1. Introduction

Obesity has emerged as a pressing global health crisis, often referred to as a pandemic due to its widespread prevalence and significant impact on public health. It is estimated to be responsible for approximately 3.4 million deaths each year worldwide, underscoring its severity as a major contributor to mortality rates [1]. Clinically, it is characterized by an excess accumulation of adipose tissue within the body, and it is formally defined as a body mass index (BMI) of ≥30 kg/m². It can affect patients both on a psychological and physical level, with overweight and obese people found to be at risk for diabetes, cardiovascular disease, cancer, and premature death [2]. This has a significant toll on life expectancy, which is shown to be reduced by 7 years at the age of 40 years [3]. Added to that, it is constantly growing in scale with an estimated projection of overweight and obese adults at 1.35 billion and 573 million, respectively, by the year 2030 [4].

Coming hand in hand with obesity, type 2 diabetes mellitus (T2DM) poses a considerable threat to individual health and a significant burden on the world’s financial health policy. Described as a disorder of glucose homeostasis and insulin sensitivity, it is primarily triggered by uncontrolled hyperglycemia, and it is responsible for a large number of microvascular (like diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy) and macrovascular complications (like diabetic foot syndrome, cerebrovascular events, and myocardial infarction) [5]. The presence of T2DM also increases susceptibility to a variety of cancers (such as liver, biliary tract, pancreas, stomach, colorectal, kidney, bladder, breast, and endometrial) and infections (like respiratory, urinary tract, and skin and soft tissue infections) [6].

A tight interplay between these two is a common finding in many patients, and many metabolic pathways show their close pathophysiological connection. For example, the global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) among diabetic patients is estimated at 65.33% and 66.44%, respectively [7].

Unhealthy diets and sedentary lifestyles are pivotal predisposing factors contributing to the growing global burden of obesity, T2DM, and metabolic dysfunction-associated fatty liver disease (MAFLD). Diets rich in saturated fats, refined carbohydrates, and ultra-processed foods—hallmarks of the Western dietary pattern—have been consistently linked to excessive adiposity, insulin resistance, and chronic systemic inflammation [8]. These conditions are central to the pathogenesis of both T2DM and MAFLD, forming a critical component of the broader metabolic syndrome. Additionally, prolonged physical inactivity further compounds these risks by diminishing metabolic flexibility and impairing insulin sensitivity, independent of body weight [9]. The synergistic effect of poor dietary quality and lack of exercise creates a fertile ground for the development and progression of metabolic disorders.

Intervention through lifestyle modification remains the first-line therapeutic strategy. Notably, adherence to the Mediterranean diet—a dietary pattern rich in fruits, vegetables, whole grains, olive oil, and lean proteins—has demonstrated significant improvements in hepatic steatosis and insulin resistance among patients with MAFLD [10]. Furthermore, structured exercise regimens incorporating both aerobic and resistance training have been shown to reduce liver fat content and improve glycemic control [11]. However, despite the well-documented benefits of lifestyle changes, maintaining long-term adherence remains a challenge for many individuals, often requiring multidisciplinary support and long-term behaviour change strategies. When necessary, pharmacological interventions are essential to eliminate the gap for effective prevention and management of these interrelated conditions.

Numerous pharmacological treatments seek to disrupt these harmful connections, with a considerable number focusing on the incretin hormonal pathways and appetite regulation. Three of the most common incretin peptide hormones are Glucagon-Like Peptide (GLP-1), Glucose-Dependent Insulinotropic Polypeptide (GIP), and Glucagon. The emergence of GLP-1 receptor agonists, such as the first clinically approved agonist, exenatide, in 2005, paved the way for the thorough exploration of these molecules [12]. Shortly, other molecules such as liraglutide, dulaglutide, and semaglutide came forth, offering a once-weekly dosage. Beyond achieving more effective glucose control and offering worthy weight loss, these medications achieved a reduction in rates of major adverse cardiovascular effects, heart failure, kidney disease, and cardiovascular death [13,14,15]. These promising results led to the development of the first dual agonists, with tirzepatide, a GIP and GLP-1 receptor agonist, being the most prominent one. Tirzepatide achieved significant reductions in Glycated Hemoglobin A1c (HbA1c) levels and body weight compared to placebo. Additionally, tirzepatide was found to have a more pronounced effect compared with the GLP-1 agonist semaglutide in people with T2DM. The incidence of gastrointestinal (GI) adverse events was increased compared with placebo; however, neither tirzepatide nor semaglutide increased the risk of serious adverse events or severe hypoglycaemia [16].

A first-of-its-class triple receptor agonist, retatrutide, aims to deliver a revolution in obesity and T2DM pharmacotherapy. This groundbreaking medication is shown to enhance therapeutic outcomes by delivering more pronounced reductions in both body weight and HbA1c levels than current pharmacotherapies.