Developing a Comprehensive Approach for Managing Cardiorenal Metabolic Diseases (CRMD) in Saudi Arabia: Thinking beyond Single Disease—Literature Review and Multidisciplinary Consensus Report

Abstract

Cardiorenal metabolic disease (CRMD) encompasses a cluster of interrelated conditions—including obesity, type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic dysfunction-associated steatotic liver disease (MASLD)—that share common pathophysiologic pathways and amplify morbidity and mortality risks. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated robust evidence across randomized controlled trials and real-world studies in improving glycemic control (mean glycated hemoglobin [HbA1c] reduction of 1.0–1.5%), inducing sustained weight loss (average 10–15%), and reducing major adverse cardiovascular events (by 26% in SUSTAIN-6 and 20% in SELECT). Its potential renal and hepatic benefits, including slower estimated glomerular filtration rate (eGFR) decline and reduction in liver fat content, highlight its suitability for integrated CRMD management. This consensus report was developed through a structured, multiphase Delphi process involving endocrinologists, cardiologists, nephrologists, hepatologists, and public health experts from across Saudi Arabia. A comprehensive literature search (PubMed, Scopus, and Saudi Digital Library [2016–2024]) prioritized high-quality evidence from randomized controlled trials (RCTs), systematic reviews, and regional data. The panel reached consensus on key recommendations: (1) early identification and holistic management are critical for effective CRMD control; (2) adults at risk should undergo systematic screening for metabolic, cardiovascular, renal, hepatic, and cognitive complications; and (3) semaglutide should be positioned as a cornerstone therapy given its multiorgan benefits and favorable safety profile. Implementation strategies emphasize the careful selection of patients, individualized dosing, patient education, and integration into national pathways. In alignment with Saudi Vision 2030, incorporating semaglutide into CRMD management, supported by provider training, multidisciplinary care models, and cost-effectiveness analyses, can significantly reduce the national burden of metabolic disease and CVD.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13300-025-01826-4.

Key Summary Points

Cardiorenal metabolic disease (CRMD) is a unified, systemic disorder arising from chronic low-grade inflammation, insulin resistance, and visceral adiposity, linking obesity, type 2 diabetes, cardiovascular disease, kidney dysfunction, and metabolic dysfunction-associated steatotic liver disease (MASLD).

Insulin resistance and adipose-driven inflammation trigger a cascade of metabolic, vascular, and lipid disturbances that accelerate atherosclerosis, hypertension, hepatic steatosis, and progressive organ dysfunction.

Traditional care barriers—such as fragmented specialty-based management, delayed diagnosis, and underuse of effective therapies—limit outcomes, underscoring the need for integrated, patient-centered strategies.

GLP-1 receptor agonists, especially semaglutide, demonstrate robust multisystem benefits beyond glycemic control, including weight reduction, improved cardiovascular outcomes, renal protection, and potential benefits in metabolic dysfunction-associated steatohepatitis (MASH) and Alzheimer’s disease.

Holistic management of CRMD requires shifting from disease-specific treatment to comprehensive, multiorgan approaches that target root metabolic dysfunctions and emphasize early intervention, lifestyle modification, and advanced pharmacotherapies.

Introduction

Cardiorenal metabolic disease (CRMD) encompasses interconnected conditions, including type 2 diabetes mellitus (T2DM), obesity, cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic-associated steatotic liver disease (MASLD). These conditions share common pathophysiological mechanisms, such as insulin resistance, systemic inflammation, and endothelial dysfunction, leading to overlapping morbidity and mortality [1, 2]. Traditional single-disease management often fails to address these interdependencies, resulting in fragmented care, delayed diagnosis, and suboptimal outcomes. Recognizing CRMD as a unified entity allows for holistic, integrated interventions that target multiple organ systems simultaneously, improving patient-centered outcomes.

While global guidelines provide robust evidence on pharmacologic therapies—including glucagon-like peptide-1 (GLP-1) receptor agonists and SGLT2 inhibitors—there is a paucity of region-specific guidance addressing the unique epidemiology, healthcare infrastructure, and patient population characteristics in Saudi Arabia. Local data indicate high prevalence rates of obesity, T2DM, MASLD, and cardiovascular risk factors, highlighting the urgent need for tailored strategies [3–5].

This narrative review and consensus report synthesizes international and regional evidence to propose practical, Saudi-focused recommendations for early detection, multidisciplinary management, and the integration of evidence-based therapies such as semaglutide. By aligning with Saudi Vision 2030, these recommendations aim to reduce the burden of CRMD through population-level interventions, optimized care pathways, and enhanced patient outcomes.

Methods

Study Design and Objective

The development of this consensus report involved data from two expert meetings with cardiologists, endocrinologists, diabetes specialists, internal medicine specialists, general practitioners, and regulatory officials. The main objective was to formulate a consensus-based strategy for the holistic management of CRMD, with a particular focus on the role of GLP-1 receptor agonists—especially semaglutide—in addressing the interrelated conditions of T2DM, obesity, CVD, MASLD, and CKD.

Literature Search

A targeted literature review was performed to capture evidence on CRMD and related conditions, including T2DM, obesity, CVD, CKD, and MASLD/metabolic dysfunction-associated steatohepatitis (MASH). Key databases included PubMed, Scopus, and the Saudi Digital Library, covering publications from 2016 to 2024. Inclusion criteria prioritized high-quality, peer-reviewed studies such as randomized controlled trials (RCTs), systematic reviews, and consensus statements; studies focusing on pharmacologic interventions, integrated care models, and regional healthcare practices were prioritized. Approximately 350 references were initially screened, with 180 included in the final synthesis on the basis of relevance and methodological rigor. Full search terms and Boolean strategies are provided in the Supplementary Material: Supplementary Table S1 to avoid protocol-level detail in the main text.

Evidence was weighted to reflect both global trial data and regional applicability. International RCTs and meta-analyses provided high-level efficacy and safety data for pharmacologic interventions, while regional studies offered context on population-specific epidemiology, healthcare infrastructure, and implementation feasibility in Saudi Arabia. Recommendations were framed by combining these sources, with any discrepancy resolved through expert panel discussion.

Expert Panel and Consensus Process

A multidisciplinary panel of 25 experts was convened, including clinicians, researchers, and regulatory advisors across endocrinology [8], cardiology [5], nephrology [4], hepatology [3], and primary care/internal medicine [5], representing ten regions in Saudi Arabia. The consensus process involved two main phases: phase 1—literature interpretation and drafting preliminary recommendations and phase 2—refinement, validation, and finalization of guidance.

Consensus was achieved using a modified Delphi method, as summarized in the Supplementary Material: Supplementary Table S2. Participants rated each recommendation on a 5-point Likert scale (1 = strongly disagree, 5 = strongly agree), with ≥ 75% agreement required for inclusion. Three iterative rounds were conducted to address discrepancies through discussion and evidence reappraisal. Final recommendations were aligned with global standards and national healthcare priorities, ensuring applicability to the Saudi context.

Potential conflicts of interest and funding influences were minimized by requiring all panelists to declare their affiliations and financial disclosures prior to participation, conducting voting and consensus rounds independently of any industry sponsorship, and using a structured literature appraisal process to prioritize high-quality, peer-reviewed evidence over expert opinion whenever possible.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Evidence Hierarchization and Integration:

Evidence from RCTs, real-world studies, and expert opinion was hierarchized for transparency. Statements were labeled on the basis of strength: level A: strong RCT evidence; level B: limited or observational evidence; and level C: expert consensus. This approach allowed balanced incorporation of international and regional data while highlighting areas of uncertainty or emerging evidence.

CRMD: The Interconnected Nature

The interlinked disorders—obesity, T2DM, CVD, and MASLD—of CRMD share common pathophysiological roots. Chronic, low-grade inflammation driven by visceral adipose tissue (VAT) dysfunction is central to this systemic process. VAT secretes proinflammatory cytokines (TNF-α, IL-6, MCP-1, resistin) and suppresses protective adiponectin, promoting insulin resistance in muscle, liver, and adipose tissue [6–8]. This leads to impaired glucose uptake, hepatic lipogenesis, and lipolysis, resulting in elevated free fatty acids (FFAs) and ectopic fat accumulation in organs such as the liver, pancreas, heart, and kidneys [9]. However, insulin resistance alone does not cause CRMD if compensated by increased insulin secretion from pancreatic beta cells. Genetic factors can impair this compensation by reducing beta-cell function or mass, leading to disease progression. These impairments, combined with environmental influences, disrupt normal glucose regulation and contribute to CRMD development. Understanding genetic effects on these compensatory mechanisms helps explain how insulin resistance progresses to clinical disease [10].

Insulin resistance links metabolic dysfunction to cardiovascular and renal injury, driving hepatic steatosis, hypertension, and atherogenic dyslipidemia [11, 12]. Oxidative stress and endothelial dysfunction further exacerbate vascular injury and macrovascular events, including myocardial infarction and stroke. The interplay between inflammation, lipotoxicity, and organ dysfunction creates a self-perpetuating cycle of metabolic injury [13–15]. Recognizing CRMD as a unified entity supports integrated, system-wide interventions targeting these shared mechanisms rather than treating each component disease in isolation [16–19].

CRMD: Natural History and Disease Progression

CRMD evolves along a predictable continuum—beginning with obesity and visceral fat accumulation, progressing through insulin resistance, T2DM, MASLD/MASH, and extending to CKD and atherosclerotic CVD [8, 20]. Without timely intervention, this cascade culminates in severe complications such as myocardial infarction, stroke, and end-stage kidney disease (ESKD). Early intervention within the “window of opportunity” is critical, as managing obesity and insulin resistance can delay or prevent downstream disease progression. Evidence supports the use of GLP-1 receptor agonists and SGLT2 inhibitors for improving glycemic control, reducing hepatic fat, promoting weight loss, and lowering cardiovascular and renal risk [1, 2, 4, 8]. Conversely, delayed management limits therapeutic efficacy and accelerates irreversible damage. Cohort studies confirm the cumulative, stepwise risk across the CRMD spectrum—individuals with early metabolic disturbances exhibit markedly higher rates of CVD and CKD, while comorbid T2DM and CKD confer mortality risks comparable to established coronary disease [2, 21, 22].

CRMD: Barriers to Optimal Management

Multiple barriers impede optimal CRMD management. At the patient level, lifestyle inertia, poor disease awareness, and medication nonadherence (owing to cost or perceived lack of symptoms) remain common [1, 4, 23–25]. Clinician-level obstacles include therapeutic inertia—failure to intensify therapy despite suboptimal control—and fragmented care, where patients are managed by separate specialists without coordination [4, 19, 23–26]. This approach delays diagnosis and prevents comprehensive management.

System-level challenges include the absence of national MASLD screening programs, limited access to advanced therapies such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and SGLT2 inhibitors, and underuse of multidisciplinary care models that integrate endocrinology, cardiology, hepatology, nephrology, and behavioral support [1, 4, 23, 27]. In Saudi Arabia, where obesity and T2DM prevalence are among the highest globally, these barriers highlight the need for health system reforms aligned with Vision 2030 to enhance chronic disease prevention and care integration.

CRMD: Holistic Management Strategies

Holistic CRMD management (Tables 1) begins with early risk identification and proactive prevention. Risk stratification—using biomarkers (glycated hemoglobin [HbA1c], estimated glomerular filtration rate [eGFR], liver enzymes, albuminuria) and comorbid profiles—enables timely, targeted interventions. Integrated management must go beyond glycemic control to address obesity, dyslipidemia, hypertension, and organ protection, since these domains are metabolically interdependent. Evidence-based combination therapies, including GLP-1RAs, SGLT2 inhibitors, and statins, complement lifestyle interventions to achieve multidimensional risk reduction [4, 19, 21, 23]. A multidisciplinary, patient-centered model that unites endocrinologists, cardiologists, nephrologists, hepatologists, dietitians, and behavioral health professionals ensures continuity and personalization of care. This holistic approach enhances treatment adherence, mitigates disease progression, and improves survival and quality of life across the CRMD spectrum [4, 19, 21, 23]

Table 1.

Component of the holistic approach

Domain	Targets	Interventions	Specialist involvement
Early risk detection	High-risk individuals with obesity, insulin resistance, or metabolic syndrome	Risk calculators, HbA1c, liver enzymes, lipid panel, Blood Pressure (BP), Estimated Glomerular Filtration Rate (eGFR), Urinary Albumin Creatinine Ratio (UACR)	Primary care, endocrinology
Glycemic control	HbA1c < 7% (or individualized)	Lifestyle changes, metformin, Glucagon-like Peptide-1 (GLP-1) receptor agonists, Sodium-GLucose co-Transporter-2 Inhibitors (SGLT2i), insulin if needed	Endocrinology
Weight reduction	5–10% total body weight loss	Calorie restriction, physical activity, GLP-1 receptor agonists, bariatric referral if indicated	Dietitian, endocrinology, bariatric surgery
Lipid management	Low-Density Lipoprotein Cholesterol (LDL-C ) < 70 mg/dL in high-risk patients	Statins, ezetimibe, Proprotein onvertase Subtilisin/Kexin type 9 (PCSK9) inhibitors	Cardiology, lipid specialist
Blood pressure	< 130/80 mmHg	Lifestyle, Angiotensin-Converting Enzyme inhibitor (ACEi)/ Angiotensin Receptor Blocker (ARB), diuretics, Calcium Channel Blockers (CCBs)	Cardiology, nephrology
Liver health (MASLD)	Reduce steatosis and fibrosis risk	Weight loss, GLP-1 receptor agonists, avoid hepatotoxic drugs	Hepatology, endocrinology
Kidney function	Preserve GFR, reduce albuminuria	ACEi/ARB, SGLT2i, BP control, glucose control	Nephrology
Lifestyle modification	All domains	Nutrition counseling, structured exercise, behavior therapy	Dietitian, behavioral health
Multidisciplinary collaboration	Integrated care approach	Shared care plans, communication across specialties, patient education	All specialties

CRMD: The Role of GLP-1 Receptor Agonists

GLP-1 receptor agonists, initially developed for T2DM, are now key in managing CRMD. They mimic endogenous GLP-1, enhancing glucose-dependent insulin secretion and suppressing glucagon. This mechanism effectively lowers glucose with minimal hypoglycemia risk. They also slow gastric emptying and reduce appetite via hypothalamic action, leading to weight loss, targeting core metabolic dysfunction in CRMD [28–30].

Beyond glucose and weight control, GLP-1 receptor agonists provide cardiovascular (Table 2) and renal protection (Fig. 1). They reduce inflammation, improve endothelial function, and lower blood pressure and lipid levels. Unlike traditional agents, they reduce major adverse cardiovascular events (MACE) in high-risk patients. They also improve liver steatosis and enzyme levels, especially with SGLT2 inhibitors, showing renal benefits [31–34].

Table 2.

Cardiovascular outcome trials (CVOTs) of GLP-1 receptor agonists

Trial name	GLP-1 receptor agonist	Main CVD outcomes (major adverse cardiovascular events [MACE])	Other important outcomes (weight, renal, etc.)
ELIXA	Lixisenatide	Neutral effect on MACE	No significant weight loss or renal benefits reported
LEADER	Liraglutide	Significant reduction in MACE	Demonstrated weight loss and reduced progression of nephropathy
SUSTAIN-6	Semaglutide (injection)	Significant reduction in MACE	Notable weight loss and reduced progression of nephropathy
EXSCEL	Exenatide XR	Neutral effect on MACE	Modest weight loss; no significant renal benefits reported
REWIND	Dulaglutide	Significant reduction in MACE	Demonstrated weight loss and reduced progression of nephropathy
PIONEER 6	Semaglutide (oral)	Neutral effect on MACE	Weight loss observed; renal outcomes not significantly different
HARMONY	Albiglutide	Significant reduction in MACE	Weight loss observed; renal outcomes not significantly different
AMPLITUDE-O	Efpeglenatide	Significant reduction in MACE	Demonstrated weight loss and significant reduction in renal outcomes

Fig. 1.

GLP-1 actions in peripheral tissues. Adapted from Baggio and Drucker [67]

Efficacy in CRMD is supported by large-scale CVOTs showing reduced cardiovascular events and mortality trends in T2DM with high CVD risk. Their multimodal benefits on weight, liver, and renal function position GLP-1 receptor agonists as ideal in holistic cardiometabolic care without causing hypoglycemia [31, 35–38].

The AMPLITUDE-O trial of efpeglenatide, a long-acting GLP-1 agonist, confirmed cardiovascular and renal benefits even with SGLT2 inhibitors, reducing MACE and albuminuria, preserving renal function across CKD statuses, and supporting combination therapy in high-risk populations [36].

Emerging data are show hepatic benefits of GLP-1 agonists such as semaglutide in patients with MASLD/MASH with obesity and T2DM. Trials have demonstrated notable reductions in liver fat, enzymes, and histological improvements, including MASH resolution and fibrosis regression, aligning with anti-inflammatory and weight-reducing effects [35].

Extensive RCTs and meta-analyses strongly support incorporating GLP-1 receptor agonists in standard CRMD care. Guidelines from American Diabetes Association (ADA), European Society of Cardiology (ESC), and American Association for the Study of Liver Diseases (AASLD) recommend them for T2DM with CVD/high cardiometabolic risk, regardless of HbA1c [39–42]. Though not yet formally approved for MASLD/MASH, AASLD acknowledges potential liver benefits. Kidney Disease: Improving Global Outcomes (KDIGO) highlights multifaceted advantages in T2DM with CKD, marking a shift from glucose-centric to comprehensive risk reduction [41, 43].

Henceforth, semaglutide was selected as the primary GLP-1RA referenced in this consensus because it currently offers the most comprehensive and consistently robust evidence across the full cardiorenal metabolic disease spectrum. Furthermore, semaglutide has recently gained wider availability and adoption within Saudi Arabia’s healthcare system, consistent with national priorities under Vision 2030 to advance obesity, diabetes, and cardiovascular disease management through evidence-based, high-impact therapies. Nonetheless, the consensus acknowledges the therapeutic value of the entire GLP-1RA class and positions semaglutide as a reference molecule reflecting the strongest and most locally relevant data.

CRMD: Semaglutide, One Molecule for Multi-Interconnected Morbidities

Semaglutide Exhibits Evidence in Glycemic Control, Weight Reduction, and Cardiovascular Protection

Semaglutide has emerged as one of the most extensively investigated and clinically effective GLP-1 receptor agonists to date. Available in both once-weekly injection and once-daily oral formulations, it caters to individuals with different preferences and clinical needs. The PIONEER trials (oral semaglutide) and the SUSTAIN trials (injectable semaglutide) provide strong evidence for their efficacy across a range of endpoints, including glycemic control, weight reduction, and cardiovascular protection. These trials form the foundation of their adoption in global treatment guidelines for T2DM and obesity [44].

In terms of glycemic control, the PIONEER 1–10 trials demonstrated that oral semaglutide consistently reduced HbA1c by 1.2–1.5%, with the higher 14 mg dose achieving the most substantial improvements. Similarly, the SUSTAIN trials demonstrated that injectable semaglutide achieved HbA1c reductions of up to 1.8%, significantly outperforming comparators such as sitagliptin, insulin glargine, and exenatide. Importantly, these effects were achieved with a very low risk of hypoglycemia, making semaglutide suitable for a wide range of patients, including those with comorbidities or advanced age [45, 46].

The Semaglutide Treatment Effect in People with Obesity (STEP) trials, especially STEP 1, 3, and 4, established semaglutide unmatched antiobesity efficacy. In STEP 1, participants on 2.4 mg weekly injection lost an average of 14.9% of weight, compared with 2.4% in the placebo group. STEP 3, which combined semaglutide with intensive lifestyle intervention, reported weight losses nearing 17–18%. These landmark findings have led to semaglutide Food and Drug Administration (FDA) approval for chronic weight management [47, 48].

Regarding Cardiovascular outcome trials (CVOTs), the SUSTAIN-6 trial was a pivotal study involving over 3200 patients with T2DM at high cardiovascular risk. It demonstrated a 26% relative risk reduction in MACE over a median 2.1-year follow-up. The reduction in nonfatal stroke (39%) was particularly significant. The PIONEER-6 trial, although smaller and shorter in duration, confirmed the cardiovascular safety of oral semaglutide, showing a favorable trend toward reduced cardiovascular death. These data highlight the utility of semaglutide in primary and secondary prevention of cardiovascular (CV) events in patients with metabolic disease [45, 46].

A recent real-world cardiovascular outcomes study, the STEER study, compared semaglutide 2.4 mg with tirzepatide in patients with overweight or obesity and established CVD without diabetes mellitus (DM). Findings presented at the ESC Congress 2025 demonstrated that semaglutide was associated with a significantly greater reduction in MACE, including myocardial infarction (MI), stroke, or death from any cause. Specifically, semaglutide reduced the risk of these outcomes by 57% compared with tirzepatide, underscoring its potential as a therapeutic option for cardiometabolic risk reduction [49].

Semaglutide and Heart Failure

Recent evidence positions semaglutide as a breakthrough therapy for heart failure with preserved ejection fraction (HFpEF) in patients with obesity, where traditional management options have been limited [50, 51]. In the STEP-HFpEF trial (Kosiborod et al., 2023), once-weekly semaglutide 2.4 mg demonstrated significant clinical benefits compared with placebo over 52 weeks. Patients receiving semaglutide experienced a greater improvement in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), reflecting a substantial reduction in symptoms and physical limitations, alongside significant and sustained weight loss [50].

Moreover, compared with placebo, patients on semaglutide achieved a significant increase in the 6-min walk distance, highlighting improved exercise capacity, and showed a marked reduction in systemic inflammation, as evidenced by lower C-reactive protein (CRP) levels. The hierarchical composite analysis, which included mortality, heart failure events, and functional outcomes, also favored semaglutide with a win ratio of 1.72. Importantly, the therapy was well tolerated, with fewer serious adverse events than placebo [50].

Findings from a recent systematic review and meta-analysis further reinforce semaglutide’s benefits across heart failure populations. By pooling results from four studies, Gupta et al. (2024) confirmed significant improvements in KCCQ-CSS, weight reduction, exercise capacity, and inflammatory markers, consistent with STEP-HFpEF findings. Importantly, the review also demonstrated a reduction in MACE (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.62–0.92), suggesting potential cardioprotective effects that extend beyond symptom control. While mild adverse effects were reported, they were not more frequent than placebo. Taken together, these data highlight semaglutide’s dual action on cardiometabolic risk modification and functional improvement, making it a promising therapeutic strategy for obesity-related HFpEF and potentially broader heart failure phenotypes [51].

Semaglutide Shows Renoprotective Properties

Semaglutide also shows renoprotective properties. While not primarily designed as renal outcome trials, SUSTAIN-6 and other studies showed a slower decline in eGFR, particularly in patients with albuminuria. When used in conjunction with SGLT2 inhibitors, which primarily reduce intraglomerular pressure, semaglutide may offer complementary benefits through metabolic and hemodynamic pathways. In addition, the FLOW study showed that semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with T2DM and CKD [52, 53].

Early evidence from cardiovascular outcomes trials primarily showed that incretin-based treatments affected albuminuria/proteinuria. However, recent dedicated renal outcomes trials, particularly the FLOW trial with semaglutide, have demonstrated benefits on renal function endpoints such as preserving eGFR slope and reducing kidney failure risk [54].

Semaglutide Potential Role in Treating MASH

A fascinating development is the potential role of semaglutide in treating MASH. In the phase 3 ESSENCE trial (NCT04822181), semaglutide 2.4 mg once weekly demonstrated significant efficacy in patients with MASH and stage 2 or 3 fibrosis. At week 72, the interim analysis showed that semaglutide led to the resolution of steatohepatitis without worsening of fibrosis in 62.9% of patients, compared with 34.3% with placebo, and fibrosis improvement without worsening of steatohepatitis in 36.8% versus 22.4%, respectively (both p < 0.001). Additionally, 32.7% of patients treated with semaglutide achieved both endpoints, compared with 16.1% treated with placebo. Semaglutide also induced substantial weight loss (mean −10.5% versus −2.0%), though gastrointestinal side effects were more frequent. These findings support semaglutide as a promising treatment for MASH with fibrosis, reflecting both histologic and metabolic benefits [55].

Potential Role in Cognitive Decline and Alzheimer’s Disease

Semaglutide is gaining recognition as a potential neuroprotective agent in neurodegenerative disorders, particularly Alzheimer’s disease (AD) and Parkinson’s disease (PD). Preclinical studies have demonstrated that semaglutide can mitigate key pathological features of AD by reducing amyloid-beta plaque deposition, attenuating neuroinflammation, and improving cognitive and behavioral outcomes. In animal models of PD, it enhances mitochondrial function, promotes neurogenesis, and preserves dopaminergic neurons, resulting in improved motor performance. Complementing these findings, a recent pilot study in a transgenic murine model of AD showed that 4 weeks of semaglutide treatment significantly reduced blood glucose levels and improved cognitive performance in object recognition tasks while also showing a potential anxiolytic effect. Although there were no significant changes in motor or exploratory activity, the dual metabolic and cognitive improvements observed add to the promise of semaglutide as a disease-modifying medication in neurodegenerative illnesses [56, 57].

A recent real-world study, utilizing a nationwide US electronic health record database, has provided compelling evidence for the potential protective effects of semaglutide against AD in patients with T2DM. By emulating seven target trials across more than 1 million eligible patients without a prior AD diagnosis, the researchers assessed the comparative risk of first-time AD diagnosis over 3 years in individuals treated with semaglutide versus those receiving other antidiabetic medications. The results showed that semaglutide was significantly associated with a reduced risk of developing AD, with the most pronounced risk reduction seen when compared with insulin (hazard ratio [HR] 0.33, 95% CI 0.21–0.51) and a more modest but still significant benefit over other GLP-1 receptor agonists (HR 0.59, 95% CI 0.37–0.95). These findings held consistently across subgroups stratified by age, sex, and obesity status [58].

The study also noted a notable reduction in AD-related medication prescriptions among semaglutide users, further suggesting a potential disease-modifying effect. These real-world data align with preclinical studies and suggest that semaglutide may play a role in delaying or even preventing the onset of AD in at-risk populations. While these findings are promising, they underscore the need for confirmatory, prospective, randomized controlled trials to definitively evaluate the potential of semaglutide in the prevention or early intervention of AD [58].

The evoke and evoke+ trials are large, randomized, double-blind, placebo-controlled phase 3 studies testing semaglutide’s disease-modifying effects in early symptomatic AD. They enroll 55–85-year-olds with mild cognitive impairment or mild dementia due to AD confirmed by amyloid pathology. Participants receive daily oral semaglutide or placebo for 156 weeks after dose escalation. The primary endpoint is change in Clinical Dementia Rating Sum of Boxes (CDR-SB) at 104 weeks. Biomarkers and cerebrospinal fluid studies assess effects on neuroinflammation and AD pathology. With over 3600 participants total, results are expected by late 2026. These trials explore whether semaglutide, approved for T2DM and obesity, offers neuroprotection in AD via anti-inflammatory and vascular mechanisms [59].

CRMD: The Potential Role of Semaglutide to Lessen the Burden in Saudi Arabia

Local clinical observations and registries have echoed the global trend of multisystem metabolic disease convergence, with increasing numbers of Saudi patients presenting with coexisting T2DM, obesity, fatty liver, and cardiovascular risk factors. However, screening programs for MASLD, CKD, and cardiovascular risk remain fragmented, and therapeutic inertia is common owing to gaps in awareness and access. Therefore, the burden of CRMD in Saudi Arabia is among the highest globally, driven by alarming rates of obesity, T2DM, hypertension, and MASLD [60–63].

In Arabia Saudi, MASLD poses a growing public health challenge mainly driven by rising rates of obesity and T2DM. Parallel to the projected escalation in the prevalence of obesity and T2DM, projections estimate that by 2030, MASLD cases will reach approximately 12.5 million in Saudi Arabia, with a disproportionately high increase in MASH cases due to population aging and disease progression. Complications such as compensated cirrhosis and advanced liver disease are expected to more than double, while liver-related deaths are projected to rise to 4800 annually. Therefore, this underscores the urgent need for nationwide comprehensive strategies, including obesity and T2DM control and the development of effective treatments, to mitigate the growing burden of liver disease in Saudi Arabia [61].

In this high-risk setting, semaglutide offers a particularly valuable intervention. Though formal national outcome studies on semaglutide use in Saudi Arabia are limited, real-world experience is growing. The EVOLUTION study, a 15-month multicenter observational study conducted across 18 centers in Saudi Arabia, evaluated the real-world safety and effectiveness of semaglutide—administered either subcutaneously or orally—in 1223 adults with uncontrolled T2DM. Patients had a high baseline HbA1c of 10.02%, which was significantly reduced by an average of 3.02% at 6 months and 3.17% at 12 months (p < 0.001), with over half of those with HbA1c < 9% achieving near-normal levels (≤ 5.7%). Semaglutide was also associated with significant improvements in the lipid profile and blood pressure, along with a marked reduction in body mass index (BMI), averaging a 13.07% and 19.89% decrease at 6 and 12 months, respectively. Additionally, the frequency of hypoglycemia declined steadily over the treatment period. These findings highlight the substantial clinical benefit of semaglutide in enhancing cardiometabolic parameters in real-life settings [64].

Complementing these findings, the REVOLUTION study specifically focused on the use of oral semaglutide in 245 patients with uncontrolled T2DM in Saudi Arabia. The mean baseline HbA1c was 10.1%, and significant reductions of 3.1% and 3.2% were observed at 6 and 12 months, respectively. Semaglutide use led to marked reductions in hypoglycemia events—from 4.4 episodes prior to treatment down to 2.2 and 0.7 episodes at 6 and 12 months, respectively. BMI was reduced by 13.0% and 19.7% at the same intervals, and notable improvements in lipid profile and blood pressure were also reported. Together, these two studies provide real-world evidence supporting the effectiveness and safety of semaglutide in managing uncontrolled T2DM among Saudi patients [65].

Further supporting these outcomes, a retrospective real-world study conducted in a Saudi tertiary care setting assessed subcutaneous semaglutide (1 mg) in 1007 patients, including both individuals with T2DM and those using the drug off-label for weight management. Among the 955 and 442 patients who completed at least 3 and 6 months of therapy, respectively, semaglutide was associated with a 4.4% weight loss and a 0.4% reduction in HbA1c among persons with T2DM. Additionally, patients without T2DM experienced comparable weight loss benefits along with a significant decrease in diastolic blood pressure. Importantly, there were no negative changes in serum creatinine or urine albumin/creatinine ratio. These findings provide additional support for semaglutide’s beneficial metabolic and cardiovascular effects [66]. These findings are consistent with worldwide data and indicate good translatability of semaglutide advantages to the Saudi population.

Despite its clinical benefits, access and affordability of GLP-1 receptor agonists such as semaglutide remain limited. Availability is largely restricted to select Ministry of Health institutions and private sectors, with cost and insurance coverage posing barriers to broader use. Integrating semaglutide into national clinical pathways and public formularies—especially for high-risk patients with overlapping CRMD features—will be crucial to maximize population-level impact. Aligning these strategies with Saudi Arabia’s Vision 2030 health goals could significantly reduce the burden of chronic metabolic diseases through early detection and comprehensive, evidence-based therapy.

Clinical Practice Recommendations

Recommendation 1: Early identification and screening for CRMD are recommended.

- Effective management of CRMD requires early identification of at-risk individuals and a holistic approach that targets multiple organs simultaneously (evidence B). - Adults aged 40 years and older—or younger in the presence of obesity, family history of T2DM, or CVD—should be assessed for T2DM, hypertension, dyslipidemia, obesity, chronic kidney disease (using eGFR and albuminuria), and MSALD (via liver enzymes and noninvasive scores such as the Fibrosis-4 Index [FIB-4]) (evidence A). - In older adults or those with T2DM, cognitive screening should be integrated into routine care (evidence B).

Recommendation 2: Implement holistic and patient-centered interventions

- Prioritize the use of integrated treatment options that address multiple conditions simultaneously, such as GLP-1 receptor agonists, which provide benefits across T2DM, obesity, MASLD, and CVD (evidence A). - Customize treatment strategies on the basis of patient profiles, considering all comorbidities and personal preferences to optimize outcomes (evidence B). - Incorporate lifestyle, dietary, and psychosocial support as components of holistic care (evidence A).

Recommendation 3: Take the benefits of semaglutide as a cornerstone therapy

- Semaglutide benefits—including glycemic control, weight loss, cardiovascular protection, renal preservation, and emerging neuroprotective effects—make it ideal for treating the multiorgan dysfunction seen in CRMD (evidence A). - Semaglutide should be established as a core component in national clinical guidelines for managing T2DM, particularly in patients with obesity, CVD, or renal complications (evidence A). - It is also appropriate for patients with early stage CKD (eGFR ≥ 30 mL/min/1.73 m2) or evidence of MASLD or MASH, especially those with elevated liver enzymes or biopsy-confirmed liver inflammation and fibrosis (evidence B). - Additionally, semaglutide may be beneficial in individuals with obesity without T2DM who are at high cardiovascular risk or show early signs of cognitive decline, given emerging evidence suggesting a possible neuroprotective role (evidence C). - Its inclusion aligns with Saudi Arabia’s Vision 2030 goal of reducing the burden of noncommunicable diseases (evidence C).

Recommendation 4: Careful patient selection for semaglutide

- Semaglutide is best suited for patients with T2DM inadequately controlled on standard therapies and for individuals with obesity with comorbid hypertension, dyslipidemia, or early CKD (evidence A). - It is also appropriate for patients with MASLD or MASH, especially those with elevated liver enzymes or biopsy-confirmed liver fibrosis (evidence B). - Those with high cardiovascular risk or early signs of cognitive decline may benefit as well (evidence C). - Caution is advised in elderly or frail patients, and it should be avoided in those with a history of pancreatitis, gastroparesis, or medullary thyroid carcinoma (evidence B).

Recommendation 5: Dosing, initiation, and monitoring

- Start semaglutide at a low dose (e.g., 0.25 mg weekly subcutaneously), gradually titrating to the target dose (1 mg/week for glycemic control or up to 2.4 mg/week for weight loss) on the basis of tolerance (evidence A). - Oral semaglutide (14 mg/day) may be used when injection is not preferred (evidence A). - Monitoring every 3–6 months should include HbA1c, fasting glucose, renal function (eGFR, creatinine, albuminuria), liver enzymes, lipid profile, blood pressure, weight, and cognitive function (e.g., Mini-Mental State Examination [MMSE] or Montreal Cognitive Assessment [MoCA] in high-risk groups) (evidence B).

Recommendation 6: Patient education and adherence

- Comprehensive patient education is vital to achieving optimal outcomes (evidence B). - Patients should be informed that semaglutide is not only a T2DM drug but also systemic therapy with multiple benefits (evidence C). - Set realistic expectations—such as gradual weight loss (5–15%)—and provide training on injection or oral use, side effect management (especially gastrointestinal [GI] issues), and the need for long-term adherence (evidence B). - Use motivational interviewing, digital reminders, and follow-ups to support sustained engagement (evidence C).

Recommendation 7: Specialist referral and multidisciplinary care

- Referral to hepatology is warranted for patients with elevated liver enzymes and FIB-4 > 1.3 or suspected advanced MASH (evidence B). - Endocrinologists should manage patients with difficult-to-control T2DM or diagnostic uncertainty (evidence A). - Neurologists may be needed in those with cognitive decline (evidence C). - Multidisciplinary teams—including endocrinologists, nephrologists, cardiologists, primary care providers, pharmacists, and nutritionists—should coordinate through integrated CRMD clinics (evidence C).

Recommendation 8: Integration into national guidelines and systems

- Semaglutide should be fully integrated into national treatment pathways, with the availability of both oral and injectable formulations to enhance personalized care (evidence C). - Clinical decision support systems within electronic medical records should flag eligible patients (evidence C). - Establishing semaglutide as a national standard aligns with Saudi health priorities and supports population-wide interventions to combat T2DM and obesity (evidence C).

Recommendation 9: Healthcare provider training and capacity building

- National CRMD training programs and multidisciplinary care models should be supported to ensure consistency in implementation and to facilitate early identification of complications (evidence C). - Healthcare providers need structured training on semaglutide indications, dosing, monitoring, and side-effect management (evidence C).

Recommendation 10: Economic evaluation and access expansion

- To ensure broad access, cost-effectiveness analyses should be conducted to support national formulary inclusion (evidence B). - Semaglutide has the potential to reduce hospital admissions, cardiovascular events, and progression to ESKD (evidence A). - Strategies such as negotiated pricing, subscription-model reimbursement, public–private partnerships, and subsidies should be used to make semaglutide more affordable, especially in underserved or high-risk populations (evidence C).

Recommendation 11: Research and registry development

- Ongoing research is crucial to explore semaglutide’s expanding role in MASLD, MASH, cognitive impairment, and CKD (evidence C). - National investment in real-world research, including establishing a Saudi CRMD registry, will help monitor outcomes, safety, and long-term efficacy (evidence C). - Studies identifying predictive biomarkers could advance precision medicine approaches and refine patient selection (evidence C).

Recommendation 12: National implementation strategy

- The Saudi Ministry of Health should consider forming a national CRMD task force to oversee guideline updates, provider training, and public awareness campaigns (evidence C). - Hospitals and clinics should integrate semaglutide into their care protocols and electronic systems, while community education campaigns should raise awareness about CRMD risks and the benefits of treatment (evidence C).

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Concept and design: Abdulrahman Alshaikh, Ali Alshehri, Lamya Alzubaidi, Hussein Elbadawi, Abdulghani Alsaeed, Mohammed Almehthel, Raed Aldahash, Fahad Alsabaan, Metib Alotaibi, Khalid Alghamdi, Hussein Alamri, Abdulmohsen Bakhsh, Marc Evans, Emad R. Issak, and Saud Alsifri. Administration: Abdulrahman Alshaikh and Saud Alsifri. Literature search and review: Abdulrahman Alshaikh, Ali Alshehri, Lamya Alzubaidi, Hussein Elbadawi, Abdulghani Alsaeed, Mohammed Almehthel, Raed Aldahash, Fahad Alsabaan, Metib Alotaibi, Khalid Alghamdi, Hussein Alamri, Abdulmohsen Bakhsh, Marc Evans, Emad R. Issak, and Saud Alsifri. Drafting the manuscript: Emad R. Issak and Saud Alsifri. Revising the manuscript: Abdulrahman Alshaikh, Ali Alshehri, Lamya Alzubaidi, Hussein Elbadawi, Abdulghani Alsaeed, Mohammed Almehthel, Raed Aldahash, Fahad Alsabaan, Metib Alotaibi, Khalid Alghamdi, Hussein Alamri, Abdulmohsen Bakhsh, Marc Evans, Emad R. Issak, and Saud Alsifri. All the authors reviewed and approved the final manuscript in line with the International Committee of Medical Journal Editors (ICMJE) guidelines.

Funding

No funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Abdulrahman Alshaikh, Ali Alshehri, Lamya Alzubaidi, Hussein Elbadawi, Abdulghani Alsaeed, Mohammed Almehthel, Raed Aldahash, Fahad Alsabaan, Metib Alotaibi, Khalid Alghamdi, Hussein Alamri, Abdulmohsen Bakhsh, Emad R. Issak, and Saud Alsifri have nothing to disclose. Marc Evans is a co-editor-in-chief of the journal Diabetes Therapy. Marc Evans was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.