Cardio-kidney-metabolic protective effects of semaglutide across the spectrum of chronic kidney disease

Abstract

There is growing evidence suggesting that semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is effective in preventing and treating chronic kidney disease (CKD) in patients with type 2 diabetes mellitus (T2D). The Evaluate Renal Function with Semaglutide Once Weekly trial demonstrated that semaglutide significantly reduced the risk of major kidney outcomes, including kidney failure, death from kidney or cardiovascular causes, reduced albuminuria and major cardiovascular events. Emerging evidence also suggests a potential kidney-protective effect of GLP-RAs in people without diabetes. Based on this data, contemporary guidelines now support GLP-1RA use, notably semaglutide, as the fourth pillar of diabetic kidney disease (DKD) management in T2D, alongside existing cardio-kidney protective agents (the other 3 pillars of DKD therapy) sodium glucose co-transporter-2 inhibitors, non-steroidal mineralocorticoid receptor antagonists and renin-angiotensin-aldosterone-system blockers. Semaglutide offers complementary and synchronous benefits through distinct mechanisms, underscoring its role in the comprehensive management of patients with T2D. Furthermore, GLP-1RA use in people with T2D and CKD improves metabolic parameters not achievable with the other DKD therapies. This review summarises the clinical evidence for semaglutide’s kidney-protective effects in individuals with and without T2D, and highlights recent trial data supporting its broader metabolic effects in CKD. Together these findings position semaglutide as a key agent in modern CKD management.

Key Words: Semaglutide; Glucagon-like peptide-1 receptor agonist; Chronic kidney disease; Diabetes; Albuminuria

Core Tip: In people with type 2 diabetes and chronic kidney disease, semaglutide, saves kidneys, hearts and lives. The glucagon-like peptide-1 receptor agonist (GLP-1RA) class of medications are now being proposed as the fourth pillar of diabetic kidney disease therapy, along with renin-angiotensin-aldosterone system blocking agents, sodium glucose co-transporter-2 inhibitors, and finerenone. We await definitive evidence to support a kidney protective effect of GLP-1RAs outside of the setting of diabetes.

INTRODUCTION

Chronic kidney disease (CKD) is a global health crisis, impacting approximately 10% of the world’s population and imposing a substantial toll on healthcare systems, as well as rates of morbidity, and mortality[1,2]. CKD is characterised by a sustained decline in kidney function or evidence of kidney damage - such as presence of albuminuria, reduced glomerular filtration rate (GFR) or structural abnormalities[3]. The aetiology and progression of CKD is often attributed to uncontrolled comorbidities such as diabetes mellitus (DM), which remains the leading cause of CKD[1]. It is estimated that 40% of individuals with DM will develop diabetic kidney disease (DKD) at some stage during their life. Whilst the prevalence of both DM and CKD continues to rise globally, effective therapeutic options for DKD have been slow to emerge. For cardio-kidney protection in patients with DKD, the treatment pillars of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and non-steroidal mineralocorticoid receptor antagonists have been only recent additions to join renin-angiotensin-aldosterone system (RAAS) blockade, which had been the sole therapeutic option since the early 2000s[1,4,5].

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, are a class of medications which have revolutionised the management of type 2 diabetes mellitus (T2D). Furthermore, with well characterised safety and tolerability profiles, their use can be considered in a broad variety of clinical scenarios[6]. The multi-organ benefits of GLP-RAs in patients with T2D is also being increasingly shown with significant mitigation of adverse metabolic, cardiovascular (CV) and kidney outcomes[7]. Recent trials, also support many of these benefits can also be translated to people without diabetes.

CV disease remains the leading cause of morbidity and mortality in individuals with CKD[3,8]. The interplay between CKD and CV disease creates a high-risk vasculopathic phenotype in which traditional interventions often fail to sufficiently mitigate. Recent CV outcomes trials have demonstrated that GLP-1RAs significantly reduce major adverse CV events (MACE), referring to a composite outcome typically including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, particularly in patients with T2 at high CV risk[7,9]. These findings are especially relevant in CKD, where attenuating CV burden can directly impact both kidney and overall prognosis[8].

The recent Evaluate Renal Function with Semaglutide Once Weekly (FLOW) trial has not only provided compelling evidence that semaglutide improves kidney outcomes in patients with T2D and CKD but also reduces the risk of major adverse CV events, reinforcing its dual benefit in managing both kidney and CV health[10]. Furthermore, emerging studies suggest that semaglutide may confer kidney-protective effects even in non-diabetic individuals, indicating a broader applicability in kidney health management and solidifying its role as a valuable therapeutic option in CKD and DKD treatment[9,11].

This review aims to synthesise the evidence highlighting the benefits of semaglutide in people with CKD, including those with and without T2D. In particular, we focus on the ability of semaglutide to slow kidney function loss, protect against CV disease and its positive metabolic effects. We also discuss the effectiveness of various doses of semaglutide and routes of administration in people with various categories of CKD and how this medication can be integrated into clinical practice.

CKD AS A GLOBAL HEALTH CHALLENGE

CKD is a life-altering, life-shortening disease which remains a major global health concern, affecting approximately 10% of the world’s population - over 800 million people[12]. Its rising prevalence can be attributed to aging populations with the increasing burden of risk factors such as diabetes mellitus and hypertension[3]. Unlike other major non-communicable diseases, the global age-standardised mortality rate in CKD is not declining[13]. The onset of a decline in kidney function and establishment of CKD is often insidious, asymptomatic, and initially an incidental finding. CKD has a significant impact on quality of life, with affected individuals potentially manifesting life-interfering symptoms such as fatigue, peripheral oedema or dyspnoea[14]. As CKD progresses, it can lead to ESKD, defined as a GFR of less than 15 mL/minute/1.73 m², at which time, dialysis or kidney transplantation is considered[3,14]. Although kidney replacement therapy can be life-saving, it is also resource intensive and associated with myriad of other unique management challenges[3]. In addition, the development of CKD and progression towards ESKD remains a significant cause of reduced quality of life and premature mortality[15], and once ESKD is reached, even with timely dialysis, patients face a mortality rate of 20% to 50% over 24 months[16]. Individuals with ESKD experience significant complications, including CV disease, infections, and hospitalisation, which further exacerbates their overall health burden and diminish life expectancy[3]. This underscores the need for effective therapeutic interventions to slow CKD progression and improve outcomes for patients at risk of developing ESKD.

The economic burden of CKD is substantial, both in terms of healthcare costs and loss of productivity. In high-income countries, the costs associated with treating CKD, especially in its advanced stages, are substantial, with an estimated annual total cost of CKD in Australia estimated to be $8.3 billion Australian dollars (AUD)[17]. Dialysis and kidney transplants account for a significant proportion of this with average costs in Australia reported to be approximately $85000 AUD per patient-year[18]. In addition, as CKD progresses, the cost of treatment increases, placing a heavy financial burden on individuals, families, and healthcare systems alike[17]. Moreover, the indirect costs related to the impact of CKD on patients’ ability to work and care for themselves further strain healthcare systems[19].

Risk factors for CKD are multifactorial and include chronic conditions such as DM and hypertension, both of which the incidence is rising[20,21], and remain the two leading causes of CKD[12]. In addition, genetic predisposition, obesity, smoking, and environmental factors can increase the risk of CKD development and progression[3]. The growing prevalence of these risk factors has led to a higher incidence of CKD, highlighting the need for early detection and close monitoring of progression, and implement effective management strategies.

MEASUREMENTS OF KIDNEY DISEASE DEVELOPMENT AND PROGRESSION

The diagnosis and assessment of CKD involves a combination of measurements to assess the extent of underlying kidney damage and function, as well as monitoring the progression of disease. CKD is defined by the authority organisation Kidney Disease Improving Global Outcomes (KDIGO) as abnormalities of kidney structure or function, present for a minimum of 3 months, with implications for health, with classification based on cause, GFR category (graded G1-G5), and albuminuria category (graded A1-A3)[3].

The most widely used markers for diagnosing and monitoring CKD progression are measurement of albuminuria, usually with urinary albumin-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR), with KDIGO recommending testing of both at least annually once a diagnosis of CKD is established[3]. Further measurements of kidney health used include kidney size, urine sediment analysis, and the presence of haematuria[3].

DKD

DKD is a clinical diagnosis defined by the presence of persistent albuminuria and/or reduced eGFR in individuals with diabetes, and represents the leading cause of CKD globally. Diagnostic criteria typically includes an eGFR < 60 mL/minute/1.73 m² and/or albuminuria ≥ 30 mg/g persisting for more than three months in the absence of other primary kidney diseases. DKD affects up to 40% of people with diabetes and is associated with markedly increased morbidity and mortality. Despite, the importance of albuminuria as being a marker for CKD and its importance as a risk factor for progressive kidney function less, the phenomenon of non-albuminuria kidney insufficiency in the setting of diabetes is well recognised[22].

Among its most serious complications is CV disease, which is the leading cause of death in this population. The CV risk in DKD patients exceeds that of individuals with diabetes without CKD and is strongly linked to both reduced eGFR and elevated albuminuria, which act as independent and multiplicative predictors of CV mortality. Manifestations include coronary artery disease, heart failure (especially with preserved ejection fraction), sudden cardiac death, stroke, and peripheral arterial disease. Despite the elevated risk, patients with DKD are often underdiagnosed, underrepresented in clinical trials, and undertreated for cardiovascular risk factors. Current management focuses on optimising glycaemic control, blood pressure, and lipid levels, but substantial gaps remain in both evidence and outcomes, highlighting the need for novel strategies and targeted interventions[23].

CAUSES OF DEATH IN PEOPLE WITH CKD

While CV disease remains the leading cause of death among individuals with CKD, non-CV mortality also constitutes a substantial proportion of total deaths, particularly as kidney function deteriorates. In large cohort studies, including analyses from the Chronic Renal Insufficiency Cohort and international dialysis registries, non-CV causes account for up to 45% of deaths in advanced CKD and dialysis populations[24,25]. These competing risks underscore the complex and multifactorial nature of morbidity and mortality in this population.

Other important causes of death in CKD include complications directly related to declining kidney function. These include electrolyte abnormalities (e.g. hyperkalaemia), metabolic acidosis, and kidney associated anaemia, each of which can independently increase the risk of sudden death, arrhythmia, hospitalisation, and reduced quality of life. The interplay between these metabolic derangements often becomes more pronounced in advanced stages of CKD and during transitions to kidney replacement therapy[3,24]. In addition, cancer and sepsis are also other major causes of death, especially in people with advanced CKD in the setting of kidney replacement therapy[24]. This broader perspective further illustrates the benefits of prevention and slowing of progression of CKD.

SEMAGLUTIDE IN CKD

The GLP-1RA semaglutide is an established effective treatment of T2D with a number of additional cardiac, metabolic and nephroprotective benefits. In several landmark studies, including the FLOW trial, a post-hoc analysis of Semaglutide Use to Stabilize and Improve Glycemic Control in Individuals with Type 2 Diabetes (SUSTAIN-6) and Semaglutide Treatment Effect in People with obesity (STEP) trials, semaglutide has demonstrated substantial kidney benefits in T2D[7,10,26]. Furthermore, a post-hoc analysis of the Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) trial also showing that semaglutide protects against kidney function loss independent of T2D status[9], highlighting its broad therapeutic potential for kidney protection. A recent meta-analysis by incorporating data from eight major randomized controlled trials including FLOW and SELECT, evaluated the impact of GLP-1RAs on kidney outcomes in 68572 patients with T2D or overweight/obesity, with or without CKD. Treatment with GLP-1RAs significantly reduced the risk of worsening kidney function (RR: 0.84; 95%CI: 0.77-0.91; P < 0.001), persistent macroalbuminuria (RR: 0.75; 95%CI: 0.69-0.83), and the composite kidney endpoint of either outcome (RR: 0.81; 95%CI: 0.74-0.88). These benefits were consistent across subgroups based on eGFR, albuminuria, sex, and body mass index (BMI)[27]. A summary of the population, inclusion criteria, baseline characteristics, semaglutide dose, duration of follow-up, and primary kidney endpoints from three major trials of subcutaneous semaglutide are presented in Table 1 with the effects of semaglutide on kidney outcomes for these three trials also being presented in Table 2. A cardiovascular outcome trial for oral semaglutide has also recently been published[28]. The details of this trial and its kidney outcomes are summarised in Table 3. In addition, the effects of semaglutide on major kidney outcome end-points for the above trial is shown in Figure 1.

Figure 1 The effects of semaglutide on the primary Kidney Outcome end-point in recent major clinical trials. FLOW: Evaluate Renal Function with Semaglutide Once Weekly. Primary kidney Outcome- New or worsening nephropathy: Macroalbuminuria, doubling of serum creatinine with estimated glomerular filtration rate (eGFR) ≤ 45, initiation of renal replacement, or renal death. SELECT: Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity. Primary Kidney Outcome- Composite: ≥ 50% decline in eGFR, kidney failure, or kidney-related death. SUSTAIN-6: Semaglutide Use to Stabilize and Improve Glycemic Control in Individuals with Type 2 Diabetes. Primary Kidney Outcome- New or worsening nephropathy: Macroalbuminuria, doubling of serum creatinine with eGFR ≤ 45, initiation of renal replacement, or renal death. SOUL: Semaglutide Cardiovascular Outcomes Trial. Primary Kidney Outcome- Includes: Cardiovascular death, kidney death, ≥ 50% eGFR decline, sustained eGFR < 15, or initiation of dialysis/transplant. eGFR: Estimated glomerular filtration rate; ACR: Albumin to creatine ratio.

Table 1 Key characteristics and kidney endpoints from the Semaglutide Use to Stabilize and Improve Glycemic Control in Individuals with Type 2 Diabetes, Evaluate Renal Function with Semaglutide Once Weekly, and Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity trials of semaglutide.

Trial	Population	Key inclusion criteria	Baseline characteristics	Semaglutide subcutaneous dose	Duration of follow-up	Kidney endpoints
SUSTAIN-6	3297 adults with T2D at high CV risk	T2D patients ≥ 50 years with established CV disease, CKD, or both	Mean age: 65.4 years- 64.5% male- HbA1c: 8.4%- Diabetes duration: 14.4 years- 83% with CV disease, CKD, or both	0.5 mg or 1.0 mg weekly	Median 2.1 years	New or worsening nephropathy: Macroalbuminuria, doubling of serum creatinine with eGFR ≤ 45, initiation of renal replacement, or renal death
FLOW	3534 adults with T2D and CKD	eGFR 25-75 + UACR 100-5000 mg/gOn stable RAAS blockade	Mean age: Approximately 65 years- 69.7% Male- Mean eGFR: Approximately 47 mL/min- Median UACR: Approximately 1000 mg/g	Up to 1.0 mg weekly	Median 3.4 years	Composite: Kidney failure (dialysis, transplant), sustained ≥ 50% decline in eGFR, or death from kidney/CV causes
SELECT	17604 adults with overweight/obesity & CV disease, no diabetes	Age ≥ 45, BMI ≥ 27, established CV disease, no diabetes	Mean age: Approximately 61 years- 72% male- Mean BMI: Approximately 33- 100% with CV disease	2.4 mg weekly	Median 3.5 years	Composite: ≥ 50% decline in eGFR, kidney failure, or kidney-related death

FLOW: Evaluate Renal Function with Semaglutide Once Weekly; SELECT: Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity; SUSTAIN-6: Semaglutide Use to Stabilize and Improve Glycemic Control in Individuals with Type 2 Diabetes; eGFR: Estimated glomerular filtration rate; ETD: Estimated treatment difference; CV: Cardiovascular; T2D: Type 2 diabetes; CKD: Chronic kidney disease; UACR: Urinary albumin-creatinine ratio.

Table 2 Effects of semaglutide on kidney outcomes in the semaglutide use to Stabilize and Improve Glycemic Control in Individuals with Type 2 Diabetes, Evaluate Renal Function with Semaglutide Once Weekly, and Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity trials.

Trial	Primary composite kidney endpoint	Effect of semaglutide on albuminuria	Composite kidney endpoint (Excl. albuminuria)	Effect of semaglutide on change in eGFR	Effect on ESKD
SUSTAIN-6	Reduced risk by 36% (HR: 0.64; 95%CI: 0.46-0.88; P = 0.005). Endpoint included macroalbuminuria, doubling of serum creatinine with eGFR ≤ 45, renal replacement, or renal death	New onset macroalbuminuria reduced by 46% (HR: 0.54, 95%CI: 0.37-0.77), P = 0.003 for semaglutide vs placebo	NR	Significant reduction in annual change in eGFR: Estimated treatment difference 06 mL/min/1.73 m2 (95%CI: 0.24-0.96, P = .001) Doubling of serum creatinine not reduced (HR: 1.28, 95%CI: 0.64-2.58)	No significant difference for semaglutide vs placebo, (HR: 0.91, 95%CI: 0.40-2.07)
FLOW	24% risk reduction (HR: 0.76; 95%CI: 0.66-0.88; P = 0.0003). Endpoint included kidney failure, ≥ 50% eGFR decline, or death from kidney/CV causes	Reduction of UACR ratio compared to placebo at week 104 to UACR at baseline (0.60 vs 0.88, HR: 0.68; 95%CI: 0.62-0.75) - significance not reached	24% risk reduction (same as primary endpoint; albuminuria not included)	Significant reduction in eGFR slope decline vs placebo (-2.19 vs -3.36 mL/min/1.73 m2 per year; between group difference, 1.16; 95%CI: 0.86-1.47; P < 0.001)	Semaglutide treated group reduced rate of persistent ≥ 50% reduction from baseline in eGFR (HR: 0.73; 95%CI: 0.59 to 0.89) and persistent eGFR < 15 mL/min/1.73 m2 (HR: 0.80; 95%CI: 0.61 to 1.06) - significance not reached
SELECT	22% reduction in composite endpoint (HR: 0.78; 95%CI: 0.64-0.95). Included eGFR < 15, ≥ 50% eGFR decline, renal death, dialysis, macroalbuminuria	Significant UACR reduction (P < 0.001)	18% risk reduction (HR 0.82; 95%CI 0.68-0.99) for endpoint excluding macroalbuminuria	Attenuated eGFR decline vs placebo at 104 weeks (-0.86 vs -1.61 mL/min/1.73 m2) with reduced eGFR slope decline in semaglutide treated group (-0.78 vs -1.17 mL/min/1.73 m2 per year (95%CI 0.3-0.48 P < 0.001)	Fewer ESKD events in semaglutide group however not significant due to low number of events

FLOW: Evaluate Renal Function with Semaglutide Once Weekly; SELECT: Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity; SUSTAIN-6: Semaglutide Use to Stabilize and Improve Glycemic Control in Individuals with Type 2 Diabetes; eGFR: Estimated glomerular filtration rate; UACR: Urinary albumin-creatinine ratio.

Table 3 Kidney Outcomes from the Semaglutide Cardiovascular Outcomes Trial (oral semaglutide in type 2 diabetes with cardiovascular or kidney disease).

Feature	Description	Oral semaglutide	Placebo	Hazard ratio (95%CI)
Major inclusion criteria	Adults ≥ 50 years with T2D and at least one of: CAD, cerebrovascular disease, symptomatic PAD, or- CKD (eGFR < 60 mL/min/1.73 m2)	-	-	-
5-point kidney composite outcome	Includes: CV death, kidney death, ≥ 50% eGFR decline, sustained eGFR < 15, or initiation of dialysis/transplant	10.4% (n = 502)	11.2% (n = 539)	0.91 (95%CI: 0.80-1.05)
4-point kidney outcome (excl. CV death)	Includes: Kidney death, ≥ 50% eGFR decline, sustained eGFR < 15, or dialysis/transplant	4.5% (n = 207)	5.2% (n = 251)	0.82 (95%CI: 0.68-0.98)
Kidney-related death	Death adjudicated as kidney-related	0.3% (n = 12)	0.3% (n = 13)	0.92 (95%CI: 0.42-2.00)
eGFR loss	Annual change in eGFR (mL/minute/1.73 m2)	-2.06	-1.67	ETD: 0.40 (95%CI: 0.27-0.53, P < 0.0001)

CV: Cardiovascular; eGFR: Estimated glomerular filtration rate; T2D: Type 2 diabetes; CKD: Chronic kidney disease; CAD: Coronary artery disease; ETD: Estimated treatment difference; PAD: Peripheral artery disease.

KIDNEY PHYSIOLOGY AND THE KIDNEY-PROTECTIVE MECHANISMS OF SEMAGLUTIDE

The kidneys play a crucial role in homeostasis through the regulation of glomerular filtration, tubular reabsorption, fluid balance, and systemic blood pressure control. In CKD, pathological processes such as endothelial dysfunction, oxidative stress, and dysregulation of the RAAS contribute to progressive nephron injury and kidney impairment[14].

Renal fibrosis is the common final pathway of progressive CKD and is characterized by excessive deposition of extracellular matrix proteins, leading to glomerulosclerosis and tubulointerstitial fibrosis. Key drivers include chronic inflammation, oxidative stress, and persistent activation of profibrotic signalling pathways such as transforming growth factor-β1 (TGF-β1)/Smad, Wnt/β-catenin, and RAAS signalling. Crosstalk between injured tubular epithelial cells, infiltrating macrophages, and activated fibroblasts sustains a self-perpetuating fibrotic environment[29]. These mechanisms present potential therapeutic targets, and agents like GLP-1 receptor agonists, proposed to modulate inflammation and oxidative stress, thereby indirectly attenuating fibrotic progression.

Experimental evidence suggests that GLP-1RAs, including semaglutide, exert direct and indirect kidney-protective effects through multiple physiological pathways, inducing natriuresis, RAAS modulation via a reduction in circulating angiotensin II levels, and further potential anti-inflammatory and anti-fibrotic actions[30,31].

Semaglutide enhances natriuresis via GLP-1RA inhibition of sodium-hydrogen exchanger 3 (NHE3) in the proximal tubule, leading to increased sodium excretion and mild extracellular fluid volume[32-34]. These natriuretic and volume-related effects are further supported by potential GLP-1RA’s suppression of RAAS activation and possible enhancement of atrial natriuretic peptide signalling[34-36].

Semaglutide also influences systemic and kidney haemodynamics through its effects on vascular tone and blood pressure regulation. It has been suggested that glucagon like peptide-1 receptor activation leads to vasodilation, likely mediated by increased nitric oxide bioavailability and reduced endothelin-1 activity, both of which contribute to lowering systemic and central blood pressure[37]. Additionally, semaglutide is thought to modulate central blood pressure control mechanisms, possibly through actions on the brainstem and autonomic nervous system, leading to decreased sympathetic outflow and improved baroreceptor sensitivity[31,38].

Beyond haemodynamic improvements, semaglutide also exhibits anti-inflammatory and anti-fibrotic properties, which are particularly relevant in CKD pathogenesis. Preclinical studies have demonstrated reduced macrophage infiltration in vascular tissue and attenuation of oxidative stress via inhibition of NADPH oxidase, accompanied by downregulation of pro-inflammatory cytokines including nuclear factor-κB (NF-κB), tumor necrosis factor alpha, interleukin-6, and monocyte chemoattractant protein-1, while concurrently reducing the expression of fibrotic markers, including TGF-β and connective tissue growth factor[34,39,40]. Additionally, semaglutide exerts potent antioxidant effects, mitigating reactive oxygen species production and enhancing cellular defence mechanisms against oxidative stress[34,41], which is a key driver of tubulointerstitial damage in CKD. Furthermore, cardiorenal syndrome pathophysiology involves RAAS overactivation and maladaptive signalling with pathways including TGF-β1 signaling, processes dampened by GLP-1RAs in preclinical studies. Semaglutide’s anti-inflammatory and antioxidative effects, including modulation of NF-κB and signalling, align with emerging therapeutic targets in cardiorenal fibrosis[42].

Moreover, GLP-RAs reduces the expression of kidney injury molecule-1[43] and inhibits receptor for advanced glycation end-products signalling[40,44]. Inhibiting this pathway reduces macrophage recruitment, tubular injury, and tubulointerstitial fibrosis. These upstream anti-inflammatory effects preserve podocyte integrity, limit mesangial matrix expansion, attenuate tubular basement membrane thickening, and reduce interstitial fibrosis which are key features in the progression to glomerulosclerosis[34,40,44].

One key kidney-protective effect of GLP-1RAs in people with T2D is improved glycaemic control. By enhancing insulin secretion and suppressing glucagon release, semaglutide helps maintain stable blood glucose levels, which is critical in preventing or delaying progression of kidney function loss in people with T2D[45]. In addition, semaglutide promotes weight loss, which can reduce the burden on the kidneys by lowering the risk of hypertension, improving metabolic health, and reducing the systemic strain caused by obesity[46,47]. Weight reduction itself is a well-established factor in slowing CKD progression and improving overall kidney function[48].

Collectively, these findings highlight the multifaceted kidney-protective actions of semaglutide, which extend beyond glycaemic control to include possible reductions and diuretic effects, vasodilation, modulation of central blood pressure control, RAAS inhibition, anti-inflammatory actions, and oxidative stress reduction. These mechanisms provide strong evidence supporting the role of semaglutide as a therapeutic agent for delaying CKD onset and progression, and improving kidney outcomes in patients with diabetes. The benefits of semaglutide in people with CKD is conceptualised in Figure 2.

Figure 2 Potential kidney-cardiovascular and metabolic effects of semaglutide in people with chronic kidney disease. ANP: Atrial natriuretic peptide; BP: Blood pressure; CKD: Chronic kidney disease; CV: Cardiovascular; HbA1c: Glycated haemoglobin; KIM-1: Kidney injury molecule-1; LDL-C: Low-density lipoprotein cholesterol; NF-κB: Nuclear factor-κB; NHE3: Sodium-hydrogen exchanger-3; NO: Nitric oxide; RAAS: Renin-angiotensin-aldosterone system; RAGE: Receptor for advanced glycation end products; TGF-β: Transforming growth factor-β. Created in BioRender (https://BioRender.com/yd9812v).

SEMAGLUTIDE IMPACT ON ONSET OF CKD

Emerging evidence suggests that semaglutide may play a pivotal role in preventing the onset of DKD in patients with T2D. Clinical trials have demonstrated that semaglutide not only improves glycaemic control but also significantly reduces the incidence of negative kidney-related outcomes, including the onset of albuminuria and decline in eGFR. In the SUSTAIN-6 trial, semaglutide was associated with a 39% reduction in the risk of developing nephropathy, which includes the progression from microalbuminuria to macroalbuminuria, and a significant preservation of kidney function, as evidenced by improved eGFR compared to placebo[7]. Furthermore it was found that treatment with semaglutide was effective in the primary prevention of DKD by up to 44% in the total study population, and up to 49% in those with high DKD risk[49]. In a separate post hoc analysis, semaglutide significantly delayed CKD onset vs placebo, with the mean time to first reaching UACR ≥ 30 mg/g or approximately 3 mg/mmol (microalbuminuria) lower in the semaglutide treatment group[50]. These effects contribute to a lower risk of kidney function loss and ultimately the development of ESKD. Furthermore, the treatment’s favourable effects on metabolic profile with weight loss, blood pressure control, and reduction of inflammatory markers enhance its kidney-protective properties. These findings underscore the therapeutic promise of semaglutide not only in managing diabetes but also in safeguarding kidney health and preventing the progression to CKD and ESKD.

SEMAGLUTIDE IMPACT PROGRESSION OF ESTABLISHED CKD

Several studies have examined the effects of semaglutide on progression of CKD. A post hoc analysis of the SUSTAIN-6 trial found that participants with T2D treated with semaglutide were more likely to move to a lower KDIGO kidney disease risk category, and less likely to move to a higher risk category, a finding consistent across baseline risk category. The FLOW trial found that semaglutide was associated with a 24% reduction in kidney-related adverse events [a composite of the onset of kidney failure (dialysis, transplantation or an eGFR of < 15 mL per minute per 1.73 m² of body surface area), > 50% reduction in eGFR from baseline, or death from kidney related causes]. In FLOW, for patients treated with semaglutide at week 104, loss of kidney function indicated by a cystatin-C-based GFR was lower by 3.39 mL per minute per 1.73 m² (95%CI: 2.63-4.15). Further reassuringly, in FLOW, changes in eGFR based on creatinine showed almost an identical difference of 3.30 mL/minute/1.73 m² at week 104 (95%CI: 2.43-4.17)[10].

SEMAGLUTIDE EFFECTS ON ALBUMINURIA

Semaglutide has shown promising effects in reducing albuminuria, marking it as an effective intervention for kidney protection. In the SUSTAIN trial, in patients with T2D, semaglutide treatment resulted in significantly reduced UACR from baseline to end of treatment, compared with placebo (treatment ratio 0.74, P < 0.001). It was also demonstrated that treatment with semaglutide compared with placebo resulted in reduction in new-onset macroalbuminuria by 46%. This reduction in albuminuria was seen even in patients with moderate kidney impairment[7,51]. Similarly, the FLOW trial found that at 104 weeks, semaglutide treatment was associated with a marked 40% reduction in UACR compared to treatment with placebo (12%), with a ratio of the value at week 104 to the value at baseline was 32% lower (95%CI: 25-38) in the semaglutide treatment group than in the placebo group[10]. These findings underscore the broad applicability of semaglutide to impact albuminuria in patients with T2D.

Semaglutide has demonstrated potential benefits in reducing albuminuria in patients with T2D and CKD, however its effects in individuals with CKD, but without DM, are still emerging. In a randomized, double-blind, placebo-controlled clinical trial, the effects of semaglutide in adults with CKD without DM in the context of a BMI ≥ 27 kg/m² were evaluated. After 24 weeks of treatment, semaglutide significantly reduced UACR by 52.1% compared to placebo (95%CI: -65.5 to -33.4; P < 0.0001)[11]. While CVOTs such as SUSTAIN-6 and REWIND were not designed with renal outcomes as primary endpoints, pooled analyses indicate a significant reduction in composite kidney outcomes, primarily driven by reduced macroalbuminuria onset[34]. These findings together suggest that semaglutide treatment results in a clinically meaningful reduction in albuminuria in patients with non-diabetic CKD and overweight/obesity, highlighting its potential as a therapeutic option in this population.

SEMAGLUTIDE EFFECTS ON GFR LOSS AND SLOPE

As discussed, the progression of CKD is typically monitored through markers to predict the GFR and extrapolate overall kidney function with the decline in eGFR slope serving as a valuable marker of kidney function loss. Semaglutide has shown promising effects on stabilising eGFR and slowing the decline in kidney function. A post hoc pooled analysis of SUSTAIN-6 and PIONEER-6 (Peptide Innovation for Early Diabetes Treatment) trials has highlighted semaglutide’s ability to positively influence GFR slope, with results indicating that in patients with T2D, there was a clinically meaningful reduction in risk of CKD with semaglutide vs placebo (HR: 0.59, 95%CI: 0.29-0.89 mL/minute/1.73 m²/year). Similarly, the FLOW trial found that semaglutide treatment was associated with slower rates of eGFR decline and stabilisation of kidney function, with the mean annual eGFR slope significantly less steep in the semaglutide treated group than in the placebo group (-2.19 m/minute/1.73 m² per year vs -3.36 m/minute/1.73 m² per year; between group difference, 1.16 mL/min/1.73 m²; 95%CI: 0.86-1.47, P < 0.001). Interestingly, despite this difference in eGFR slope, creatinine-based eGFR values at week 104 were nearly identical between the two groups (FLOW[10]). This likely reflects the cumulative nature of eGFR slope as a measure of decline over time, where small annual differences may not translate into substantial absolute separation over shorter follow-up intervals. Additionally, variability in serum creatinine and individual eGFR trajectories may obscure early between-group differences at fixed time points, even when overall decline is slower in the treatment arm. The effects of semaglutide on the average annual change in eGFR in FLOW, SELECT and SUSTAIN-6 are shown in Figure 3.

Figure 3 The effects of semaglutide on the average annual change in estimated glomerular filtration rate in Evaluate Renal Function with Semaglutide Once Weekly, Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity and Semaglutide Use to Stabilize and Improve Glycemic Control in Individuals with Type 2 Diabetes. FLOW: Evaluate Renal Function with Semaglutide Once Weekly; SELECT: Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity; SUSTAIN-6: Semaglutide Use to Stabilize and Improve Glycemic Control in Individuals with Type 2 Diabetes; eGFR: Estimated glomerular filtration rate; ETD: Estimated treatment difference.

SEMAGLUTIDE AND PROGRESSION TO ESKD

As CKD advances, patients are at increasing risk of requiring kidney replacement therapy. However, emerging evidence suggests that semaglutide can positively influence end-stage kidney outcomes, reducing the need for these intensive and costly treatments. In SUSTAIN-6 semaglutide treatment was associated with a reduced rate of kidney-related complications, including progression to ESKD[50]. Furthermore, the FLOW trial indicated that semaglutide significantly reduced the risk of multiple pooled composite kidney-specific endpoints including kidney failure with persistent eGFR < 15 mL/minute/1.73 m², and the need for dialysis or kidney transplantation. Individually, these groups were all numerically in favour of semaglutide however individually did not reach significance[10]. These findings highlight semaglutide’s potential to delay the need for kidney replacement therapies, a critical endpoint in CKD management. The theoretical benefits of delaying onset of kidney failure, in terms of years gained, for patients in FLOW treated with semaglutide vs placebo, if the amelioration of eGFR decline occurs a constant rate with semaglutide, is shown in Figure 4.

Figure 4 The theoretical benefits of delaying onset of kidney failure, in terms of years gained, for patients in Evaluate Renal Function with Semaglutide Once Weekly treated with semaglutide vs placebo, if the amelioration of estimated glomerular filtration rate decline occurs a constant rate with semaglutide. eGFR: Estimated glomerular filtration rate; CKD: Chronic kidney disease; FLOW: Evaluate Renal Function with Semaglutide Once Weekly.

SEMAGLUTIDE USE IN ESKD

The use of semaglutide in patients with ESKD has gained attention due to its potential benefits in managing metabolic conditions and improving outcomes in this high-risk population. Patients with more advanced CKD have been underrepresented in previous trials and effect of GLP-1RA on albuminuria in ESKD not yet shown to translate into reduced risk in these patients[52]. In one retrospective cohort study, semaglutide was evaluated in patients with kidney failure, revealing favourable outcomes in terms of glycaemic control, weight loss, and reductions in CV risk factors[53]. Furthermore, a prospective observational open-label study conducted specifically assessed semaglutide in patients with kidney failure and obesity undergoing dialysis who wished to be transplanted. This study demonstrated that semaglutide not only improved glycaemic control and facilitated significant weight loss, but also positively impacted other metabolic parameters, which are crucial for patients preparing for kidney transplantation[47]. Further case reports of the use of semaglutide to achieve target BMI for patients with ESKD pre kidney transplant have shown the potential for tolerability and therapeutic success[54].

Recent data from a national observational cohort of over 150000 patients with T2D on dialysis demonstrated promising outcomes associated with GLP-1RA use, including semaglutide. Compared to non-users, those prescribed GLP-1RAs experienced significantly greater reductions in body weight and BMI, as well as a 23% reduction in all-cause mortality (adjusted HR: 0.77, 95%CI: 0.70-0.85). Importantly, GLP-1RA use was associated with a 66% higher likelihood of being waitlisted for kidney transplantation, suggesting broader systemic benefits that may help optimize patients for transplant candidacy[55]. These findings are particularly noteworthy given the historical exclusion of dialysis patients from major GLP-1RA trials, and they provide critical real-world evidence to support the potential use of semaglutide in ESKD.

Collectively, these findings support the therapeutic use of semaglutide in ESKD, indicating that it may improve overall metabolic health and potentially enhance outcomes for patients awaiting kidney transplantation.

ROLE OF SEMAGLUTIDE IN CARDIOVASCULAR PROTECTION IN PATIENTS WITH CKD

CV disease remains the leading cause of morbidity and mortality in individuals with CKD. The interplay between impaired kidney function and accelerated atherosclerosis heightens the risk of major CV events, particularly in those with T2D. Semaglutide has demonstrated CV benefits in multiple large-scale trials, offering a dual therapeutic opportunity in this high-risk population.

In SUSTAIN-6 3297 patients with T2D and high CV risk were randomised to weekly subcutaneous semaglutide (0.5 mg or 1.0 mg) or placebo. Semaglutide reduced the incidence of MACE by 26% (HR: 0.74; 95%CI: 0.58-0.95; P = 0.02). This included a significant 39% reduction in non-fatal stroke (HR: 0.61; 95%CI: 0.38-0.99) and a non-significant trend toward lower non-fatal myocardial infarction (HR: 0.74; 95%CI: 0.51-1.08). Importantly, a substantial proportion of participants had established CKD, lending relevance to these findings within the renally impaired population. Furthermore, in the FLOW trial, semaglutide demonstrated a 17% relative risk reduction in MACE compared to placebo (HR: 0.83; 95%CI: 0.70-0.98). This composite outcome included cardiovascular death, nonfatal MI, and nonfatal stroke, with all individual components showing numerically favourable trends. While the trial was not powered to detect significance for individual outcomes, semaglutide was associated with lower rates of CV death, MI, and stroke. Furthermore treatment with semaglutide reduced the risk of the composite outcome of first heart failure event or cardiovascular death by 27% compared to placebo (HR: 0.73; 95%CI: 0.62-0.87). The incidence of new or worsening heart failure events requiring hospitalization or urgent care was also significantly lower in the semaglutide group. These findings support semaglutide’s cardioprotective role, particularly in high-risk patients with comorbid kidney disease[10]. A pre-specified analysis of heart failure outcomes, published separately, found that semaglutide reduced the composite of first hospitalization for heart failure or urgent heart failure visit by 18% (HR: 0.82; 95%CI: 0.68-0.98), though the analysis did not differentiate between heart failure with preserved or reduced ejection fraction[56].

The Semaglutide Cardiovascular Outcomes Trial (SOUL) evaluated the cardiovascular efficacy and safety of oral semaglutide (14 mg daily) vs placebo in 9654 individuals with T2D and either established atherosclerotic CV disease, CKD, or both. Over a median follow-up of 49.5 months, oral semaglutide significantly reduced the risk of MACE by 14% compared to placebo (HR: 0.86; 95%CI: 0.77-0.96; P = 0.006). However, the effect on kidney outcomes which were assessed as a five-point composite including ≥ 50% eGFR decline, kidney failure, or death from kidney causes, was not statistically significant (HR: 0.91; 95%CI: 0.80-1.05; P = 0.19). A four-point composite end-point, that was identical to the above but with the exclusion of CV outcomes was also not significantly reduced with oral semaglutide. However, mean annual eGFR decrease was less with oral semaglutide than placebo (-6.67 vs -2.06 mL/minute/1.73 m², respectively). The estimated treatment difference between the two groups was 0.4 mL/minute/1.73 m² per year (75%CI: 0.27-0.53, P < 0.001)[28].

It is important to note that SOUL was designed as a CV safety and efficacy trial, not a dedicated kidney outcomes trial. The relatively preserved baseline kidney function and lower event rate in the population studied may have limited the ability to detect significant kidney benefits[28]. As mentioned, the inclusion criteria and kidney-related outcomes from the SOUL trial are presented in Table 3.

Cardiovascular protection with semaglutide is not limited to patients with diabetes. In the SELECT trial, 17604 adults classified overweight or obesity and established cardiovascular disease, but without diabetes, were randomised to receive semaglutide 2.4 mg weekly or placebo. Semaglutide reduced MACE by 20% (HR: 0.80; 95%CI: 0.72-0.90; P < 0.001), with significant reductions observed in CV death (HR: 0.85), non-fatal myocardial infarction (HR: 0.72), and non-fatal stroke (HR: 0.83). Although kidney endpoints were not primary outcomes, participants treated with semaglutide experienced slower eGFR decline and lower UACR, suggesting kidney-protective potential even in the absence of T2D[57,58].

Semaglutide’s CV benefits are mediated through a combination of direct and indirect mechanisms. Clinical trials have demonstrated that semaglutide treatment leads to significant reductions in systolic blood pressure (SBP), with decreases ranging from 2 to 5 mmHg[59]. For instance, an individual patient data meta-analysis reported a mean SBP reduction of approximately 4.5 mmHg in patients treated with semaglutide compared to placebo[60].

In the context of heart failure, semaglutide has demonstrated beneficial effects. A pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials showed that semaglutide reduced the risk of the composite endpoint of cardiovascular death or heart failure events by 31% compared to placebo (HR: 0.69, 96%CI: 0.53-0.89; P = 0.0045)[61].

It is worthwhile to note that one meta-analysis of SGLT2i use in various degrees of heart failure, their use significantly improved composite renal outcomes, especially in patients without heart failure (HF) or with reduced ejection fraction. The renal benefit was attenuated in HFpEF populations (HR: 0.60 vs 0.94; P = 0.04)[62]. This suggests heterogeneity in cardiorenal benefit based on cardiovascular phenotype in SGLT2is, and is an important factor with future research regarding semaglutide’s potential differential effects across CKD populations with or without overt HF[62].

Collectively, these findings highlight semaglutide’s multifaceted role in CV risk reduction, including improvements in hemodynamic parameters, metabolic profiles, inflammatory status, and heart failure outcomes - all of which are implicated as part of kidney health. The effects of semaglutide on major kidney and CV outcomes in the FLOW trial is shown in Figure 5.

Figure 5 The effects of semaglutide on major kidney and cardiovascular outcomes in the Evaluate Renal Function with Semaglutide Once Weekly trial. Evaluate Renal Function with Semaglutide Once Weekly kidney outcome- New or worsening nephropathy: Macroalbuminuria, doubling of serum creatinine with estimated glomerular filtration rate (eGFR ≤ 45), initiation of renal replacement, or renal death. Major CV events: Major CV events including CV death, non-fatal myocardial infarction, or non-fatal stroke and heart failure with secondary/exploratory outcomes included hospitalization for heart failure; CV: Cardiovascular; HF: Heart failure; FLOW: Evaluate Renal Function with Semaglutide Once Weekly.

METABOLIC EFFECTS OF SEMAGLUTIDE IN CHRONIC KIDNEY DISEASE

Semaglutide has demonstrated consistent and clinically meaningful metabolic benefits in individuals with DKD, particularly in the domains of glycaemic control, weight reduction, and blood pressure management. In patients with CKD, tight glycaemic control is a cornerstone of therapy, as hyperglycaemia contributes directly to glomerular injury, tubulointerstitial fibrosis, and progression to end-stage kidney disease. Across multiple randomised controlled trials - including SUSTAIN and PIONEER - semaglutide has shown substantial efficacy in lowering glycated haemoglobin (HbA1c). In patients with moderate kidney impairment (eGFR < 60 mL/minute/1.73 m²), semaglutide 1.0 mg weekly reduced HbA1c by approximately 1.2%-1.5% from baseline, with similar efficacy observed in patients with preserved or impaired kidney function[7,63,64]. Notably, this glucose-lowering effect is sustained over time and associated with a low risk of hypoglycaemia, particularly when used without insulin or sulfonylureas.

In addition to glucose control, weight reduction is a prominent and clinically important effect of semaglutide therapy. Obesity accelerates CKD progression by promoting insulin resistance, systemic inflammation, glomerular hyperfiltration, and hypertension. In both diabetic and non-diabetic populations, semaglutide has been associated with average weight losses ranging from 4-7 kg at doses of 0.5 mg to 1.0 mg weekly, and up to 15% total body weight loss with 2.4 mg dosing as seen in non-diabetic individuals in the STEP trials[26]. In the FLOW trial, participants with DKD and T2D treated with semaglutide experienced clinically meaningful weight loss (mean difference -3.5 kg compared to placebo), supporting its value in managing obesity-related metabolic stress in the context of CKD[10].

Taken together, these metabolic effects including sustained improvements in HbA1c and clinically significant weight loss highlight semaglutide’s value as a foundational therapy in the management of patients with DKD, beyond its emerging CV and kidney protective roles.

UNMET NEED FOR DKD TREATMENT OPTIONS IN T1DM

Despite advancements in the management of type 1 diabetes mellitus (T1D), there remains a significant unmet need for effective therapeutic options that address both glycaemic control and associated complications, particularly DKD. Recent calls for further investigation into the use of semaglutide in T1D patients emphasises the need for well-designed clinical trials to evaluate the efficacy and safety of GLP-1 receptor agonists in this population[65]. While insulin remains the cornerstone of T1D treatment, many patients struggle to achieve optimal glycaemic targets, leading to an increased risk of long-term complications, including DKD. Recent evidence suggests that semaglutide and other GLP-1RAs may offer beneficial effects in this population. For instance, one study involving 76 patients with T1D using GLP-1RA, at 12 months had statistically significant reductions in weight, HbA1c and insulin requirement[66]. Whilst in this this study the use of GLP-1RA was discontinued in 26.9% of cases due to adverse effects, the potential role of GLP-1RAs in improving metabolic control and reducing the risk of DKD progression in individuals with T1D can be considered. Addressing these unmet needs is crucial for enhancing treatment options and improving outcomes for individuals living with T1D, particularly those at risk for kidney disease.

COMPARISON WITH OTHER GLP-1 RAS AND DUAL RECEPTOR MODULATORS

Semaglutide stands out among GLP-1 receptor agonists due to its superior efficacy in promoting weight loss, improving glycaemic control, and reducing albuminuria in patients with CKD. One of the key advantages of semaglutide is its longer half-life compared to liraglutide and exenatide, allowing for once-weekly administration, which enhances patient adherence to treatment regimens and contributes to better overall management of diabetes and its complications. Clinical studies have shown that semaglutide is more effective than liraglutide in reducing HbA1c levels, with the SUSTAIN-6 trial reporting a significant reduction in HbA1c of 1.5% compared to 0.7% with liraglutide[7]. Moreover, semaglutide has demonstrated more pronounced kidney benefits in individuals with diabetic nephropathy, including substantial reductions in albuminuria and a slower decline in eGFR; the SUSTAIN-6 trial also highlighted a 39% reduction in the risk of nephropathy-related outcomes.

The AWARD-7 (Dulaglutide vs insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease) trial evaluated the effects of dulaglutide, a GLP-1 receptor agonist, in patients with T2D and moderate-to-severe CKD. Over a 52-week period, dulaglutide demonstrated a slower decline in eGFR and a reduction in UACR compared to insulin glargine. Notably, dulaglutide 1.5 mg weekly was associated with a significant reduction in the composite outcome of ≥ 40% eGFR decline or progression to ESKD, particularly among participants with macroalbuminuria. These findings suggest that the kidney-protective effects observed with semaglutide may extend to other agents within the GLP-1RA class, such as dulaglutide[67].

Furthermore, a recent large-scale meta-analysis incorporating data from 10 placebo-controlled trials (n = 71351), including the FLOW and SOUL trials, confirmed that as a group, long-acting GLP-1RAs, including both injectable and oral formulations, significantly reduce the incidence of MACE hospitalisation for heart failure, kidney events, and all-cause mortality in people with T2D. Notably, the composite kidney outcome was reduced by 17% (HR: 0.83; 95%CI: 0.75-0.92), with effects likely driven predominantly by reductions in albuminuria rather than sustained preservation of eGFR. There were no increased risks of severe hypoglycaemia, retinopathy, or pancreatic events. As a group, long-acting GLP-1RAs demonstrate consistent cardio-renal protective effects regardless of administration route, further supporting their broad applicability in contemporary management of DKD[68].

In addition to traditional GLP-1RAs, the development of dual receptor modulators, such as GLP-1 and gastric inhibitory polypeptide (GIP) receptor agonists, represents a promising frontier in CKD treatment. These agents combine the actions of GLP-1 with those of GIP, a hormone involved in glucose metabolism and insulin secretion. Recent studies, including a trial on tirzepatide, have shown significant improvements in glycaemic control, weight loss, and kidney outcomes. The study found that tirzepatide treatment resulted in a significant reduction in UACR, indicating potential kidney-protective effects, as well as improvements in eGFR in patients with T2D and CKD[69]. While early evidence suggests that dual receptor modulators may offer enhanced metabolic control and potentially greater kidney protection compared to standard GLP-1RAs, further research is needed to establish conclusive outcomes and determine their role in the therapeutic landscape for CKD management.

SEMAGLUTIDE USE WITH SGLT2IS IN CKD

The combination of semaglutide and SGLT2is presents a promising therapeutic strategy for managing CKD in patients with T2D. Both classes of medications have demonstrated distinct yet complementary mechanisms that enhance kidney protection and improve metabolic outcomes. SGLT2is, such as empagliflozin and canagliflozin, are well-established for their ability to reduce albuminuria, slow the decline in eGFR, and lower the risk of CV events in diabetic patients with CKD. Evidence from pivotal trials, such as the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose) and CANVAS (Canagliflozin Cardiovascular Assessment Study) studies, underscores the kidney benefits of SGLT2is, highlighting significant reductions in the progression of kidney disease and CV mortality[70,71].

Emerging data suggest that semaglutide can further augment these benefits through its effects on glycaemic control. The results of one population-based cohort study, designed to emulate a randomised controlled trial, suggest that the combined use of GLP-1RAs and SGLT-2is is associated with a reduced risk of major adverse CV events and serious kidney events, compared with using either drug class alone. The addition of an SGLT2i to existing GLP-1RA use was also associated with a reduced risk of CV mortality and heart failure compared with GLP-1RAs alone[72]. A recent meta-analysis and systematic review of 1743 patients evaluating the use of a range of GLP-1RAs, including semaglutide, in combination with SGLT2is, demonstrated that the effects on kidney outcomes did not significantly vary based on the use of SGLT2is. Specifically, the composite kidney outcome had a risk ratio of 0.79 (95%CI: 0.66-0.95), and the eGFR slope showed a reduction of 0.78 mL/minute/1.73 m²/year (95%CI: 0.57-0.98), with no significant heterogeneity observed (P-heterogeneity = 0.53 and 0.94, respectively). Moreover, serious adverse events and severe hypoglycaemia rates were comparable regardless of whether an SGLT2i was used, with P-heterogeneity values of 0.29 and 0.50, respectively. These findings suggest that the addition of SGLT2is does not modify the overall benefit-risk profile of GLP-1RAs, including semaglutide, when used in patients with CKD[73].

From a mortality and financial perspective the scope of benefit is enormous. In a population of 13.1 million patients with cardio-kidney-metabolic syndrome, treatment with dapagliflozin in addition to standard of care prevented 613545 hospitalizations for heart failure, 285041 cases of kidney failure, and 450355 deaths over four years, resulting in a $99.3 billion healthcare cost offset[74]. This study demonstrates the magnitude of benefit when targeting CKD, HF, and T2D concurrently in real-world populations, highlighting the value of therapies that span cardio-kidney-metabolic domains like SGLT2is, and by extension, or addition of GLP-1RAs like semaglutide.

Thus, the combination of semaglutide and SGLT2is offers a multifaceted approach to optimise treatment outcomes for patients with CKD and T2D, underscoring the need for further research to establish definitive guidelines for their combined use in clinical practice.

ADVERSE EVENTS OF SEMAGLUTIDE USE IN CHRONIC KIDNEY DISEASE

Semaglutide use comes with potential side effects and complications. The most common adverse effects include gastrointestinal symptoms such as nausea, vomiting, and diarrhea, which can be problematic in CKD patients, as they may exacerbate dehydration and electrolyte imbalances[75]. Furthermore, while semaglutide is generally considered safe for individuals with mild to moderate kidney impairment, there remains a lack of robust long-term data on its safety in advanced CKD[47,76,77]. Current KDIGO guidelines in fact recommend that semaglutide may be used in CKD with no dose adjustment however acknowledges there is a lack of robust data in ESKD[78].

The use GLP-1RAs in patients with T2D and advanced or ESKD has been evaluated in several studies assessing blood glucose control and adverse events. In one meta-analysis, GLP-1RAs did not significantly increase the risk of hypoglycaemic events compared to controls in patients with advanced CKD, with a pooled odds ratio of 1.8 (95%CI: 0.6-5.1; I² = 48%) across three trials. Additionally, GLP-1RAs did not significantly lower minimum blood glucose levels more than controls, as measured by continuous glucose monitoring, with a standardised mean difference of -3.4 mg/dL (95%CI: -9.4 to 2.7; I² = 0%) in two trials. Serious adverse events (SAEs) were reported in six studies, with 6 of 135 patients (8.6%) in the GLP-1RA group experiencing SAEs, compared to just one patient (1.5%) in the control group. These SAEs included chest pain, infection, clotted arteriovenous fistula, catheter infection, lumbar spinal stenosis, and acute appendicitis, with most occurring in a single RCT. Gastrointestinal (GI) side effects were more prevalent in the GLP-1RA group, with nausea reported at an incidence rate of 30.1 days per 1000 patient-days in the GLP-1RA group compared to 7.9 days per 1000 patient-days in the control group. Vomiting was also more frequent in the GLP-1RA group (10.7 days/1000 patient-days vs 0.3 days/1000 patient-days), and reduced appetite occurred at an incidence rate of 183 days/1000 patient-days in the GLP-1RA group compared to 10.7 days/1000 patient-days in the control group. Additionally, injection site reactions were noted in one RCT, affecting 14.3% of the GLP-1RA group and 40% of the control group[76].

Clinical trials have consistently shown that semaglutide is associated with higher rates of treatment discontinuation compared to placebo, primarily due to GI side effects. For instance, in the SELECT trial, nearly 30% of participants discontinued semaglutide, while real-world estimates suggest discontinuation rates between 50% and 75% at 12 months[79]. Similarly, the SUSTAIN-6 trial reported a 16.6% discontinuation rate in the semaglutide group vs 8.2% in the placebo group[7].

Whilst there is a lack of data, the safety profile of GLP-1RAs in dialysis patients is generally reassuring. In one observational study of over 150000 patients on dialysis with T2D using semaglutide, there were no significant associations with acute pancreatitis, biliary disease, or medullary thyroid cancer. However, a modest increase in diabetic retinopathy risk was observed (aHR: 1.32, 95%CI: 1.12-1.56; P = 0.001), consistent with prior observations in earlier-phase trials[55]. While these results warrant cautious interpretation, especially in patients with pre-existing proliferative retinopathy, they support an overall favourable benefit-risk ratio for GLP-1RA use in advanced kidney disease, including ESKD.

These findings suggest that while tolerability issues, particularly gastrointestinal side effects, may impact long-term adherence for some patients, semaglutide maintains a favourable safety profile in the broader population studied

CONTEMPORARY APPROACH TO CKD MANAGEMENT IN THE SETTING OF TYPE 2 DIABETES

Incorporating semaglutide into the management strategy for DKD and non-diabetic CKD requires a thoughtful and pragmatic approach that considers the multifaceted nature of these conditions. Managing CKD in T2D patients involves not only pharmacological therapies but also lifestyle interventions and ongoing monitoring to slow disease progression and mitigate complications. The treatment strategy must encompass optimal blood glucose control while addressing critical CV and kidney risk factors[3].

The 2025 KDIGO commentary highlights growing evidence that GLP-1RAs, particularly semaglutide, offer clinically meaningful kidney and CV protection in people with CKD, including those without DM. Citing recent trials such as FLOW and SELECT, the authors suggest that the benefits of GLP-1 RAs extend beyond glycaemic control, supporting their use as organ-protective therapies. These findings may justify broader use of incretin mimetics in CKD, potentially even as first-line agents alongside or instead of metformin[80].

SGLT2is have become foundational due to their established benefits in reducing albuminuria, preserving GFR, and lowering the risk of CV events. Similarly, nonsteroidal-mineralocorticoid receptor antagonists (ns-MRA), in particular finerenone, play a vital role in combating kidney fibrosis and inflammation, thereby preserving kidney function. RAAS blockers remain essential for managing hypertension and reducing proteinuria, crucial for preventing further kidney damage[3].

A recent study estimated the lifetime benefits of combination therapy with an SGLT2i, GLP-1RA, and ns-MRA in patients with T2D and albuminuria. Compared to conventional care, this triple therapy approach was projected to reduce the risk of major adverse CV events (HR: 0.65), CKD progression (HR: 0.42), CV death (HR: 0.64), and all-cause mortality (HR: 0.67). These benefits translated into substantial estimated gains in event-free survival, including 5.5 years for CKD progression and 3.2 years for heart failure hospitalization in a 50-year-old patient. Even under conservative assumptions of partial additivity or treatment waning, clinically meaningful benefits persisted. These findings underscore the potential of a multifaceted, pillar-based strategy in improving long-term cardio-renal outcomes for high-risk individuals with T2D[81].

Further recent international guidelines advocate for a structured, tiered approach to managing DKD, emphasising individualised, multifactorial risk reduction. Core strategies include lifestyle modification, blood pressure and glycaemic control, and lipid management (Tier 1), with early initiation of evidence-based pharmacotherapies RAAS blockers, SGLT2is, and statins (Tier 2). In patients with persistent albuminuria despite optimised therapy, the addition of finerenone and/or GLP-1RAs is recommended (Tier 3), leveraging their demonstrated cardio-renal benefits. Treatment intensification should be guided by individual cardio-renal risk profiles (Tier 4), and the guidelines highlight the importance of patient engagement and cross-sector collaboration to address health inequalities and improve outcomes in DKD. Notably, the authors challenge the rigid “pillared” paradigm by proposing a flexible tiered model that integrates both foundational and advanced therapies, allowing care to be personalized based on patient context, comorbidities, and risk. They emphasize that despite the availability of high-quality evidence and effective therapies, gaps in implementation remain substantial - particularly in underserved populations - and must be urgently addressed through better education, system-wide support, and policy alignment[82].

A further 2024 meta-analysis offers compelling evidence that GLPRAs- provide clinically meaningful benefits for both kidney and CV outcomes in individuals with and without T2D. Including data from 11 randomized controlled trials and over 85000 participants, the study demonstrated that GLP-1RAs significantly reduced the risk of a composite kidney outcome by 18%, kidney failure by 16%, MACE by 13%, and all-cause mortality by 12%. Crucially, the analysis excluded surrogate markers like macroalbuminuria, focusing instead on hard clinical endpoints such as sustained eGFR decline, kidney replacement therapy, and death from kidney failure. These findings suggest that GLP-1RAs may be a valuable therapeutic strategy in CKD management beyond glycaemic control. However, an increased rate of treatment discontinuation due to adverse events highlights the importance of patient selection and monitoring[83]. Despite promising data supporting the use of semaglutide in CKD populations, several gaps in evidence remain. The use of cardio-kidney composite outcomes in clinical trials presents key methodological challenges, including inconsistent definitions of renal endpoints, differing timelines for cardiovascular vs renal event accrual, and varied organ-specific responses to therapy. These issues complicate the interpretation of trial findings and necessitate refined trial designs tailored to dual-organ outcomes[83]. Furthermore, cost-effectiveness analyses specific to semaglutide in CKD remain limited, particularly in comparison to established therapies such as SGLT2is, which have demonstrated substantial healthcare savings when applied to cardio-kidney-metabolic populations[74]. There is scope for further research to address and validate the efficacy of semaglutide use across CKD strata, but also the economic sustainability of semaglutide as part of routine CKD care.

Considering this, semaglutide emerges as a valuable adjunct therapy. Its ability to enhance glycaemic control, promote weight loss, and improve CV outcomes aligns well with the goals of CKD management. Current evidence supports the integration of semaglutide into a comprehensive treatment regimen alongside SGLT2is, ns-MRAs, and RAAS blockers. This multi-drug approach not only targets the primary aspects of T2D and CKD but also addresses the intricate interplay between these conditions. By incorporating semaglutide, clinicians can optimise patient outcomes, enhance kidney health, and reduce the overall burden of disease, paving the way for improved quality of life in patients with CKD and T2D.

CONCLUSION

Semaglutide and the GLP-1RAs have now been positioned as the fourth pillar in the pharmaco-management of CKD. Evidence shows its utility offering benefits in preventing the development and progression of CKD, improving CV health, and enhancing metabolic profile of patients. Recent evidence underscores its ability to reduce albuminuria, slow GFR decline, and provide CV protection, making it a valuable therapeutic option for CKD patients with and without DM. However, several challenges remain, including the need for expanded the evidence base for a beneficial effect of semaglutide, and other GLP-1RA like medications in CKD populations without DM. Additionally, the accessibility and cost of therapy pose barriers to widespread adoption of GLP-1RAs as kidney protective agents. Addressing these challenges will require further clinical research, particularly focusing on identifying patient subgroups that benefit most from semaglutide treatment, in particular when combined with other “pillars” of CKD management, as well as establishing optimal dosing strategies and clinical endpoints for monitoring efficacy and safety and tolerability. The tolerability, safety and efficacy of semaglutide for patients with very advanced CKD and those that have progressed to ESKD still requires further studies. Despite the above, semaglutide should now be considered as a key protective agent for most people with T2D and CKD as it reduces the risk of clinically import kidney and CV outcomes and also improves multiple metabolic parameters.

ACKNOWLEDGEMENTS

We would like to acknowledge the assistance of Varuni Obeyesekere for helping to generate the figures used in this review.