The biological foundation for these effects lies in the incretin hormones themselves. GLP-1 is secreted by enteroendocrine L cells in the distal small intestine and colon, rising rapidly after meals rich in carbohydrates and fats. It enhances glucose-dependent insulin secretion, suppresses glucagon under hyperglycemic conditions, delays gastric emptying, and promotes satiety. GIP, its counterpart, is released by K cells in the duodenum and proximal jejunum and similarly boosts insulin secretion in a glucose-dependent manner. Both hormones are rapidly degraded by the enzyme dipeptidyl peptidase-4, which is why pharmaceutical versions have been engineered to resist degradation and act for days or weeks. Crucially, GLP-1 receptors are found not only in the pancreas but also in the gastrointestinal tract, the central nervous system, the heart, blood vessels, and the kidneys, providing a mechanistic basis for effects that extend well beyond blood sugar control.

The review details how GLP-1 receptor agonism may protect the cardiovascular system through several converging routes. Central receptor activation enhances satiety and reduces energy intake, and the resulting weight loss improves blood pressure, glycemic control, and lipid metabolism. Experimental and clinical evidence also points to direct anti-inflammatory, antioxidative, and vascular effects that improve endothelial function and attenuate fibrosis and cellular injury. In the kidneys, receptor activation promotes natriuresis, partly through modulation of sodium transport in the proximal tubule, and may influence kidney hemodynamics and glomerular hyperfiltration. However, the authors caution that GLP-1 receptor expression in the human kidney appears more restricted than previously assumed, meaning kidney protection likely arises from a combination of direct and indirect mechanisms, including improvements in glycemia, body weight, blood pressure, vascular function, and inflammation.

Tirzepatide occupies a distinct pharmacological position as a single peptide that activates both GIP and GLP-1 receptors. Pharmacological studies have shown an imbalanced signaling profile, with greater engagement of the GIP receptor than the GLP-1 receptor and distinct signaling properties at the latter. GIP receptors are expressed in pancreatic beta cells, adipose tissue, and brain regions involved in appetite regulation, and simultaneous activation of both receptors produces complementary effects on glucose regulation, energy intake, and body weight. This dual mechanism underpins the pronounced metabolic efficacy seen across the SURPASS and SURMOUNT trial programs, and it has fueled interest in whether such metabolic gains translate into cardiovascular and kidney protection.

The cardiovascular evidence for single GLP-1 receptor agonists is now firmly established. In the LEADER trial, liraglutide reduced the primary composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke with a hazard ratio of 0.87. REWIND showed a similar benefit for dulaglutide with a hazard ratio of 0.88, HARMONY Outcomes demonstrated a hazard ratio of 0.78 for albiglutide, and AMPLITUDE-O reported a hazard ratio of 0.73 for efpeglenatide. Semaglutide produced a hazard ratio of 0.74 in SUSTAIN-6, and the SELECT trial extended this benefit to people with overweight or obesity and established cardiovascular disease but without diabetes, with a hazard ratio of 0.80. The absence of diabetes in SELECT is particularly significant, demonstrating that glucose lowering is not required for cardiovascular benefit, although the trial does not establish independence from weight loss or other metabolic changes.

The kidney story has evolved more gradually and with important caveats. Early kidney findings from cardiovascular outcome trials were largely prespecified secondary or exploratory composites dominated by albuminuria, a frequent but relatively early marker of kidney damage. In LEADER, the kidney benefit was driven primarily by a reduction in new-onset persistent macroalbuminuria, while doubling of serum creatinine and end-stage kidney disease were not significantly reduced. REWIND showed a similar pattern, with the strongest effect on new macroalbuminuria and no individual significance for sustained eGFR decline or chronic kidney replacement therapy. The review emphasizes that improvement in albuminuria should not be considered equivalent to prevention of progressive loss of kidney function, a distinction that separates the earlier evidence from the dedicated kidney outcome trial FLOW.

FLOW changed the landscape by making chronic kidney disease progression the primary focus. In patients with type 2 diabetes and chronic kidney disease, semaglutide reduced the composite of kidney failure, sustained 50 percent or greater reduction in eGFR, or death from kidney-related or cardiovascular causes by 24 percent, with a hazard ratio of 0.76. Cardiovascular mortality fell with a hazard ratio of 0.71, all-cause mortality with 0.80, and the mean annual decline in eGFR was 1.16 milliliters per minute per 1.73 square meters per year less steep than with placebo. A subsequent prespecified participant-level pooled analysis of SELECT, FLOW, and SOUL, encompassing 30,787 participants across different formulations, doses, and diabetes statuses, found a 16 percent reduction in a harmonized kidney composite, with the association persisting even when cardiovascular death was excluded from the endpoint.

For tirzepatide, the cardiovascular evidence is expanding but remains qualitatively different. The SURPASS-CVOT trial directly compared tirzepatide with dulaglutide in patients with type 2 diabetes and established atherosclerotic cardiovascular disease, finding non-inferiority but not statistical superiority for major adverse cardiovascular events despite greater reductions in body weight and HbA1c. This finding illustrates a central theme of the review: greater metabolic efficacy does not necessarily translate proportionally into greater reduction in hard cardiovascular outcomes. In contrast, the SUMMIT trial produced particularly encouraging results in obesity-related heart failure with preserved ejection fraction, reducing the composite risk of cardiovascular death or worsening heart failure, an effect driven primarily by fewer worsening heart failure events rather than a standalone reduction in cardiovascular mortality.

The kidney evidence for tirzepatide remains the least mature component of its profile. Post-hoc analyses of SURPASS-4 suggest slower eGFR decline, reduced albuminuria, and a lower risk of composite kidney endpoints compared with insulin glargine, and a separate analysis using cystatin C-based estimates supported slower kidney function decline. However, these findings derive from trials not designed or powered to evaluate chronic kidney disease progression, and the review stresses that they should be interpreted as supportive and hypothesis-generating rather than definitive. No dedicated kidney outcome trial exists for tirzepatide, in stark contrast to the FLOW evidence for semaglutide.

The review also addresses combination therapy, safety, and future directions. Contemporary guidelines, including the 2026 AHA/ACC/ADA/ASN guideline, support the use of SGLT2 inhibitors, GLP-1-based therapies, or both in appropriate patients, and meta-analytic evidence suggests GLP-1 receptor agonist benefits are preserved during background SGLT2 inhibitor treatment, although the precise magnitude of incremental benefit from combination therapy remains uncertain. Gastrointestinal adverse events remain the most frequent tolerability limitation, concentrated during dose escalation, while meta-analyses have identified increased risks of gallbladder and biliary disease with both drug classes. Acute pancreatitis has not shown a statistically significant increase in trial meta-analyses, and the excess diabetic retinopathy complications seen with semaglutide in SUSTAIN-6 appear concentrated among patients with pre-existing retinopathy and rapid glycemic improvement. Looking ahead, the triple agonist retatrutide, targeting GLP-1, GIP, and glucagon receptors, is being evaluated in the ongoing TRIUMPH-Outcomes trial, and the authors argue that treatment selection should ultimately follow a phenotype-oriented framework in which the choice of incretin-based therapy reflects the clinical outcome most important to modify, the maturity of evidence supporting that outcome, and patient-specific characteristics rather than metabolic potency alone.

Subject of Research: Cardiovascular and kidney effects of GLP-1 receptor agonists and tirzepatide in cardiovascular-kidney-metabolic syndrome

Article Title: Beyond glycemic control: cardiovascular and kidney benefits of GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide: a narrative review

Article References: Kierzkowski, F., Skrzypek, W., Bryl, W., Paczkowska, A., & Hoffmann, K. (2026). Beyond glycemic control: cardiovascular and kidney benefits of GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide: a narrative review. Frontiers in Endocrinology, 17, Article 1977433. https://doi.org/10.3389/fendo.2026.1977433

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1977433

Keywords: GLP-1 receptor agonists, tirzepatide, semaglutide, cardiovascular-kidney-metabolic syndrome, chronic kidney disease, obesity, type 2 diabetes, heart failure with preserved ejection fraction, FLOW trial, SELECT trial, SURPASS-CVOT, incretin therapies