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Endocrinology and Metabolism

Cite as: Archiv EuroMedica. 2026. 16; 4. DOI 10.35630/2026/16/Iss.4.13

Received 16 June 2026;
Accepted 29 July 2026;
Published 10 August 2026

TIRZEPATIDE BEYOND WEIGHT LOSS: A NARRATIVE REVIEW OF METABOLIC AND ORGAN-SPECIFIC EFFECTS

Jowita Wiktoria Maksymiuk¹ , Mateusz Onopiuk¹ ,
Urszula Gadomska¹ , Natalia Dejewska¹ ,
Zuzanna Walewska¹ , Zuzanna Wiktoria Szumska² ,
Mikołaj Daniluk³ , Jonasz Żuk³ ,
Kinga Bukała⁴ , Szymon Klimaszewski⁵

¹ Bielański Hospital named after Rev. Jerzy Popiełuszko, Warsaw, Poland
² Otwock County Hospital, Otwock, Poland
³ Independent Public Central Clinical Hospital in Warsaw, Poland
⁴ Medical University of Lodz, Poland
⁵ Dental practice Szymon Klimaszewski, Gdańsk, Poland

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  jowita@maksymiuk.com

ABSTRACT

Background

Obesity is increasingly recognized as a chronic systemic disease associated with multiple metabolic and organ-specific complications. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated substantial efficacy in reducing body weight. However, its potential effects beyond weight reduction are of growing clinical interest.

Aim

This narrative review aimed to summarize and critically evaluate current evidence on the metabolic and organ-specific effects of tirzepatide beyond body weight reduction, with particular emphasis on cardiovascular, renal, hepatic, respiratory, reproductive-metabolic, and safety outcomes.

Materials and Methods

A narrative literature review was conducted using PubMed. The search included English-language publications from 2021 to 2026, with the last search performed in May 2026. Randomized controlled trials, prespecified and post hoc analyses of major clinical trials, meta-analyses, clinical guidelines, and relevant mechanistic reviews were prioritized. Earlier publications were included when they provided essential background or mechanistic context. A total of 42 publications were included, and the findings were synthesized descriptively.

Results

Tirzepatide was associated with improvements in waist circumference, blood pressure, lipid parameters, albuminuria, liver fat content, histological MASH outcomes, and obstructive sleep apnea severity. In patients with obesity-related heart failure with preserved ejection fraction, tirzepatide reduced the risk of cardiovascular death or worsening heart failure, although the benefit was driven mainly by fewer worsening heart failure events. Renal evidence showed a consistent reduction in albuminuria, whereas effects on eGFR decline and hard renal outcomes remained uncertain. In MASLD/MASH, tirzepatide reduced liver fat content and improved histological outcomes, including MASH resolution and fibrosis stage. In obstructive sleep apnea, treatment reduced the apnea–hypopnea index, hypoxic burden, body weight, hsCRP, and systolic blood pressure. Evidence regarding PCOS remained limited and was based mainly on theoretical considerations and review-based data. Gastrointestinal adverse events were the most commonly reported safety concern, while evidence on uncommon and long-term adverse events remained limited.

Conclusions

Tirzepatide may provide clinically relevant benefits beyond body weight reduction, particularly in obesity-related cardiometabolic complications, heart failure with preserved ejection fraction, MASLD/MASH, and obstructive sleep apnea. However, the extent to which these effects are independent of weight loss remains uncertain, and evidence for direct cardiovascular and renal protection is still limited. Further long-term randomized studies with hard clinical endpoints are required.

Keywords: Tirzepatide; Obesity; Cardiovascular Diseases; Heart Failure; Albuminuria; Kidney Diseases; Metabolic Dysfunction-Associated Steatotic Liver Disease; Fatty Liver; Sleep Apnea, Obstructive; Polycystic Ovary Syndrome

INTRODUCTION

Obesity is one of the most common chronic diseases worldwide, affecting approximately 890 million people globally [1]. According to a report published by the Polish National Health Fund (NFZ), the prevalence of obesity in Poland was 13.6% in 2022 and is projected to increase to 33.0% by 2033 [35].

Obesity is a major risk factor for a wide range of metabolic diseases, including type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD), and chronic kidney disease (CKD), and is associated with a substantial increase in cardiovascular risk and premature mortality [36].

Clinical obesity has been defined as a chronic systemic disease in which excess adiposity leads to disturbances in the function of tissues, organs, or the whole organism. Increasingly, obesity is no longer regarded merely as isolated excess body weight, but as a chronic systemic illness associated with multiple diseases, including cardiovascular disease, certain types of cancer, and mental disorders. Therefore, the treatment of obesity should not focus solely on body weight reduction, but also on improving organ function and reducing obesity-related complications [2].

One of the novel pharmacological agents used for weight reduction is tirzepatide, a dual agonist of the GIP and GLP-1 receptors, administered subcutaneously once weekly. Over a 72-week follow-up period, treatment with tirzepatide at doses of 5 mg, 10 mg, or 15 mg resulted in substantial dose-dependent body weight reduction, reaching approximately 21% with the 15 mg dose, compared with approximately 3% in the placebo group. The authors emphasized that the magnitude of weight reduction achieved with tirzepatide was considerably greater than that observed with previously available pharmacological treatments for obesity [3].

Although the weight-reducing efficacy of tirzepatide has been extensively investigated, its effects beyond body weight reduction have been reported across multiple clinical trials involving different organ systems and patient populations. However, these findings remain dispersed across the literature, and there is currently no concise narrative review integrating the available evidence on the cardiometabolic, renal, hepatic, respiratory, and emerging reproductive-metabolic effects of tirzepatide. A comprehensive synthesis of these data may facilitate a broader understanding of the potential role of tirzepatide in the management of obesity as a chronic systemic disease.

Given the well-documented efficacy of tirzepatide in reducing body weight, a comprehensive evaluation of its organ-specific effects is warranted.

AIM

The aim of this narrative review was to summarize and critically evaluate the current evidence on the effects of tirzepatide beyond body weight reduction.

The objectives were to assess the cardiovascular effects of tirzepatide, including cardiometabolic risk factors and obesity-related heart failure with preserved ejection fraction; evaluate its renal and hepatic effects; summarize the evidence concerning obstructive sleep apnea and the potential role of tirzepatide in reproductive-metabolic disorders, particularly PCOS; and assess its safety while identifying the principal limitations of the available evidence and priorities for future research.

METHODS

This narrative review was prepared to summarize current scientific evidence on the effects of tirzepatide beyond body weight reduction, with particular emphasis on selected cardiovascular, renal, hepatic, respiratory, reproductive metabolic, and safety outcomes. This review was not designed as a systematic review, and no formal risk of bias assessment or meta analysis was performed.

The primary literature search was conducted using PubMed and was limited to articles published between 2021 and 2026. The last literature search was performed in May 2026. The term “tirzepatide” was combined using the Boolean operator AND with each of the following terms: “GIP/GLP 1 receptor agonist”, “obesity”, “cardiovascular outcomes”, “heart failure with preserved ejection fraction”, “blood pressure”, “lipids”, “kidney outcomes”, “albuminuria”, “eGFR”, “MASLD”, “MASH”, “liver steatosis”, “obstructive sleep apnea”, “PCOS”, “fertility”, “safety”, “adverse events”, “gastrointestinal adverse events”, “pancreatitis”, and “biliary disease”.

Eligible publications included randomized controlled trials, prespecified and post hoc analyses of major clinical trials, meta analyses, clinical guidelines, and narrative or mechanistic reviews published in English. Conference abstracts, editorials, letters, duplicate publications, and studies not directly related to the topic of this review were excluded. Animal studies were excluded from the clinical evidence synthesis. Selected preclinical studies were included only when they provided relevant mechanistic information.

Priority was given to randomized controlled trials, major prespecified or post hoc trial analyses, meta analyses, and current clinical guidelines. Narrative reviews and preclinical studies were used primarily to provide mechanistic and contextual information.

Articles were identified through the literature search and selected based on their titles, abstracts, full text assessment when necessary, study design, clinical relevance, and contribution to the understanding of the selected effects of tirzepatide. The reference lists of the included articles were also manually screened to identify additional relevant publications. Earlier studies published before 2021 were included only when they provided essential background or mechanistic context and were identified through manual screening of reference lists. A total of 42 publications were included in this narrative review.

The findings were synthesized descriptively and organized according to the main clinical areas evaluated in the review, including cardiovascular effects, kidney outcomes, hepatic effects, obstructive sleep apnea, reproductive metabolic disorders, and safety.

RESULTS

1. Mechanisms Beyond Weight Reduction

1.1. Incretin system
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut-derived hormones known as incretins. They participate in the regulation of glucose and insulin metabolism, among other mechanisms, by stimulating pancreatic beta cells to secrete insulin. GIP is involved in the regulation of gastrointestinal function by inhibiting gastric secretion and also exerts insulin-like effects in adipocytes by limiting lipolysis and promoting lipogenesis. GLP-1 additionally suppresses glucagon secretion, slows gastric emptying, and increases satiety. Both incretin hormones influence glycemic control, appetite, lipid metabolism, and adipose tissue function. Preclinical and clinical data suggest that, when acting synergistically, they may enhance the effectiveness of weight reduction compared with targeting a single incretin pathway [4].

1.2. Mechanism of tirzepatide
Tirzepatide is a dual agonist of GIP and GLP-1 receptors. Its main clinical effects are related to appetite suppression, reduced energy intake, improved glycemic control, and substantial body weight reduction. This mechanism results from the simultaneous activation of two incretin pathways that influence insulin secretion, glucagon suppression, gastric emptying, satiety, and adipose tissue metabolism [5].

However, the effects of tirzepatide may extend beyond weight reduction alone. GIP and GLP-1 receptors show heterogeneous expression in metabolic tissues, and some of the effects of tirzepatide may result from both direct and indirect mechanisms. The presence of GIP receptors in adipocytes suggests a possible role of the GIP component in regulating adipose tissue metabolism and distribution. In contrast, effects on hepatocytes and skeletal myocytes may be more indirect and may depend, among other factors, on weight loss, improved insulin sensitivity, changes in lipid metabolism, neural signals, circulating mediators, or vascular effects [5,6].

The improvement in lipid profile observed in clinical trials, particularly the reduction in triglyceride levels, does not appear to be fully explained by weight loss alone, supporting the concept of additional metabolic effects of tirzepatide. These observations suggest that the effects of tirzepatide may include both weight loss-dependent effects and potential metabolic effects independent of body weight reduction itself [5,7].

2. Cardiovascular Effects

2.1. Cardiometabolic risk factors: blood pressure and lipids
Tirzepatide affects the cardiovascular system mainly by improving cardiometabolic risk factors. In the SURMOUNT-1 trial, in addition to its effects on body weight reduction and glucose metabolism, tirzepatide therapy was associated with favorable changes in metabolic parameters, including lipid metabolism, a reduction in systolic blood pressure (SBP), and a decrease in waist circumference [3]. Studies have shown an improvement in lipid profile, including reductions in total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides, as well as an increase in high-density lipoprotein cholesterol (HDL-C) [8,41].

Obesity is an important risk factor for hypertension and other cardiovascular diseases; therefore, the effect of tirzepatide on SBP reduction is highly relevant when assessing its potential cardiometabolic benefits. The effect of tirzepatide on blood pressure was evaluated, among others, in the SURMOUNT-1 ambulatory blood pressure monitoring substudy, which used 24-hour ambulatory blood pressure monitoring (ABPM). In adults with a body mass index (BMI) ≥27 kg/m² and without type 2 diabetes, tirzepatide treatment was associated with reductions in 24-hour SBP compared with placebo: −7.4 mmHg with tirzepatide 5 mg, −10.6 mmHg with 10 mg, and −8.0 mmHg with 15 mg. This effect was observed in both daytime and nighttime measurements. These findings are clinically important because ABPM better reflects cardiovascular risk, while nighttime blood pressure is a particularly important prognostic predictor [9].

However, it should be emphasized that the beneficial effects on blood pressure and lipid parameters may be largely related to body weight reduction and a decrease in visceral adipose tissue. Therefore, it remains difficult to distinguish the direct pharmacological effects of tirzepatide from the indirect effects resulting from weight loss [9].

2.2. Obesity-related HFpEF: clinical and mechanistic evidence
Heart failure with preserved ejection fraction (HFpEF) frequently coexists with obesity. Patients with obesity-related HFpEF are characterized by increased circulating blood volume and pressure overload, which may contribute to impaired cardiac function. Obesity is a recognized risk factor for HFpEF and is associated with a distinct phenotype of the disease, characterized, among other features, by more concentric cardiac remodeling compared with patients without obesity. Increased epicardial adipose tissue (EAT) is also observed in patients with obesity. EAT may contribute to the progression of HFpEF, among other mechanisms, through the local secretion of pro-inflammatory adipocytokines and adverse effects on myocardial structure and function [10,11,12].

The clinical relevance of tirzepatide was evaluated in the randomized, double-blind, placebo-controlled SUMMIT trial, which included patients with HFpEF and a BMI ≥30 kg/m². Participants were assigned to receive either tirzepatide or placebo, and the median follow-up was 104 weeks. Treatment with tirzepatide was associated with a lower risk of the composite endpoint of cardiovascular death or worsening heart failure. This event occurred in 9.9% of patients in the tirzepatide group and in 15.3% of patients in the placebo group. This effect was primarily driven by a reduction in episodes of worsening heart failure, which occurred in 8.0% and 14.2% of patients, respectively [10].

Data from the CMR substudy of the SUMMIT program suggest that tirzepatide treatment may be associated with a reduction in left ventricular mass and paracardiac adipose tissue, potentially indicating a favorable effect on cardiac remodeling [11]. In turn, a mechanistic analysis of the SUMMIT trial showed that the beneficial effects of tirzepatide in patients with HFpEF and obesity may be related to reduced volume and pressure overload, decreased inflammation, and lower markers of cardio-renal injury [12]. However, these effects should be interpreted with caution, as they may be largely related to body weight reduction. Moreover, in the SUMMIT trial, the clinical benefit was mainly driven by a reduction in episodes of worsening heart failure, rather than by a clearly demonstrated reduction in cardiovascular mortality [10–12]. Complementary real-world evidence showed that initiation of semaglutide or tirzepatide in patients with cardiometabolic HFpEF was associated with a lower risk of hospitalization for heart failure or all-cause mortality compared with sitagliptin, while no clear difference was observed between tirzepatide and semaglutide [40].

2.3. Cardiovascular outcomes and clinical positioning
When assessing the effects of tirzepatide on the cardiovascular system, it is important to refer to major adverse cardiovascular events (MACE). MACE is a composite endpoint that includes serious cardiovascular events, most commonly cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke [13].

To evaluate the effect of tirzepatide on MACE, the SURPASS-CVOT trial compared tirzepatide with dulaglutide, a GLP-1 receptor agonist with an already established benefit in reducing MACE [14,15]. The primary endpoint was the classic composite MACE-3 endpoint, including death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. The authors did not demonstrate a statistically significant superiority of tirzepatide over dulaglutide in reducing MACE. Therefore, the trial supports the cardiovascular safety of tirzepatide in relation to an established GLP-1 receptor agonist comparator, but does not establish its superiority over dulaglutide in reducing MACE [14].

Complementary evidence from a large retrospective cohort study suggested that, compared with GLP-1 receptor agonists, tirzepatide was associated with lower hazards of all-cause mortality, major adverse cardiovascular events, and adverse kidney outcomes in patients with type 2 diabetes [42]. However, these findings should be interpreted with caution because they were derived from observational real-world data rather than randomized clinical trials.

Despite promising data on the effects of tirzepatide on cardiovascular risk factors, body weight reduction, and obesity-related HFpEF, the evidence regarding its direct cardiovascular and renal benefits remains less conclusive than for therapies with well-established protective effects, such as SGLT2 inhibitors or selected GLP-1 receptor agonists. Therefore, in patients at high cardiovascular or renal risk, tirzepatide should not automatically replace drugs with better-documented effects on reducing these complications, despite its stronger weight-lowering efficacy [16].

3. Tirzepatide and Kidney Outcomes

3.1. Albuminuria and eGFR: clinical evidence
Obesity, particularly when coexisting with type 2 diabetes, is one of the major factors increasing the risk of chronic kidney disease, among others through metabolic, hemodynamic, and inflammatory mechanisms [17]. Therefore, it is important to analyze the effects of tirzepatide on parameters reflecting kidney function, such as albuminuria and estimated glomerular filtration rate (eGFR).

Data from the SURPASS-4 trial suggest a potential nephroprotective effect of tirzepatide. The authors compared the effects of tirzepatide and insulin glargine on kidney-related parameters and endpoints in patients with type 2 diabetes and high cardiovascular risk. Compared with insulin glargine, tirzepatide prevented the increase in albuminuria observed in the control group and reduced the risk of progression to more advanced albuminuria categories. It also reduced the urinary albumin-to-creatinine ratio (UACR). In addition, tirzepatide slowed the annual rate of eGFR decline compared with insulin glargine, and this effect was particularly pronounced in patients with a baseline eGFR <60 mL/min/1.73 m². However, it should be emphasized that this was a post hoc analysis of a trial whose primary objective was not the assessment of hard renal endpoints; therefore, these findings require confirmation in dedicated studies [18].

Another analysis, including data from the SURPASS-1–5 program, assessed whether albuminuria reduction is observed more broadly across clinical trials of tirzepatide [19]. In the pooled SURPASS-1–5 analysis, tirzepatide was associated with a dose-dependent reduction in UACR compared with comparators, strengthening the hypothesis of a potential albuminuria-lowering effect. Compared with semaglutide 1 mg, differences in UACR were not significant in the overall population; however, among patients with UACR ≥30 mg/g, the highest dose of tirzepatide was associated with a greater reduction in albuminuria. This suggests that potential renal benefits may be particularly relevant in patients with an already present marker of kidney damage [19].

In contrast to the more pronounced effect on UACR, this analysis did not show significant differences in eGFR between tirzepatide and comparators. This finding should be interpreted in the context of the short follow-up period and preserved kidney function in most participants [19]. Furthermore, the SUMMIT analysis highlights an important methodological issue: in patients with obesity treated with incretin-based therapies, assessment of kidney function based on eGFR may be distorted by changes in fat and muscle mass. Differences between creatinine-based and cystatin C-based eGFR suggest that a single marker may not fully reflect the true change in kidney function [20].

Overall, the available data indicate that the most consistent renal signal observed during tirzepatide therapy is a reduction in albuminuria, whereas its effect on eGFR remains less conclusive [18,19].

3.2. Mechanisms of kidney protection
The potential beneficial effects of tirzepatide on the kidneys may be partly related to improved glycemic control and body weight reduction; however, they do not appear to be fully explained by these factors alone. This supports the hypothesis that additional mechanisms may be involved, such as reduced intraglomerular pressure, anti-inflammatory effects, effects on the glomerular filtration barrier, or modulation of tubular function [19].

Preclinical data also suggest that tirzepatide may modulate the gut microbiota and the gut–kidney axis, which could potentially contribute to its nephroprotective effects [21]. However, it should be emphasized that some of the proposed mechanisms have not yet been clearly confirmed, and establishing the true nephroprotective effect of tirzepatide requires dedicated studies with hard renal endpoints.

4. Hepatic Effects

4.1. Metabolic Rationale for Tirzepatide in Steatotic Liver Disease
Steatotic liver disease (SLD) is an umbrella term that includes various liver diseases characterized by hepatic steatosis. One of these conditions is metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD). MASLD is defined as hepatic steatosis coexisting with at least one cardiometabolic risk factor. The spectrum of MASLD includes isolated hepatic steatosis, metabolic dysfunction-associated steatohepatitis (MASH), previously referred to as NASH, as well as more advanced stages of disease, including fibrosis and cirrhosis [22,23].

MASLD should be considered a hepatic manifestation of metabolic dysfunction, as it frequently coexists with obesity, type 2 diabetes, and cardiovascular risk factors. Its clinical significance extends beyond the liver and also includes cardiovascular and renal risk. In the context of MASLD/MASH, fibrosis is the most important factor in risk assessment. Therefore, studies evaluating not only the reduction of liver fat, but also the effects of therapy on histological MASH activity and the degree of fibrosis, are of particular importance [23].

The EASL–EASD–EASO guidelines emphasize that, in adults with MASLD and overweight, body weight reduction is recommended to improve liver injury. They also indicate weight loss thresholds of ≥5% for reducing liver fat, 7–10% for improving inflammation, and ≥10% for improving fibrosis [23].

4.2. Effects on Liver Fat Content and Metabolic Parameters
GLP-1-based therapies may be promising in MASLD/MASH because they reduce body weight, improve glycemic control and insulin sensitivity, and decrease liver fat content [24]. For this reason, tirzepatide, as a dual GIP and GLP-1 receptor agonist, represents a particularly interesting therapeutic option in the context of metabolically driven steatotic liver disease.

In the SURPASS-3 MRI substudy, the effects of tirzepatide on liver fat content, visceral adipose tissue (VAT), and abdominal subcutaneous adipose tissue (ASAT) were evaluated in comparison with insulin degludec in patients with type 2 diabetes. The study included individuals at increased risk of fatty liver disease, including those with a fatty liver index (FLI) ≥60. The primary endpoint was the change in liver fat content assessed by MRI-PDFF after 52 weeks.

The pooled tirzepatide 10 mg and 15 mg groups achieved a greater reduction in liver fat content (LFC) than insulin degludec, with mean decreases of 8.09 and 3.38 percentage points, respectively. The reduction in LFC correlated with decreases in body weight and in the volumes of VAT and ASAT. Tirzepatide also reduced VAT and ASAT, whereas increases in these parameters were observed in the insulin degludec group [7].

These findings suggest that tirzepatide may favorably affect the metabolic background of MASLD by reducing hepatic steatosis and improving adipose tissue distribution. However, it should be emphasized that the SURPASS-3 MRI substudy did not include liver biopsy; therefore, it did not allow assessment of histological MASH response or changes in fibrosis [7].

4.3. Histological Response in MASH and Fibrosis
The most important histological data come from the SYNERGY-NASH trial, which included patients with biopsy-confirmed MASH and F2–F3 fibrosis. After 52 weeks of treatment, tirzepatide led to MASH resolution without worsening of fibrosis significantly more often than placebo. The proportion of patients achieving this endpoint was 44%, 56%, and 62% for tirzepatide doses of 5 mg, 10 mg, and 15 mg, respectively, compared with 10% in the placebo group. An improvement in fibrosis by at least one stage without worsening of MASH was observed in 55%, 51%, and 51% of patients in the tirzepatide groups, respectively, compared with 30% in the placebo group [25]. The SYNERGY-NASH data complement the findings from SURPASS-3 MRI, as in patients with confirmed MASH, tirzepatide also reduced liver fat content assessed by MRI-PDFF, body weight, and liver enzyme activity. After 52 weeks of treatment, liver fat content (LFC) was reduced by 45.7–57.0% in the tirzepatide groups compared with 9.8% in the placebo group, along with reductions in ALT, AST, and GGT activity [25].

The analysis by Caussy et al. provides further insight into the relationship between metabolic and histological responses. In this post hoc analysis of the SYNERGY-NASH trial, patients who achieved MASH resolution or fibrosis improvement had greater body weight reduction, greater improvement in glycemic control, and more frequently achieved normalization of liver fat content. Liver fat normalization, defined as MRI-PDFF <5%, was significantly associated with both MASH resolution and fibrosis improvement [26].

Overall, the available data indicate that tirzepatide may have beneficial effects on MASLD/MASH through improvements in metabolic and imaging parameters as well as through histological response. However, it should be emphasized that SYNERGY-NASH was a phase 2 trial, and the analysis by Caussy et al. was post hoc and exploratory. Therefore, the effects of tirzepatide on fibrosis and long-term endpoints, such as cirrhosis, hepatic decompensation, and major adverse liver outcomes, require further confirmation in larger and longer studies [26].

5. Obstructive Sleep Apnea as an Obesity-Related Therapeutic Target

Obstructive sleep apnea (OSA) is a common disorder strongly associated with obesity. OSA results from recurrent episodes of upper airway obstruction during sleep, directly caused by increased pharyngeal collapsibility. Obesity may contribute to this phenomenon both through the mechanical effects of adipose tissue on pharyngeal soft tissues and lung volume, as well as through signaling factors affecting the central nervous system. Body weight reduction remains one of the most important treatment strategies for OSA in patients with overweight or obesity [27].

The SURMOUNT-OSA trial evaluated the efficacy of tirzepatide in adults with obesity and moderate-to-severe OSA [28]. Two randomized, double-blind phase 3 trials were conducted: one in patients not using positive airway pressure (PAP) therapy and the other in patients continuing PAP therapy. After 52 weeks of treatment, tirzepatide significantly reduced the apnea–hypopnea index (AHI) compared with placebo. The estimated treatment difference versus placebo was −20.0 events per hour in the first trial and −23.8 events per hour in the second trial. Treatment was also associated with body weight reduction, decreased hypoxic burden, lower high-sensitivity C-reactive protein (hsCRP) levels and systolic blood pressure (SBP), as well as improvement in patient-reported sleep outcomes. These findings suggest that tirzepatide may be relevant not only as a weight-reducing agent, but also as a potential therapy for selected obesity-related complications, such as OSA [28].

An additional analysis showed that improvements in OSA parameters, such as AHI and sleep apnea-specific hypoxic burden (SASHB), independently mediated improvements in hsCRP, homeostatic model assessment for insulin resistance (HOMA-IR), and triglyceride levels, which may translate into improved cardiovascular risk in patients with OSA and obesity. The authors suggest that the greatest cardiometabolic benefits in this population may be achieved when treatment addresses both sleep-disordered breathing and obesity itself [29].

Importantly, the regulatory status of tirzepatide for OSA differs between regions; while it has received a specific FDA approval for moderate-to-severe OSA in adults with obesity, the EMA considered the available evidence to be covered by the existing weight-management indication [30,31].

6. PCOS and Reproductive-Metabolic Disorders

Polycystic ovary syndrome (PCOS) is another condition closely associated with obesity, as well as with insulin resistance, type 2 diabetes, and increased cardiovascular risk [32,33]. In many women with PCOS, excess body weight exacerbates both metabolic and reproductive disturbances; therefore, weight reduction remains an important component of management. Even moderate weight loss, in the range of 5–10%, may be associated with clinically significant improvement in women with PCOS [33].

The potential usefulness of tirzepatide in this population is primarily related to its effects on body weight reduction and improved insulin sensitivity, which are two important metabolic problems observed in some patients with PCOS. This may be relevant not only for the metabolic profile, but also indirectly for ovulatory dysfunction and other aspects of reproductive function associated with obesity and insulin resistance. However, current data on tirzepatide in PCOS are mainly theoretical and review-based. Therefore, tirzepatide should be discussed as a potential future therapeutic strategy requiring confirmation in well-designed clinical trials [33,34].

The main clinical studies evaluating the efficacy and organ-specific effects of tirzepatide are summarized in Table 1.

DISCUSSION

The available evidence indicates that tirzepatide may exert clinically relevant effects beyond body weight reduction, particularly in obesity-related cardiometabolic, hepatic, and respiratory complications. Although these effects are likely mediated predominantly by substantial weight loss and improvement in metabolic risk factors, changes in lipid profile, inflammatory markers, organ-specific outcomes, and albuminuria [18,19] suggest that additional mechanisms may also contribute. The most robust evidence currently concerns obesity-related HFpEF, MASLD/MASH, and obstructive sleep apnea. In patients with HFpEF and obesity, tirzepatide reduced the risk of cardiovascular death or worsening heart failure, although the benefit was driven mainly by fewer worsening heart failure events rather than a demonstrated reduction in cardiovascular mortality [10–12]. In MASLD/MASH, tirzepatide reduced liver fat content and improved histological outcomes, including MASH resolution and improvement in fibrosis stage [7,25]. In obstructive sleep apnea, treatment reduced the apnea–hypopnea index, hypoxic burden, body weight, hsCRP, and systolic blood pressure [28].

Renal outcomes remain less conclusive. The most consistent finding is a reduction in albuminuria, particularly in patients with pre-existing markers of kidney damage, whereas the effects of tirzepatide on eGFR decline and hard renal outcomes remain uncertain and require confirmation in dedicated renal outcome trials [18,19]. Although tirzepatide improves several cardiovascular risk factors, current evidence does not demonstrate superiority over dulaglutide in reducing MACE. Evidence regarding PCOS and other reproductive-metabolic disorders remains largely theoretical and review-based; therefore, this area should be regarded as a potential direction for future research rather than an established clinical indication [33,34].

Several limitations should be considered when interpreting the available evidence. Some key findings are derived from post hoc or exploratory analyses rather than from trials specifically designed to evaluate the corresponding organ-specific outcomes [18,19,26]. In addition, the major clinical trials enrolled distinct selected populations, including patients with type 2 diabetes, obesity-related HFpEF, biopsy-confirmed MASH, or moderate-to-severe OSA with obesity, which may limit the generalizability of their findings to broader patient groups [10,18,25,28]. It also remains difficult to determine to what extent the observed effects are attributable to direct pharmacological actions of tirzepatide rather than to weight loss and associated metabolic improvements [7,19]. Evidence regarding sustained effects on eGFR, progression of chronic kidney disease, MACE, mortality, cirrhosis, hepatic decompensation, and major adverse liver outcomes remains limited, and longer randomized trials specifically designed to assess these endpoints are required [18,19,23,26]. Real-world studies will also be important for evaluating long-term effectiveness, tolerability, treatment persistence, and safety in routine clinical practice.

Safety

The most frequently reported adverse events associated with tirzepatide were mild-to-moderate gastrointestinal symptoms, including nausea, diarrhea, and vomiting, which occurred mainly during dose escalation [3,10,37–39]. In comparative trials, gastrointestinal adverse events were more frequent with tirzepatide than with some active comparators [14,37,39]. Available evidence on uncommon and long-term adverse events remains limited, and further studies are needed to clarify the long-term safety profile of tirzepatide.

CONCLUSIONS

Current evidence indicates that tirzepatide may provide clinically relevant benefits beyond body weight reduction, particularly in obesity-related cardiometabolic complications, heart failure with preserved ejection fraction, MASLD/MASH, and obstructive sleep apnea. However, the extent to which these effects are independent of weight loss and associated metabolic improvement remains uncertain. Evidence for direct cardiovascular and renal protection is still limited. Data regarding the use of tirzepatide in PCOS remain insufficient and are based mainly on theoretical considerations and review-based evidence rather than dedicated clinical trials. Gastrointestinal adverse events are the most commonly reported safety concern, while evidence on uncommon and long-term adverse events remains limited. Further long-term randomized studies are needed to evaluate hard cardiovascular and renal outcomes, clarify the mechanisms underlying organ-specific effects, and determine the potential role of tirzepatide in reproductive-metabolic disorders.

DISCLOSURE

Author Contributions

Conceptualization: Jowita Wiktoria Maksymiuk. Literature search: Jowita Wiktoria Maksymiuk, Mateusz Onopiuk, Urszula Gadomska, and Zuzanna Wiktoria Szumska. Writing, original draft preparation: Urszula Gadomska, Natalia Dejewska, Zuzanna Walewska, and Mikołaj Daniluk. Writing, review and editing: Jowita Wiktoria Maksymiuk, Zuzanna Wiktoria Szumska, Mateusz Onopiuk, Jonasz Żuk, Kinga Bukała, and Szymon Klimaszewski.

All authors have read and agreed with the published version of the manuscript.

Funding

This research received no external funding.

Conflict of Interest

The authors declare no conflict of interest.

Use of Artificial Intelligence

The authors used Artificial Intelligence to assist with language editing and translation of the manuscript. All scientific content, interpretation of the literature, and final responsibility for the manuscript remain with the authors.

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