterol, LDL-C and triglycerides alongside higher HDL-C versus placebo, whereas comparisons with GLP-1 receptor agonists have not consistently shown clear superiority. ²³ Preclinical work with incretin-based therapies, including GLP-1–pathway agonism, also suggests potential direct vascular effects, such as improved endothelial function and attenuation of inflammatory signalling, which could be relevant to the initiation and progression of atherosclerosis. ²⁴ Clinically, these findings support the view that tirzepatide may reduce atherosclerotic risk primarily through cardiometabolic risk-factor modification; in patients with established atherosclerosis, any benefit would be expected to complement standard secondary-prevention strategies aimed at limiting progression and preventing events.

3.5. Hypertension

Ambulatory and office-based data indicate that tirzepatide is associated with lower blood pressure versus control treatments. In pooled analyses, the average reduction is about 4.8 mmHg for systolic BP and 1.7 mmHg for diastolic BP. ²⁵ Evidence from Japanese phase 3 studies suggests a larger response in some cohorts; at the 15 mg dose, mean changes from baseline were approximately −11.0 mmHg systolic and −5.6 mmHg diastolic. ²⁶ Additional insight comes from 24-hour ambulatory monitoring. In the SURMOUNT-1 ABPM substudy conducted in adults with obesity without T2DM, tirzepatide reduced mean 24-hour systolic BP across all tested doses by week 36, while mean 24-hour diastolic BP decreased mainly at the lower dose levels. ²⁷ Over the same period, 24-hour mean heart rate increased with higher tirzepatide doses. ²⁷ Available evidence to date has not demonstrated a clear increase in atrial fibrillation risk with tirzepatide. ²⁸

3.6. Nephropathy

Exploratory renal analyses suggest that tirzepatide may confer benefits on kidney-related markers and outcomes. In a secondary analysis of SURPASS-4 once-weekly tirzepatide (5, 10, or 15 mg) was compared with insulin glargine and, over a median follow-up of roughly 85–104 weeks, was related with fewer events in a prespecified composite kidney outcome including a ≥40% decline in eGFR, renal death, progression to kidney failure, or incident macroalbuminuria. ²⁹ Baseline chronic kidney disease was common (close to 60% of participants), and the relative reductions in heart-failure events appeared comparable in those with versus without renal impairment. In a dedicated renal assessment, eGFR displayed a small early decrease compatible with a haemodynamic effect, followed by a more stable trajectory over 52 weeks compared with placebo; concomitant reductions in albuminuria were again observed, supporting the possibility of kidney protection in addition to broader cardiometabolic effects. ³⁰

3.7. Obstructive Sleep Apnea

In December 2024 the FDA authorized tirzepatide for the treatment of moderate-to-severe obstructive sleep apnea in adults with obesity, as an adjunct to diet and physical activity. The decision was supported by the phase 3 SURMOUNT-OSA program, two 52-week randomized, placebo-controlled trials in adults with obesity, enrolling participants either using or not using positive airway pressure therapy. ³¹ Tirzepatide at the maximum tolerated weekly dose of 10 or 15 mg produced substantially greater reductions in the apnea–hypopnea index than placebo, with mean decreases of roughly 25–29 events per hour compared with about 5–6 events per hour on placebo, alongside marked weight loss of about 18–20% versus approximately 2% with placebo. ³¹ In addition, a recent post hoc analysis from SURMOUNT-OSA reported improvements in patient-reported sleepiness and functional measures, with larger gains among participants who were moderately to very sleepy at baseline, particularly in those not on positive airway pressure therapy. ³² At present, the evidence base is limited to patients with obesity and one-year follow-up, and it remains uncertain whether improvements in OSA severity translate into durable long-term cardiovascular risk reduction.

3.8. Heart Failure

Evidence in HF appears phenotype-dependent. The strongest signal to date concerns obesity-related HFpEF. In the SUMMIT trial, adults with symptomatic HFpEF and obesity assigned to once-weekly tirzepatide, titrated up to 15 mg, experienced fewer cardiovascular death or worsening HF events than placebo, an effect driven predominantly by fewer worsening HF events requiring hospitalization or urgent treatment; health status and functional capacity also improved. ³³ Mechanistic and imaging substudies are consistent with a parallel reduction in congestion and cardiac loading, including favorable changes in left ventricular mass and paracardiac adipose tissue. ³⁴ These findings are clinically important, but several limitations deserve emphasis. First, follow-up was relatively short for a chronic HF syndrome (median approximately 2 years), limiting inference regarding long-term durability, mortality, and structural remodeling. Second, SUMMIT studied a specific obesity-related HFpEF phenotype rather than the full heterogeneous HFpEF spectrum; therefore, generalization to leaner patients, those without prominent adiposity-driven pathophysiology, or broader HFpEF populations should be cautious. Third, the apparent benefit was driven mainly by worsening HF events, whereas a clear reduction in cardiovascular death alone was not established. By contrast, randomized experience with GLP-1 receptor agonists in HFrEF has not provided consistent evidence of clinical benefit and has occasionally suggested possible harm, as in LIVE, in which liraglutide was associated with more serious cardiac events than placebo. ³⁵ A recent meta-analysis likewise failed to show reductions in HF outcomes for GLP-1 receptor agonists in HFrEF. ³⁶ Accordingly, extrapolation of tirzepatide beyond obesity-related HFpEF remains premature, and use in HFrEF should remain cautious and individualized pending dedicated data.

3.9. Inflammation

Chronic inflammation is an important contributor in the onset and progression of cardiovascular disease, largely through oxidative stress. Excess reactive oxygen species (ROS) promotes advanced glycation end-product (AGE) formation and activates NF-κB signalling, pathways that can be attenuated by GLP-1 receptor agonists.^37,38 Tirzepatide has also been linked to a favourable anti-inflammatory profile. In a post hoc evaluation of a phase 2 study, 26 weeks of therapy was associated with significant declines in several circulating markers, including YKL-40, intercellular adhesion molecule-1 (ICAM-1), C-reactive protein (CRP), leptin, and growth differentiation factor 15 (GDF-15). ³⁹ Li et al. reported that, in a murine sepsis model, tirzepatide attenuated cardiac inflammation, suggesting that its cardioprotective effects may be partly mediated by anti-inflammatory activity. ⁴⁰ Despite these early observations, the pathways underlying tirzepatide’s anti-inflammatory effects remain incompletely defined. One plausible explanation relates to its dual incretin receptor engagement. Both GLP-1 and GIP signalling have been reported to exert anti-inflammatory responses, and simultaneous activation of the two pathways may generate additive or synergistic attenuation of inflammatory signalling compared with either incretin signal alone. ⁴¹

4. Safety and Tolerability

Tirzepatide is generally associated with an adverse-event profile dominated by gastrointestinal (GI) symptoms, including nausea, vomiting, diarrhea or constipation, abdominal discomfort and early satiety, particularly during dose escalation. Because these effects originate in the gut and are typical of incretin-based therapies, it has been hypothesized that tirzepatide could also influence intestinal biology, potentially including the gut microbiome, although this remains mechanistically unproven. ⁴² Quantitatively, a network meta-analysis reported a higher likelihood of diarrhea versus placebo and an increased risk of nausea and vomiting with GLP-1–based therapies. ²¹ In the obesity trials, GI adverse events were likewise common representing the main tolerability issues; most events occurred early after initiation or dose escalation and only a minority led to permanent treatment discontinuation. These points are clinically important because tolerability directly influences adherence and therefore real-world effectiveness. Beyond gastrointestinal tolerability, discontinuation rates due to adverse events should be interpreted alongside efficacy. In major trials, withdrawals related to adverse events were generally higher with tirzepatide than with placebo and tended to rise with dose, reinforcing the practical value of gradual up-titration and anticipatory counseling. Beyond gastrointestinal tolerability, post-marketing pharmacovigilance has raised questions about possible neuropsychiatric adverse events such as anxiety and depressive disorders although causality and underlying biological mechanisms are uncertain. ⁴³ As with other agents in the incretin class, tirzepatide carries a boxed warning regarding medullary thyroid carcinoma, and it is contraindicated in individuals with a personal or family history of MTC or multiple endocrine neoplasia type 2. A recent analysis reported an increased reporting odds ratio for thyroid cancer among tirzepatide users relative to other glucose-lowering drugs, but such signals are subject to reporting bias and do not establish causation. ⁴⁴ Accordingly, the current concern is primarily precautionary and class-based rather than definitively confirmed in clinical outcome studies. Rare hypersensitivity reactions have also been described. For example, one case report documented a systemic allergic reaction occurring after the first tirzepatide dose in a patient with T2DM underscoring the need for clinical vigilance for allergic manifestations, particularly at initiation. ⁴⁵ Hepatobiliary safety also deserves structured consideration. Rapid weight loss itself may increase the risk of cholelithiasis or cholecystitis, making it difficult to distinguish drug-specific from weight-loss-related mechanisms. Available meta-analytic and case-based evidence suggests that serious hepatobiliary events are uncommon, but clinicians should remain alert to gallbladder symptoms and rare reports of liver injury, especially in patients with pre-existing hepatic vulnerability or unexplained liver test abnormalities.^46,47 Overall, the safety profile of tirzepatide appears manageable in most patients, but benefit-risk assessment should integrate both its robust efficacy and the predictable, dose-related gastrointestinal burden together with less common but clinically relevant thyroid and hepatobiliary considerations (Figures 1 and 2).

Figure 1.

Central illustration. Overview of the proposed mechanisms through which tirzepatide (dual GIP/GLP-1 receptor agonist) may improve cardiovascular risk across the cardiometabolic continuum

Figure 2.

Proposed clinical algorithm. Pragmatic phenotype-based framework for considering tirzepatide in different clinical scenarios (type 2 diabetes with obesity, obesity without type 2 diabetes, type 2 diabetes with coronary artery disease and obesity-related HFpEF). Colors indicate the overall strength of evidence supporting use in each phenotype and highlight where tirzepatide may be prioritized to address cardiometabolic risk and obesity-driven cardiac dysfunction

5. Conclusion

Tirzepatide has rapidly evolved from a glucose-lowering therapy into a broader cardiometabolic intervention with clinically relevant effects on glycaemia, body weight, blood pressure, lipid parameters, inflammatory markers, and exploratory kidney outcomes. Across randomized programs in type 2 diabetes and obesity, the consistency and magnitude of these effects make tirzepatide an important option when excess adiposity and insulin resistance are major drivers of cardiovascular risk. The dedicated outcomes evidence is also increasingly meaningful: SURPASS-CVOT showed cardiovascular noninferiority versus dulaglutide in patients with type 2 diabetes and established ASCVD, supporting preservation of cardiovascular benefit relative to an active comparator with proven efficacy, while SUMMIT extended the evidence base to obesity-related HFpEF by reducing worsening HF events and improving health status. At the same time, important uncertainties remain. Superiority over established GLP-1 receptor agonists for hard cardiovascular outcomes has not yet been proven, the HF data are currently strongest only in a specific obesity-related HFpEF phenotype, and long-term safety and real-world durability require continued study. From a practical perspective, treatment decisions should balance tirzepatide’s potent metabolic efficacy against its predictable dose-related gastrointestinal burden and other less common safety considerations. Future work should refine patient selection, clarify comparative positioning versus established GLP-1 receptor agonists, and determine whether the favorable cardiometabolic profile translates into broader and more durable reductions in cardiovascular and renal events across routine care settings (Tables 1 and 2).

Table 1.

Selected Efficacy and Outcome Findings From Major Tirzepatide Trials

Trial	Population/follow-up	Comparator	HbA1c reduction	Weight change	Cardiovascular/renal findings
SURPASS-1	T2DM; 40 weeks	Placebo	Up to approximately −2.1%	Up to approximately −9.5 kg	Metabolic efficacy trial; not powered for cardiovascular events
SURPASS-2	T2DM; 40 weeks	Semaglutide 1 mg	Approximately −2.0% to −2.3%; greater than semaglutide	Up to −11.2 kg; greater than semaglutide	Direct head-to-head evidence versus a GLP-1 receptor agonist for glycaemic and weight outcomes
SURPASS-3	T2DM; 52 weeks	Insulin degludec	Approximately −1.9% to −2.4%	Up to -12.9 kg; with insulin weight increased	MRI substudy suggested reduction in liver fat
SURPASS-4	T2DM with increased cardiovascular risk; 52 weeks primary report	Insulin glargine	Approximately −2.4% to −2.6%	Approximately −7 to −12 kg	Exploratory kidney composite favored tirzepatide; cardiovascular outcomes were exploratory
SURPASS-5	T2DM on basal insulin; 40 weeks	Placebo added to insulin glargine	Up to approximately −2.3% to −2.6%	Approximately −5 to −10 kg	Supports efficacy on top of background insulin
SURPASS-CVOT	T2DM with established ASCVD; median 4 years	Dulaglutide 1.5 mg	Greater HbA1c reduction than dulaglutide	Greater weight reduction than dulaglutide	3-point MACE: 12.2% vs 13.1%; HR 0.92 (95.3% CI 0.83–1.01); noninferior, superiority not met; post hoc analyses suggest favorable cardiorenal trends
SURMOUNT-1	Obesity without diabetes; 72 weeks	Placebo	Not primary focus	Up to −20.9%	Improved waist circumference, blood pressure, triglycerides, and inflammatory markers
SURMOUNT-2	Obesity with T2DM; 72 weeks	Placebo	Substantial reduction; HbA1c approached non-diabetic range in many participants	Up to approximately −14.7%	Improved cardiometabolic risk factors alongside weight loss
SURMOUNT-3	Obesity after intensive lifestyle run-in; 72 weeks	Placebo	Not primary focus	Mean reduction − 20.8%	Supports added value after lifestyle intervention
SURMOUNT-4	Obesity; 36-week lead-in plus 52-week randomized withdrawal	Placebo withdrawal	Not primary focus	Mean reduction − 20.9%	Highlights need for continued therapy to maintain benefit
SUMMIT	Obesity-related HFpEF; median approximately 2 years; randomized	Placebo	Not primary focus	Mean reduction − 13.9%	Reduced worsening heart failure events and improved health status; no clear reduction in cardiovascular death alone

Table 2.

Practical Safety Summary From Major Tirzepatide Trials and Pooled Analyses

Safety domain	Representative findings	Clinical interpretation
Gastrointestinal tolerability	Nausea approximately 12–24%, diarrhea 12–22%, vomiting 2–13% across SURPASS; pooled GI adverse events approximately 39%, 46%, and 49% with 5, 10, and 15 mg, respectively	Most common adverse events; usually mild-to-moderate, early, and dose-related
Discontinuation due to adverse events	Higher with tirzepatide than placebo/comparators; pooled analyses suggest discontinuation may approach approximately 10% at 15 mg	Supports slow titration, patient education, and individualized dose selection
Hypoglycaemia	Low intrinsic risk, but greater concern when used with insulin or sulfonylureas	Background therapy should be reviewed and adjusted where appropriate
Thyroid cancer/MTC warning	Boxed warning based on class precaution and preclinical data; human pharmacovigilance signals are inconclusive and non-causal	Avoid in patients with personal/family history of MTC or MEN2; counsel without overstating unproven risk
Hepatobiliary events	Gallbladder events and rare liver injury reports have been described; serious events appear uncommon	Monitor symptoms and liver tests when clinically indicated, particularly with rapid weight loss or hepatic comorbidity
Hypersensitivity	Rare case reports of systemic allergic reactions	Maintain vigilance at initiation and discontinue if significant hypersensitivity occurs
Neuropsychiatric disorders	Post-marketing pharmacovigilance analyses reported signals for anxiety, depressive disorders and other psychiatric adverse events	Monitor mood and behavioral changes in susceptible individuals; current evidence is insufficient to establish a causal association

ORCID iD

Antonio LM Parlati https://orcid.org/0009-0005-2297-7845