Obesity, defined as a body mass index (BMI) of 30 kg/m² or higher, is one of the most significant public health challenges of the 21st century, affecting over 650 million adults globally [1]. It is a multifactorial condition involving genetic, environmental, behavioral, and metabolic components. The World Health Organization (WHO) has recognized obesity as a disease that significantly increases the risk of developing type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), hypertension, non-alcoholic fatty liver disease (NAFLD), and certain cancers [2,3]. In the United States alone, the prevalence of obesity exceeds 42%, and it is a primary contributor to reduced life expectancy and increased healthcare costs [4].

Despite significant public health efforts emphasizing lifestyle modifications such as diet and physical activity, long-term weight loss maintenance remains elusive for many individuals. Behavioral interventions often lead to modest weight reductions, with high rates of weight regain, highlighting the need for alternative strategies [5]. Bariatric surgery has emerged as the most effective intervention for sustained weight loss and metabolic improvement; however, its invasiveness, cost, and access limitations render it unsuitable for a large segment of the population [6].

Over the past 20 years, the pharmacotherapy of obesity has evolved from adrenergic agents and appetite suppressants with a poor safety profile to (likely) target therapies that exploit gut-brain signaling and incretin pathways. None outshine the glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as liraglutide and semaglutide [7]. For obesity, these agents were initially created for T2DM but have shown striking impacts on weight and cardiometabolic risk factors, leading to their approval [8,9].

The pharmacological toolbox has continued to expand with newer agents including tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist. Tirzepatide provides more body weight reduction and better metabolic parameters than GLP-1 RAs as a single agent [10]. Other agents aimed at different pathways, such as amylin analogs (eg; cagrilintide) and melanocortin 4 receptor (MC4R) agonists, are in clinical evaluation and could present new areas for future treatment [11,12].

The pharmacologic approach of inducing weight loss is increasingly seen as not just a means of reaching a desired BMI threshold but as an avenue toward response of the underlying metabolic dysfunction of obesity. Weight loss drugs have also shown to improve glycemic control, lipid profile, blood pressure, and inflammatory biomarkers independent of body weight loss [13]. Semaglutide has been linked to a decrease in C-reactive protein (CRP)[13], and tirzepatide has been associated with substantial improvements in insulin sensitivity, HbA1c, and triglyceride levels in subjects with and without diabetes[14,15].

Beyond direct metabolic effects, weight loss pharmacotherapy has been associated with improved hepatic outcomes, including reduction in hepatic fat content, as well as other markers of NAFLD (non-alcoholic fatty liver disease) and NASH (non-alcoholic steatohepatitis). Such benefits are particularly pertinent in populations with common coexisting metabolic ills such as insulin resistance and dyslipidemia [16].

Given the complex interplay between obesity, insulin resistance, and systemic inflammation, new-generation anti-obesity drugs are poised to redefine the therapeutic landscape by offering holistic improvements in metabolic health. However, important questions remain regarding the long-term safety, durability of response, and comparative effectiveness of these agents, particularly when used in diverse patient populations [17].

This systematic review seeks to summarize the current literature on the effects of recently approved and investigational weight loss medications on glucose metabolism. We discuss their impact on glycemic control, lipid metabolism, insulin sensitivity, hepatic markers, and inflammatory mediators, with the intent to inform clinicians, researchers, and policy makers on the expanded use of these agents in the prevention and management of chronic disease [18,19]. because of its association with type 2 diabetes, cardiovascular disease and metabolic syndrome. Conventional approaches, including lifestyle changes and bariatric surgery, do not have a long-term impact, often because of lack of adherence or availability. Pharmacotherapies have changed the landscape of obesity, with recent developments having shown benefits on both weight loss and metabolic health. This review highlights the metabolic advantages of newer agents such as semaglutide, liraglutide, tirzepatide, and others.

This systematic review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines to ensure transparency, reproducibility, and comprehensiveness in the review process [20].

Search Strategy A systematic search was conducted using the PubMed, Scopus, and Web of Science databases from January 2018 to March 2024. Search terms included combinations of keywords such as: “weight loss drugs,” “anti-obesity agents,” “GLP-1 receptor agonist,” “semaglutide,” “tirzepatide,” “cagrilintide,” “MC4R agonist,” “metabolism,” “insulin resistance,” and “obesity pharmacotherapy.” Boolean operators (AND, OR) and filters were applied to focus on human studies published in English.

 Inclusion and Exclusion Criteria Studies were included if they:

• Evaluated pharmacological agents targeting weight loss approved after 2018.
• Reported metabolic outcomes, including glycemic parameters (HbA1c, fasting glucose), lipid profile (LDL, HDL, triglycerides), insulin sensitivity (HOMA-IR), liver function markers (ALT, AST), or inflammatory markers (CRP, IL-6).
• Were randomized controlled trials (RCTs), cohort studies, or meta-analyses.
• Included adults (age ≥18 years) with overweight or obesity (BMI ≥25 kg/m²).

Exclusion criteria:

• Animal or in vitro studies.
• Case reports, editorials, or conference abstracts.
• Studies without primary data on metabolic effects.

Study Selection and Data Extraction Two independent reviewers screened titles and abstracts using Rayyan software. Eligible studies were subjected to full-text review. Discrepancies were resolved by a third reviewer. Data extracted included: author, year, study design, sample size, drug studied, duration of intervention, metabolic outcomes measured, and key findings.

Quality Assessment The Cochrane Risk of Bias tool (RoB 2.0) was used to assess the methodological quality of RCTs. The Newcastle-Ottawa Scale (NOS) was used for cohort studies. Meta-analyses were assessed using AMSTAR 2 guidelines [21]. Studies were graded as low, moderate, or high risk of bias.

Data Synthesis Results were synthesized narratively and by outcome category. For homogenous outcomes, pooled effect estimates were reviewed from existing meta-analyses. Due to heterogeneity in population characteristics and interventions, a meta-analysis was not performed.

 PRISMA Flow Diagram

Characteristics of studies Among the 48 studies included:

•  28 were randomized controlled trials.
• 10 were prospective cohort studies
• 10 were systematic reviews/meta-analyses.

Drugs assessed included semaglutide (n=22), tirzepatide (n=15), liraglutide (n=9), cagrilintide (n=6), and MC4R agonists (n=4). Follow-up varied between trials, averaging between 12 weeks and 72 weeks.

Ethical statement Given that this study was a review of previously published data, no ethical approval or informed consent was required [22]. Ethical practice in source studies was assessed when determining quality.

Limitations Limitations of this review were language bias, unavailable individual patient data, and potential publication bias because of underreporting of negative results. Subsequent studies should seek to incorporate real-world evidence, longer follow-up, and head-to-head drug comparisons [23,24]. via PubMed, Scopus, and Web of Science databases for articles published from 2018 to October 2024 using the following keywords: “weight loss drugs,” “GLP-1 receptor agonist,” “tirzepatide,” “metabolism,” and “obesity pharmacotherapy.” Included studies were clinical trials, observational studies and meta-analyses assessing metabolic parameters, including insulin sensitivity, HbA1c level, lipid profile and inflammatory markers. Data extraction was performed following PRISMA guidelines.

Glycemic Control GLP-1 receptor agonists can significantly reduce HbA1c and fasting glucose levels in patients with obesity, regardless of the presence of type 2 diabetes mellitus (T2DM), according to several randomized controlled trials (RCT). In the STEP 2 trial, semaglutide (2.4 mg weekly) produced a mean decrease in HbA1c of 1.6% at 68 weeks in participants with T2DM [25]. In the SURPASS-2 trial, tirzepatide also demonstrated dose-dependent HbA1c reductions of up to 2.4% vs semaglutide and other monotherapies [26]. These effects were evident even in participants with fairly short diabetes duration and in those naive to antihyperglycemic therapies.

Insulin Sensitivity and Resistance Several studies have assessed the impact of weight loss drugs on insulin sensitivity using HOMA-IR and euglycemic clamp techniques. Treatment with GLP-1 RAs and dual agonists has consistently led to reductions in insulin resistance. In a 52-week trial, tirzepatide significantly lowered fasting insulin levels and HOMA-IR scores in non-diabetic patients with obesity [27]. The improvement in insulin sensitivity was found to be independent of weight loss, suggesting a direct insulin-sensitizing effect of these agents.

Lipid Metabolism Pharmacological approaches to changing lipid profiles also have been a well- described topic. Semaglutide- and tirzepatide-based treatment leads to lower total cholesterol, LDL and triglyceride levels and a modest increase in HDL cholesterol [28]. In the SURMOUNT-1 trial, tirzepatide treatment induced 25% and 15% relative reductions in triglyceride and LDL levels, respectively, after 72 weeks [29]. These are clinically meaningful changes, especially in populations with increased cardiovascular risk.

Inflammatory Markers Chronic inflammation is a characteristic feature of the metabolic syndrome and obesity. Recent results suggest that GLP-1 RAs and dual agonists could have anti-inflammatory effects. Multiple clinical trials have reported reductions in hsCRP and IL-6. A meta-analysis of 12 studies showed that GLP-1 RAs reduced hsCRP by 25% compared to placebo [30]. These data point to the possibility that these agents, which were not only blockade of metabolic pathways, but also optimized systemic inflammation.

Liver Function and NAFLD Markers Positive effects of semaglutide and tirzepatide on hepatic fat content and liver enzymes were noted. In a 48-week trial in patients with non-alcoholic fatty liver disease (NAFLD), semaglutide led to a decrease in ALT and AST levels, as well as a reduction of MRI-PDFF liver fat score [31]. Tirzepatide has also been more promising, with the resolution of steatohepatitis occurring in 40–60% of participants in some trials after 72 weeks [32].

Collectively, the findings support that new-generation weight loss drugs produce clinically meaningful metabolic improvements across multiple parameters. These effects extend beyond weight reduction and are likely attributable to pleiotropic mechanisms involving incretin biology, insulin-glucagon balance, lipid regulation, and inflammatory modulation [33]. (e.g., SURPASS and STEP series) indicate significant reductions in HbA1c and improvements in insulin sensitivity with GLP-1 receptor agonists and dual agonists. Semaglutide has shown reduction in CRP levels and triglycerides. Tirzepatide, a dual GIP and GLP-1 agonist, demonstrates superior effects on glycemic control and lipid metabolism. Emerging agents, such as amylin analogues and MC4R agonists, also show early metabolic benefits.

The findings of this review reveal that new-generation weight loss pharmacotherapies—primarily GLP-1 receptor agonists and dual agonists such as tirzepatide—extend benefits far beyond weight loss. Their ability to significantly improve metabolic markers including glycemic indices, lipid profiles, and inflammatory markers positions them as essential components in managing cardiometabolic risk [34].

Mechanisms of Metabolic Improvement The metabolic actions of GLP-1 and dual GIP/GLP-1 receptor agonists are ascribed to several central mechanisms. To do this, they stimulate glucose-dependent insulin secretion and suppress glucagon secretion, achieving glycemic control without inducing hypoglycemia [35]. These agents also slow gastric emptying and decrease appetite via central hypothalamic pathways, leading to profound caloric restriction [36]. Crucially, their mechanisms of action on adipose tissue metabolism and mitochondrial efficiency may explain some of their weight-independent effects on insulin sensitivity and liver lipid storage [37,38].

Glycemic Control and Diabetes Remission The significant HbA1c reductions reported in both diabetic and non-diabetic subjects imply a preventive effect of these agents on the progression of prediabetes to type 2 diabetes. Numerous patients have been reported to experience remission of T2DM with tirzepatide, and this effect remained up to 1 year after the treatment in some trials [39,40]. This remission seems to be mediated not only through weight loss but also through direct effects on pancreatic β-cell function and hepatic insulin sensitivity.

Cardiovascular and Lipid Outcomes The amelioration of lipid metabolism, particularly the reduction of triglycerides and LDL-C, is of clinical relevance, especially for those patients with metabolic syndrome or with an increased cardiovascular risk [41]. Recent cardiovascular outcome trials (CVOTs) have demonstrated a reduction in major adverse cardiovascular events (MACE) with GLP-1 RAs such as liraglutide and semaglutide [42].

Whether tirzepatide offers similar or superior cardiovascular protection remains to be confirmed in ongoing trials, but initial data are promising [43].

Inflammation and Immunometabolism Chronic low-grade inflammation underpins the pathophysiology of insulin resistance, atherosclerosis, and NAFLD. GLP-1-based therapies have demonstrated anti-inflammatory properties by reducing levels of CRP, TNF-α, and IL-6 [44]. These effects may be mediated through suppression of nuclear factor kappa B (NF-κB) signaling in adipocytes and macrophages [45]. As a result, these agents not only improve metabolic parameters but may also reduce systemic inflammation that contributes to chronic disease progression.

 Hepatic and Renal Effects Non-alcoholic fatty liver disease (NAFLD) and its more severe stage, non-alcoholic steatohepatitis (NASH) are highly prevalent in people with obesity and type 2 diabetes. For example, trials evaluating the effects of semaglutide and tirzepatide reported major reductions in liver enzymes, hepatic fat content, and histological features of resolution of NASH without worsening fibrosis [46]. Also, these agents exhibit nephroprotective potential through the decrease of albuminuria and slowing progression of eGFR in diabetic kidney disease patients [47].

Safeness and Tolerability However, these therapies also have some drawbacks despite their efficacy. The most frequent adverse events are gastrointestinal (including nausea, vomiting, and diarrhea) and are frequently dose-dependent. Pancreatitis and gallbladder disease are rare but serious concerns. Most of these side effects are manageable, but long-term safety data are still missing, in particular for dual agonists and newer agents such as MC4R agonists [48].

Knowledge Gaps and Future Directions There are a number of knowledge gaps that warrant the attention of funded scientists. First, real-world adherence and availability may influence clinical effectiveness. Second, the majority of the available studies have low ethnic and age diversity, therefore limiting generalisability. Third, there are few head-to-head trials of pharmacotherapies. Finally, the expense of these therapies must be contemplated, particularly in resource-limited environments.

To address these gaps, future research should:

• Include long-term follow-up to assess durability of metabolic benefits.
• Investigate synergistic effects of combining pharmacotherapy with digital health or behavioral interventions.
• Evaluate cost-benefit analyses across healthcare systems.
• Establish biomarkers to predict individual response to therapy.

In summary, new-generation weight loss agents offer multifaceted improvements in metabolic health. They hold particular promise for reducing the global burden of obesity-related chronic diseases. However, their optimal implementation requires careful consideration of safety, access, and long-term outcomes. not only appetite suppression and delayed gastric emptying but also modulation of insulin secretion, glucagon release, and inflammatory pathways. Beyond weight loss, these agents provide systemic benefits, including improved endothelial function and reduced hepatic steatosis. However, limitations include gastrointestinal side effects, variable cardiovascular outcomes, and lack of long-term data.

New weight loss drugs, especially GLP-1 and dual agonists, offer not only effective weight reduction but also meaningful improvements in metabolic health. These agents have shown benefits in glycemic control, lipid regulation, inflammation, and liver function. As evidence grows, they are becoming essential tools in managing obesity and preventing chronic metabolic diseases. However, long-term safety, cost, and access remain key challenges. Continued research is critical to define their optimal role in clinical and public health settings.

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