GLP-1 based therapy for the cardio-kidney-metabolic syndromes

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Reference: November 2025 | Issue 11 | Vol 11 | Page 50

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The growing convergence of cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic dysfunction has given rise to the concept of the cardio-kidney-metabolic (CKM) syndrome.¹ This integrated framework recognises that obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and related metabolic disturbances are not isolated pathologies, but deeply interconnected processes that accelerate morbidity and mortality.²

Collectively, these overlapping disorders contribute to an enormous global health burden – recent analyses suggest that nearly one-in-four adults worldwide is affected by at least one component of the CKM spectrum, and coexistence of two or more dramatically increases the risk of premature death.³

Understanding CKM syndrome as a unified disease process has profound therapeutic implications. Traditional management has typically addressed cardiovascular, renal, and metabolic diseases separately, but this reductionist approach fails to capture their shared pathophysiologic roots, including chronic inflammation, adipose tissue dysfunction, oxidative stress, endothelial injury, and neurohormonal activation.²

In this context, glucagon-like peptide-1 (GLP-1)-based therapies have emerged as a transformative class capable of modifying disease across multiple organ systems, especially as these medications have weight-loss dependent and weight-loss independent benefits on CKM syndrome.

Initially developed for glycaemic control in T2DM, GLP-1 receptor agonists (GLP-1 RAs) have demonstrated far broader benefits, encompassing weight reduction, improvement in cardiometabolic risk factors, renal protection, and cardiovascular event reduction. Landmark cardiovascular outcome trials, including LEADER (liraglutide),⁴ REWIND (dulaglutide),⁵ and SUSTAIN-6 followed by SELECT (semaglutide),^6,7 established these benefits across diverse populations.

Beyond the first-generation agents, newer multi agonist incretin therapies are redefining the therapeutic landscape. The dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA tirzepatide has demonstrated improvements in weight, glycaemic control, and surrogate cardiovascular and renal endpoints.^8,9

Similarly, emerging agents such as CagriSema (semaglutide plus cagrilintide),¹⁰ survodutide (GLP-1/glucagon dual agonist),¹¹ retatrutide (triple GIP/GLP-1/glucagon agonist),¹² and MariTide (GLP-1 agonist plus GIP receptor antagonist)¹³ have shown remarkable efficacy in early phase studies, suggesting the potential for deeper, sustained modification of the CKM disease continuum.

Because CKM syndrome represents a systemic cycle of metabolic overload, endothelial dysfunction, and organ crosstalk between the heart, kidney, and adipose liver axis, therapies that can act by improving metabolic health while protecting cardiovascular and renal systems may hold the greatest promise. GLP-1-based treatments, through their integrated metabolic, vascular, and renal benefits, now stand at the forefront of this evolving paradigm.

Cardiovascular outcomes

CVD remains the principal cause of morbidity and mortality in individuals with obesity, diabetes, and CKD, representing the dominant endpoint within the CKM spectrum.⁵ Evidence from major outcome trials has established GLP-1 RAs as a therapeutic class with clinically significant cardiovascular benefit extending beyond glycaemic control, as illustrated in Table 1.

TABLE 1: Cardiovascular outcomes

In the LEADER trial, liraglutide reduced major adverse cardiovascular events (MACE) by 13 per cent (hazard ratio [HR] 0.87, 95% CI 0.78-0.97), with a 22 per cent reduction in cardiovascular death (HR 0.78, 95% CI 0.66-0.93).⁴ These benefits were accompanied by modest declines in systolic blood pressure (≈2-3mmHg) and triglycerides, and reductions in C-reactive protein (CRP), suggesting pleiotropic vascular protection.^4,15,16

Dulaglutide demonstrated a similar pattern in the REWIND trial, with a 12 per cent reduction in MACE (HR 0.88, 95% CI 0.79-0.99) and a 24 per cent lower stroke risk (HR 0.76, 95% CI 0.61-0.95) across a population that included participants without established CVD, confirming benefit across a broad risk spectrum.^5,15,16

Semaglutide further strengthened this evidence base. In SUSTAIN-6, semaglutide achieved a 26 per cent MACE reduction (HR 0.74, 95% CI 0.58-0.95) in individuals with T2DM,⁶ while the SELECT trial extended these findings to adults with obesity but no diabetes, reducing cardiovascular events by 20 per cent (HR 0.80, 95% CI 0.72–0.90).⁷

Across both trials, reductions in systolic and diastolic blood pressure (4-6mmHg and 2-3mmHg, respectively) and 30-40 per cent declines in high sensitivity CRP confirmed the anti-inflammatory and anti-atherogenic potential of GLP-1 RAs.^6,7

The dual GIP/GLP-1 RA tirzepatide has produced improvements in cardio-kidney-metabolic risk factors, lowering systolic blood pressure by up to 10mmHg, improving lipid profiles, and reducing inflammatory markers in the SURMOUNT-1 and SURPASS programmes.^8,24,26,27 Preliminary top line findings from SURPASS-CVOT show non-inferiority to dulaglutide for MACE, with an approximate 8 per cent lower event rate.^22,23 Although full publication is pending, these data indicate potent risk factor modification that may translate into long-term cardiovascular benefit.^{8,22,25,26,27,28,29}

Emerging multi-target agonist therapies, including CagriSema (semaglutide+cagrilintide), survodutide (GLP-1/glucagon co-agonist), retatrutide (triple GIP/GLP-1/glucagon agonist), and MariTide (GLP-1 agonist + GIP receptor antagonist), show consistent patterns of weight-driven blood pressure reduction, lipid improvement, and inflammatory attenuation in phase 2 programmes.^{10,13,18,30,32,34,35}

While long term cardiovascular outcome trials are ongoing, the convergence of metabolic, haemodynamic, and anti-inflammatory effects suggests a trajectory toward disease-modifying therapy across the CKM continuum.

Taken together, the capacity of GLP-1 based and multi-agonist incretin therapies to favourably influence blood pressure, lipids, and systemic inflammation establishes them as essential tools for reducing cardiovascular mortality, the leading cause of death in this interconnected disease spectrum.^{1,3,4,7,10,13,16,35}

Kidney outcomes

CKD represents a central component of the CKM syndrome and a major determinant of cardiovascular and all-cause mortality. Recent analyses from the Global Burden of Disease CKM Working Group confirm that reduced estimated glomerular filtration rate (eGFR) and albuminuria are strong, independent predictors of premature cardiovascular death across metabolic and renal disorders.³

The American Heart Association CKM Advisory similarly identifies kidney dysfunction as a key “risk amplifier”, accelerating both heart failure and atherosclerotic events within the metabolic spectrum.¹ Against this background, GLP-1-based therapies have emerged as agents with measurable kidney protective effects, reducing albuminuria and slowing eGFR decline through haemodynamic, anti-inflammatory, and metabolic mechanisms, which are demonstrated in Table 2.¹⁶

TABLE 2: Kidney outcomes

Among established GLP-1 RAs, liraglutide provided the first evidence of renal benefit. In the LEADER renal analysis, liraglutide reduced composite kidney outcomes by 22 per cent (HR 0.78, 95% CI 0.67–0.92) and macroalbuminuria by 26 per cent (HR 0.74, 95% CI 0.60–0.91).¹⁷ These findings were reinforced by post hoc analyses linking albuminuria reduction to improved renal and cardiovascular outcomes.³⁶

Dulaglutide demonstrated consistent benefit in REWIND, lowering new onset macroalbuminuria by 23 per cent (HR 0.77, 95 % CI 0.68-0.87) and the broader kidney composite by 15 per cent (HR 0.85, 95% CI 0.77-0.93), alongside slower annual eGFR decline.³⁶ Together, these studies established liraglutide and dulaglutide as early GLP-1 RAs with proven albuminuria and kidney risk reduction.^16,36

Semaglutide has since provided definitive evidence of renal protection. In SUSTAIN-6, semaglutide reduced the risk of new or worsening nephropathy primarily through lower rates of macroalbuminuria.⁶

The FLOW trial confirmed these findings, showing a 24 per cent reduction in major kidney outcomes (HR 0.76, 95% CI 0.66-0.88) in patients with T2DM and CKD.²⁰ Complementary data from the SELECT kidney analysis extended these effects to individuals with obesity without diabetes, highlighting renoprotection independent of glycaemic status.²¹

Dual incretin therapy with tirzepatide has produced similarly strong renal signals. In SURPASS-4, tirzepatide reduced composite kidney outcomes by 42 per cent (HR 0.58, 95% CI 0.43–0.80), decreased urinary albumin-to-creatinine ratio by approximately 32 per cent, and slowed eGFR decline versus insulin glargine.^9,28

Comparable trends were observed in obesity trials, where improvements in kidney parameters paralleled reductions in body weight and blood pressure.²⁹ Although a dedicated kidney outcomes trial is pending, these findings suggest meaningful renoprotective potential.^{8,9,16,24,25,28,29}

Next generation incretin dual agonists show emerging but promising data. CagriSema (semaglutide+cagrilintide) and survodutide (GLP-1/glucagon) both achieved substantial weight loss and blood pressure reduction, changes that are expected to translate into kidney benefit once longer-term trials report.^{10,11,18,30,32}

Retatrutide demonstrated early exploratory evidence of reduced albuminuria (≈30%) and improved eGFR by 5-9mL/min/1.73m²,^12,33,34 while data for MariTide remain preliminary.^13,16,33,35

Overall, GLP-1-based therapies now represent a major advance in kidney protection across the CKM spectrum. Liraglutide and dulaglutide provide consistent evidence of albuminuria and composite renal risk reduction, semaglutide has confirmed disease-modifying benefit in a dedicated outcomes trial, and tirzepatide offers a strong multidimensional renal signal.

The emerging multi agonists extend this trajectory toward integrated metabolic and renal therapy, marking a shift from glycaemic control to comprehensive organ protection across the cardio–kidney-metabolic axis.^{1,3,6,8,13,35}

Metabolic outcomes

Obesity, insulin resistance, and metabolic dysfunction have a large impact on the CKM continuum and serve as the primary drivers of both cardiovascular and renal deterioration.¹ Excess adiposity, particularly visceral fat, contributes to a proinflammatory and insulin resistant state that accelerates atherosclerosis, hypertension, and kidney injury.¹

Within this framework, GLP-1-based and multi-agonist incretin therapies have redefined metabolic management by producing durable reductions in adiposity, HbA1c, and incident diabetes effects that directly modify long-term cardiovascular and renal risk.¹⁶

Liraglutide was the first GLP-1 RA to demonstrate meaningful metabolic benefit. In the SCALE Obesity and Prediabetes trial, liraglutide 3.0mg led to an average 8 per cent weight loss and a 79 per cent reduction in new-onset diabetes compared with placebo.³⁷

In the LEADER trial, participants experienced a modest additional weight loss of approximately 2kg and an HbA1c reduction of 0.4 per cent, benefits that contributed to improved cardio-kidney-metabolic outcomes.^4,16

Dulaglutide produced similar though slightly smaller effects, achieving a 2.5kg weight reduction, and a mean HbA1c decrease of 0.6 per cent.^15,16 These findings confirmed that GLP-1 RAs can delay progression from prediabetes to diabetes and provide glycaemic improvement independent of weight loss or baseline CVD.

Semaglutide has markedly expanded the magnitude of achievable metabolic benefit. Across the SUSTAIN-6, STEP 1, and SELECT trials, semaglutide produced weight losses ranging from 9 per cent to 15 per cent, HbA1c reductions of 1.1-1.6 per cent, and approximately 70 per cent lower diabetes incidence among participants with obesity.^6,7,16,20,21 These effects were consistent across populations, demonstrating that semaglutide can induce substantial weight loss and metabolic normalisation, even in individuals without hyperglycaemia.

Tirzepatide has further advanced metabolic outcomes. In the SURMOUNT-1 obesity trial, tirzepatide induced weight reductions of 15-21 per cent and achieved HbA1c reductions of 2.0-2.4 per cent in the SURPASS T2DM studies.^{8,9,13,16,25,26,27,28,29}

A three-year extension of SURMOUNT-1 demonstrated a 94 per cent reduction in new onset diabetes compared with placebo,^9,13 suggesting a profound preventive effect. These metabolic improvements are accompanied by favourable changes in blood pressure, lipids, and inflammatory biomarkers, positioning tirzepatide as the most potent pharmacological intervention currently available for comprehensive metabolic risk reduction.

The generation dual agonists and triple agonists further expand this paradigm. CagriSema (semaglutide+cagrilintide) achieved 15-20 per cent weight loss and HbA1c reductions of 1.5-2 per cent in early REDEFINE studies, outperforming either component alone.^10,30,31,32 Survodutide, a GLP-1/glucagon co-agonist, produced 10-13 per cent weight loss and HbA1c decreases of 1.1-1.3 per cent, with additional improvement in hepatic steatosis and insulin sensitivity.^11,16,18,33

TABLE 3: Metabolic outcomes

Retatrutide, a triple GIP/GLP-1/glucagon agonist, achieved the largest reported pharmacological weight loss to date, up to 24 per cent at the highest dose, along with HbA1c reductions of 1.6-2.0 per cent and 98 per cent reversion from prediabetes to normoglycemia.^12,33,34 MariTide (GLP-1 + GIPR antagonist) demonstrated early phase weight loss of 14-18 per cent and HbA1c reductions of 1-1.4 per cent, with preliminary evidence of diabetes risk reduction.^13,32,35

Collectively, these findings confirm that incretin-based therapies produce clinically meaningful and durable metabolic improvements across the CKM spectrum. Traditional GLP-1 RAs such as liraglutide and dulaglutide provide modest but consistent benefits in weight, glycaemia, and diabetes prevention – semaglutide extends these effects to populations without diabetes; and tirzepatide and emerging multi-agonists deliver near metabolic normalisation. Within the integrated CKM framework, these agents act not only as glucose-lowering medications, but as systemic disease-modifying therapies capable of reversing the metabolic drivers that underlie CKM syndromes.^{1,3,13,18,24,28,30}

Conclusion

In summary, large-scale outcome trials have reshaped how CKM diseases are understood and managed. GLP-1 RAs and emerging incretin-based therapies have demonstrated that targeting the metabolic core of obesity and insulin resistance can translate into meaningful cardio-kidney-metabolic protection.

Beyond glucose-lowering, these agents redefine disease modification by addressing the shared pathways that link metabolic overload to endothelial dysfunction and organ decline. As next generation dual agonists achieve deeper and more sustained effects across weight, inflammation, and kidney health, the management of CKM syndrome is shifting toward a single, integrated therapeutic strategy – one that restores systemic metabolic balance and mitigates the long-term burden of cardio, kidney, and metabolic diseases.