Dual Incretin Agonism in Type 2 Diabetes and Obesity: Systematic Review of Tirzepatide Mechanisms and Clinical Outcomes

Jefferson Lorençoni de Morais¹*, Lanna Araújo Gomes²,

                                               Larissa Neres Barbosa          

1.      Polytechnic School of the Alves Faria University Center - UNIALFA.

2.      Institute of Pharmaceutical Sciences. University Center of Goiás – UNIGOIÁS

*Correspondence: jefferson.morais@unialfa.com.br

DOI: https://doi.org/10.71431/IJRPAS.2026.5309      

 INTRODUCTION  

Diabetes mellitus represents one of the most significant global public health challenges of the 21st century, with a continuously increasing prevalence and substantial socioeconomic impact. Historical descriptions date back to ancient Egyptian and Greek medical texts, which reported polyuria and weight loss as hallmark manifestations. Only in the late 19th and early 20th centuries did advances in physiology and biochemistry enable the identification of insulin deficiency and resistance as central disease mechanisms. The progression of T2DM is characterized by a complex interplay between insulin resistance, β-cell dysfunction, genetic predisposition, and environmental factors. Longitudinal studies have demonstrated that reductions in insulin sensitivity and impaired insulin secretion precede the clinical onset of hyperglycemia by several years, establishing T2DM as a progressive and multifactorial disorder.[2][3]

Beyond classical metabolic pathways, increasing evidence highlights the involvement of the renin–angiotensin system (RAS) in the pathogenesis of diabetes-related complications. Angiotensin II exerts pleiotropic effects on vascular tone, inflammation, oxidative stress, and cellular proliferation, contributing to microvascular and macrovascular damage in diabetic patients.[2][3][4][5] The identification of incretin hormones, particularly glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), represented a paradigm shift in metabolic endocrinology. Incretins play a fundamental role in postprandial glucose regulation, enhancing glucose-dependent insulin secretion, suppressing glucagon release, delaying gastric emptying, and promoting satiety. Dysregulation of incretin signaling has been consistently observed in T2DM, contributing to impaired glycemic control and progressive β-cell failure.[15][19][20][23]

In this context, tirzepatide emerged as a novel therapeutic agent designed as a dual agonist of both GIP and GLP-1 receptors, representing a new paradigm in polypharmacology for metabolic diseases. Since its clinical introduction, tirzepatide has demonstrated superior efficacy in reducing glycated hemoglobin (HbA1c), promoting significant and sustained weight loss, and improving insulin sensitivity compared with traditional incretin-based therapies.[9][11][21][52]G iven the rapid expansion of clinical and mechanistic evidence surrounding tirzepatide, this systematic review critically evaluates studies published between 2006 and 2025, focusing on molecular mechanisms, physiological effects, and long-term metabolic outcomes associated with tirzepatide therapy in diabetes and obesity, following PRISMA 2020 guidelines.

Figure 1. Historical and pathophysiological evolution of diabetes mellitus and therapeutic targets. Figure prepared by the authors.

MATERIALS AND METHODS

2.1 Study Design and Reporting Guidelines

This study was conducted as a systematic review in accordance with PRISMA 2020 guidelines. The protocol was designed to ensure methodological transparency, reproducibility, and comprehensive synthesis of available evidence regarding tirzepatide in the management of diabetes mellitus and obesity.

2.2 Eligibility Criteria (PICOS Framework)

The population (P) comprised adults (≥18 years) diagnosed with T2DM, obesity, or metabolic syndrome. The intervention (I) consisted of tirzepatide administered alone or compared with other incretin-based therapies. Comparators (C) included placebo, lifestyle intervention, metformin, or other GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide). Outcomes (O) included HbA1c reduction, body weight changes, insulin sensitivity, cardiovascular outcomes, and adverse events. Study designs (S) encompassed RCTs, cohort studies, observational studies, and high-quality systematic or narrative reviews. Inclusion criteria required articles published between January 2006 and December 2025, peer-reviewed, and written in English, Spanish, or Portuguese. Exclusion criteria comprised case reports, editorials, letters, conference abstracts, pediatric studies, and animal-only studies without translational relevance.

2.3 Information Sources and Search Strategy

A comprehensive literature search was conducted across PubMed/MEDLINE, Scopus, Web of Science, ScienceDirect, and Embase. The search strategy combined MeSH terms and free-text keywords: "Diabetes Mellitus" OR "Type 2 Diabetes" OR "Insulin Resistance" AND "GLP-1" OR "GIP" OR "Incretins" AND "Tirzepatide" AND "Renin-Angiotensin System" OR "Angiotensin II". Reference lists of included studies were manually screened for additional relevant publications.

2.4 Study Selection and Data Extraction

The initial search identified 180 records. After duplicate removal, titles and abstracts were independently screened based on eligibility criteria, followed by full-text assessment of potentially relevant studies. Discrepancies were resolved through consensus, resulting in 20 studies for qualitative synthesis (Figure 2). Data extraction captured author(s) and year of publication, study design and sample size, intervention details, comparators, primary and secondary outcomes, key mechanistic findings, and safety profiles.

2.5 Risk of Bias Assessment

Methodological quality of RCTs was assessed using the Cochrane Risk of Bias Tool, while observational studies were evaluated using the Newcastle–Ottawa Scale (NOS). Only studies demonstrating moderate-to-high methodological quality were included.

2.6 Data Synthesis

Given heterogeneity in study designs, populations, and outcome measures, a qualitative narrative synthesis was performed. Findings were grouped into four thematic categories: (1) pathophysiology of diabetes and insulin resistance; (2) role of the renin–angiotensin system in metabolic dysfunction; (3) incretin signaling and dual receptor activation; (4) clinical efficacy and safety of tirzepatide.

Figure 2. PRISMA 2020 flow diagram of study selection. A total of 180 records were identified; 20 studies were included in the qualitative synthesis.

Table 1. Characteristics of the 20 included studies

RESULTS AND DISCUSSION

3.1 Pathophysiology of Diabetes and Metabolic Dysfunction

The analysis of selected studies revealed that T2DM pathophysiology is driven by a progressive and interconnected network of metabolic, hormonal, and vascular disturbances. Central to disease development is the combination of insulin resistance in peripheral tissues and pancreatic β-cell dysfunction, leading to sustained hyperglycemia and long-term metabolic deterioration.[2][4][10]

Multiple longitudinal studies demonstrated that insulin resistance typically precedes clinical diagnosis of T2DM by several years. Reduced insulin sensitivity in skeletal muscle and adipose tissue leads to impaired glucose uptake, increased lipolysis, and ectopic lipid accumulation, placing excessive secretory demand on pancreatic β-cells. This initially results in compensatory hyperinsulinemia, followed by gradual β-cell exhaustion and impaired insulin secretion.[4][35][36][37]

A consistent finding across the reviewed literature is the involvement of the RAS as a key mediator of metabolic dysfunction. Elevated angiotensin II levels exacerbate insulin resistance and β-cell dysfunction through oxidative stress, inflammation, and endothelial dysfunction.[5][9][10][11][12][13][14]

At the pancreatic level, angiotensin II negatively affects β-cell viability by inducing inflammatory signaling pathways and increasing reactive oxygen species (ROS) production, compromising glucose-stimulated insulin secretion and accelerating β-cell apoptosis.[1][5][57][58][59] In peripheral tissues, RAS activation interferes with insulin receptor signaling and glucose transporter translocation, resulting in reduced glucose uptake and increased release of pro-inflammatory adipokines.[5][10][55][57]

Vascular dysfunction represents another critical consequence of RAS overactivation. Elevated angiotensin II induces increased pro-inflammatory cytokines, oxidative stress, and reduced nitric oxide bioavailability, contributing to hypertension, impaired tissue perfusion, and the development of diabetic retinopathy, nephropathy, and cardiovascular disease.[6][1]

Figure 3. Renin–angiotensin system involvement in diabetes and metabolic dysfunction. Figure prepared by the authors.

3.2 Incretin System Dysfunction and Therapeutic Implications

Under physiological conditions, GLP-1 and GIP are released from the intestinal tract in response to nutrient intake, enhancing glucose-dependent insulin secretion, suppressing glucagon release, delaying gastric emptying, and promoting satiety.[15][19][20][23] This coordinated response, known as the incretin effect, accounts for a substantial proportion of post-prandial insulin secretion. However, multiple studies indicate that this effect is markedly impaired in T2DM, contributing to inadequate insulin secretion and persistent hyperglycemia.[15][19][23]

Incretin dysfunction in T2DM is multifactorial: reduced GLP-1 secretion, impaired receptor signaling, and resistance to GIP-mediated insulinotropic effects have all been documented. Notably, while circulating GIP levels may remain normal or elevated, pancreatic β-cells exhibit diminished responsiveness to GIP, rendering its insulinotropic action ineffective in advanced disease stages. In contrast, GLP-1 receptor signaling is partially preserved, providing the rationale for the clinical success of GLP-1 receptor agonists.[15][19][45]

Pharmacological strategies targeting the incretin system initially focused on selective GLP-1 receptor agonists and DPP-4 inhibitors, both demonstrating clinically meaningful improvements in glycemic control and body weight. However, the reviewed studies highlight important limitations including gastrointestinal intolerance, variable weight loss, and incomplete metabolic coverage, particularly in patients with advanced insulin resistance.[17][19][24][25][45]

Recent advances introduced dual incretin receptor agonism, aimed at simultaneously activating GLP-1 and GIP receptors to restore complementary incretin signaling and achieve more physiological regulation of glucose and energy homeostasis. Tirzepatide has emerged as the first clinically approved dual GIP/GLP-1 receptor agonist, representing a significant paradigm shift in T2DM and obesity treatment.[6][7][8][9][10][11][21]

Figure 4. Incretin signaling pathways and dual GIP/GLP-1 receptor agonism with tirzepatide. Figure prepared by the authors.

3.3 Clinical Efficacy and Metabolic Outcomes of Tirzepatide

The reviewed clinical evidence consistently demonstrates that tirzepatide produces robust and clinically meaningful improvements in metabolic control among T2DM and obesity patients. Across RCTs and systematic reviews, tirzepatide showed superior efficacy compared with placebo, lifestyle intervention, metformin, and selective GLP-1 receptor agonists.[9][11][21][52]

A primary outcome consistently reported was substantial HbA1c reduction. Tirzepatide therapy was associated with mean HbA1c reductions ranging from approximately 1.8% to 2.4%, depending on dosage and baseline metabolic status. These reductions exceeded those observed with semaglutide and liraglutide, highlighting the enhanced glycemic efficacy of dual incretin receptor activation.[9][21][22][23][25][52]

Body weight reduction emerged as a major metabolic benefit, with mean reductions reaching 15–20% of baseline body weight in some populations — surpassing that typically achieved with selective GLP-1 receptor agonists and clinically relevant for improving insulin sensitivity, cardiovascular risk factors, and overall metabolic health.[7][8][9][25][52]

Improvements in insulin sensitivity were also consistently observed. The dual activation of GIP and GLP-1 receptors appears to restore complementary incretin signaling pathways, reducing β-cell secretory burden while simultaneously improving peripheral glucose uptake and metabolic flexibility.[9][10][11][48][52]

Several studies reported favorable effects on cardiometabolic risk markers, including reductions in blood pressure, improvements in lipid profiles, and decreases in inflammatory markers, consistent with the known pleiotropic effects of incretin signaling on vascular function and systemic inflammation.[8][9][54]

Regarding safety and tolerability, tirzepatide demonstrated a profile comparable to other incretin-based therapies. The most frequently reported adverse events were gastrointestinal in nature (nausea, vomiting, diarrhea), generally mild to moderate and diminishing over time. Hypoglycemia incidence was low, reflecting the glucose-dependent mechanism of action. Serious adverse events were uncommon, and treatment discontinuation rates were comparable to selective GLP-1 receptor agonists.[9][11][21][52]

Taken together, the findings support a paradigm shift in the pharmacological management of T2DM and obesity. Tirzepatide exemplifies a polypharmacological strategy that aligns more closely with the complex pathophysiology of metabolic disease, integrating hormonal, metabolic, and vascular effects to offer a more comprehensive approach to disease modification.[9][10][11][48][52]

From a pharmacy practice perspective, the findings have important implications for medication management and patient-centered care. Pharmacists play a key role in optimizing the use of novel incretin-based therapies through appropriate patient selection, counseling on dose titration and gastrointestinal adverse effects, and monitoring treatment adherence and therapeutic outcomes.[44][47]

CONCLUSION

This systematic review synthesizes two decades of evidence to highlight the complex and multifactorial nature of T2DM and obesity, emphasizing the interplay between insulin resistance, β-cell dysfunction, vascular impairment, and hormonal dysregulation. The convergence of RAS activation and incretin system dysfunction creates a self-perpetuating cycle of metabolic deterioration that demands multitarget therapeutic approaches.[2][4][5][10]

Within this context, dual incretin receptor agonism represents a significant conceptual and clinical advancement. Tirzepatide, by simultaneously activating GIP and GLP-1 receptors, demonstrates superior efficacy in glycemic control (HbA1c reductions of 1.8–2.4%), substantial and sustained weight loss (up to 20% of baseline body weight), and improvements in insulin sensitivity compared with conventional incretin-based therapies. These effects reflect a shift toward polypharmacological approaches that more closely mimic physiological mechanisms.[9][11][21][48][52]

Although long-term outcomes and real-world effectiveness continue to be evaluated, the current evidence supports tirzepatide as a promising next-generation therapy for T2DM and obesity. Future research should explore its role in earlier stages of metabolic disease (prediabetes, obesity without overt diabetes), clarify the molecular basis of restored GIP responsiveness, evaluate cost-effectiveness in low- and middle-income settings, and investigate comparative effectiveness against emerging multi-agonist therapies. Addressing these gaps will be critical for fully realizing the potential of dual incretin receptor agonism in personalized metabolic care.[9][14][46][52]

CONFLICT OF INTEREST

The authors declare no conflict of interest.

ACKNOWLEDGEMENT

The authors declare no funding sources for this study. The authors are grateful for the institutional support provided throughout the preparation of this manuscript.

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