Evolutionary Role of GIP & GLP-1 Beyond Glycaemia Review: non-glycaemic role of GIP and GLP1 in current clinical practice

Authors

  • MBBS, MD (Medicine), IMS BHU Fellowship in Diabetes (DFID), CMC Vellore DMSc (Endocrinology), University of South Wales, UK Consultant Endocrinologist, Panacea Hospital English Author

Keywords:

GLP-1, GIP, Incretin hormones, Non-glycaemic effects, Cardiovascular outcomes, Renal protection, Adipose tissue biology, Ectopic fat, Inflammation, Dual GIP/GLP-1 receptor agonists, Tirzepatide, Cardio-renal-metabolic medicine

Abstract

Abstract

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were initially identified as incretin hormones responsible for glucose-dependent insulin secretion after nutrient intake. While early therapeutic strategies focused primarily on glycaemic control in type 2 diabetes, a growing body of evidence now demonstrates that these hormones exert extensive non-glycaemic effects across multiple organ systems. Large cardiovascular outcome trials have consistently shown that long-acting GLP-1 receptor agonists reduce major adverse cardiovascular events by approximately 20–26%, with benefits that cannot be fully explained by modest reductions in HbA1c. Parallel data from renal outcome analyses and dedicated chronic kidney disease trials indicate that GLP-1 receptor agonists slow estimated glomerular filtration rate decline, reduce albuminuria, and delay progression to kidney failure through mechanisms largely independent of glucose lowering.

Beyond the cardio-renal axis, GLP-1 signalling influences appetite regulation, body-weight reduction, adipose tissue quality, hepatic lipid metabolism, systemic inflammation, and central nervous system function. GIP, once considered primarily obesogenic, is now recognised as a context-dependent modulator of adipose tissue biology, lipid handling, and inflammation. Dual GIP/GLP-1 receptor co-agonism, exemplified by tirzepatide, integrates these complementary pathways, producing greater weight loss, improved lipid profiles, reduced hepatic steatosis, and enhanced cardiometabolic risk reduction compared with GLP-1 receptor agonism alone.

Collectively, current evidence supports a paradigm shift in which GLP-1 and GIP are viewed as cardio-renal-metabolic and neuroendocrine hormones rather than solely incretins. Understanding and harnessing their non-glycaemic biology is central to contemporary strategies aimed at preventing cardiovascular disease, kidney failure, obesity-related complications, and potentially neurodegenerative disorders in people with diabetes and related metabolic diseases.

Evolutionary Role of GIP & GLP-1 Beyond Glycaemia Review: non-glycemic role of GIP and GLP1 in current clinical practice Dr. Ashutosh Mishra Journal Watch MBBS, MD (Medicine), IMS BHU Fellowship in Diabetes (DFID), CMC Vellore DMSc (Endocrinology), University of South Wales, UK Consultant Endocrinologist, Panacea Hospital Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were initially recognized as incretin hormones that enhance glucose-dependent insulin secretion following nutrient intake, establishing the physiological foundation for the "incretin effect," which contributes to 50–70% of post-prandial insulin release in healthy individuals. Historically, their therapeutic application centred on glycaemic regulation in type 2 diabetes via GLP-1 receptor agonists (GLP-1RAs) and, more recently, dual GIP/GLP-1 receptor co-agonists like tirzepatide. In the last ten years, though, a lot of research has been done on Experimental, genetic, and clinical outcome evidence has shown that GLP-1 and GIP have many effects on the cardiovascular, renal, hepatic, adipose, and central nervous systems that change the way these hormones are seen in cardio-renal-metabolic medicine. Extensive cardiovascular outcome trials (CVOTs) utilising long-acting GLP-1 receptor agonists (GLP-1RAs)—including Liraglutide, semaglutide, and dulaglutide have consistently demonstrated relative risk reductions of approximately 20–26% for three-point major adverse cardiovascular events (MACE). cardiovascular mortality, non-fatal myocardial infarction, or non-fatal stroke in high-risk individuals’ people who have type 2 diabetes. The differences in HbA1c between the groups in these trials are small, usually between 0.3 and 0.5 percentage points. However, the absolute reductions in hard cardiovascular endpoints are clinically significant, strongly suggesting that mechanisms A significant portion of the benefit is attributable to factors beyond enhanced glycaemic control. Mechanistic studies show that GLP-1 receptors are present on cardiomyocytes, endothelial cells, and vascular smooth muscle cells. When these receptors are activated, they increase the availability of nitric oxide in endothelial cells, reduce oxidative stress, and suppress signalling that causes inflammation in the vascular wall. These changes lead to better vasodilation, slower progression of atherosclerosis, and stronger heart muscle response to ischaemia–reperfusion injury. There is now evidence that protects the kidneys. Pooled analyses of renal outcomes from CVOTs, together with the dedicated FLOW trial in chronic kidney disease, indicate that GLP-1RAs reduce a composite kidney end point—comprising sustained ≥50% decline in estimated glomerular filtration rate (eGFR), progression to kidney failure or renal death— with a risk ratio of around 0.79, and slow chronic eGFR decline by approximately 0.7–0.8 mL/min/1.73 m² per year. These benefits are observed across a broad range of baseline eGFR and albuminuria and remain largely preserved after adjustment for differences in HbA1c, supporting the concept of direct Reno protective actions. Proposed mechanism includes natriuresis and modest reductions in intraglomerular pressure, anti-inflammatory and anti-oxidative effects within glomerular and tubulo-interstitial compartments, and improved glomerular barrier function with reductions in albuminuria. Beyond the cardio-renal axis, GLP-1 signalling in the hypothalamus and brainstem exerts potent anorectic effects, reducing hunger, increasing satiety and shifting food preference towards lower-energy, nutrient-dense options. Chronic GLP-1RA therapy in obesity trials produces average weight losses of 10–20% of baseline body weight, accompanied by improvements in blood pressure, obstructive sleep apnoea, liver steatosis and joint pain. GLP-1 also influences hepatic lipid handling, lowers fasting and post-prandial triglycerides and improves non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in early histological studies. In the central nervous system (CNS), GLP-1 receptors in hippocampal and cortical circuits support synaptic plasticity and neuronal survival, while mesolimbic GLP-1 pathways modulate reward, hedonic eating and possibly mood. GIP, historically regarded chiefly as a β-cell hormone and sometimes labelled “obesogenic”, has an increasingly nuanced profile. Chronic pharmacological GIP-receptor activation can “rehabilitate” white adipose tissue by enhancing subcutaneous lipid storage capacity, reducing visceral and ectopic fat and improving plasma lipid profiles in preclinical models, while human genetic data link GIP pathway variants with cardiometabolic traits and coronary risk. Tirzepatide, the first dual GIP/GLP-1 receptor co-agonist, exploits these complementary mechanisms and produces greater weight loss, improvements in blood pressure, triglycerides and hepatic fat than high-dose GLP-1RAs alone, again indicating a substantial non-glycaemic contribution to its clinical benefits. Taken together, these findings support a modern paradigm in which GLP-1 and GIP are viewed as multi-system cardio-renal-metabolic and neuroendocrine hormones, and incretin-based therapies are conceptualized as organ-protective agents rather than simply glucose-lowering drugs. The following sections examine the principal non-glycaemic actions of GLP-1 and GIP across cardiovascular, renal, adipose, hepatic and central nervous systems, and explore how dual agonism integrates these effects to modify disease trajectories in cardio-renal-metabolic disorders. Cardiovascular Protection Beyond Glucose Evidence from outcome trials Meta-analyses of GLP-1RA CVOTs show that long-acting agents reduce three-point MACE by roughly 14–26% relative to placebo, with point estimates around a hazard ratio (HR) of 0.79. Trials such as LEADER (liraglutide), SUSTAIN-6 (semaglutide), REWIND (dulaglutide) and others consistently demonstrate fewer cardiovascular deaths, non-fatal myocardial infarctions and strokes in participants allocated to GLP-1RAs than in those receiving standard of care. Importantly, these benefits are seen across subgroups defined by baseline HbA1c, prior cardiovascular disease, kidney function and use of other cardioprotective agents such as SGLT2 inhibitors, indicating that cardioprotection is not restricted to particular glycaemic strata. Although dedicated cardiovascular outcome data for pure GIP agonists are limited, human genetic studies and preclinical experiments support a role for GIP signalling in atherosclerosis modulation. In LDL-receptor-deficient mice, chronic administration of an acylated GIP analogue reduced aortic atherosclerotic lesion area and improved lipid profiles independent of changes in body weight or insulin concentrations. Transcriptomic analyses of adipose tissue from these animals revealed smaller, more insulin-sensitive adipocytes and downregulation of complement and coagulation pathways associated with pro-thrombotic inflammation, suggesting that favourable adipose remodeling contributes to reduced vascular risk. Mendelian randomization studies in humans link GIP-pathway variants to lower coronary artery disease risk and improved lipid traits, although the net cardiovascular effect of pharmacological GIP modulation in humans likely depends on metabolic context and concurrent GLP-1 receptor activation. Mechanistic pathways in the heart and vasculature GLP-1 receptors are expressed in coronary endothelium, vascular smooth-muscle cells and cardiomyocytes. Activation of endothelial GLP-1R increases nitric-oxide synthase activity, improves nitric-oxide bioavailability and reduces oxidative stress, culminating in enhanced endothelium-dependent vasodilation. In experimental models of atherosclerosis, GLP-1R activation reduces macrophage infiltration and foam-cell formation, downregulates adhesion molecules and inflammatory cytokines, and stabilises plaques by increasing fibrous-cap thickness and reducing necrotic-core size. In ischemia–reperfusion models, GLP-1 and GLP-1RAs limit infarct size, preserve mitochondrial function and reduce cardiomyocyte apoptosis, suggesting a direct myocardial preconditioning effect that may operate alongside hemodynamic and metabolic improvements. GIP receptors in the cardiovascular system are less extensively characterized but are present in endothelial cells and vascular smooth muscle. Acute human GIP infusion can increase heart rate and produce modest changes in blood pressure, reflecting direct autonomic or vascular effects independent of glycaemia. In adipose tissue, GIP mediated improvements in lipid handling and reduction of inflammatory gene expression indirectly relieve vascular stress by lowering circulating triglyceriderich particles and proinflammatory mediators. When GIPR activation is combined with GLP1R stimulation, as in tirzepatide therapy, these effects appear to synergise, yielding greater reductions in blood pressure, triglycerides and inflammatory markers than GLP1RAs alone. Renal Effects and Cardio-Renal Integration Reno protective outcomes Renal data from GLP-1RA trials have evolved from exploratory endpoints to robust evidence supporting kidney protection. Pooled analyses of LEADER, SUSTAIN-6, REWIND, AMPLITUDE-O and other CVOTs, together with the FLOW trial, show that GLP-1RAs reduce risk of composite kidney outcomes—typically defined as sustained ≥50% eGFR decrease, progression to kidney failure or renal death—with relative risk reductions around 20–25%. GLP-1RAs also reduce new-onset macroalbuminuria and slow chronic eGFR decline by about 0.7–0.8 mL/min/1.73 m² per year, with consistent benefits across diverse baseline kidney-function strata. The magnitude and independence of these effects from HbA1c change strongly support genuine non-glycaemic renoprotection. Direct renal effects of GIP are less clearly defined. GIP receptors are expressed in renal vasculature and tubular segments, and preclinical studies suggest that GIP signalling can modulate renal blood flow, natriuresis and renin–angiotensin–aldosterone system activity. Observational and mechanistic data on dual GIP/GLP-1 agonism indicate potentially favourable effects on albuminuria, eGFR trajectories and renal biomarkers, but dedicated renal outcome trials for tirzepatide are still ongoing. Mechanisms along the nephron: Multiple mechanisms likely mediate the kidney benefits of GLP-1RAs. At the glomerular level, GLP-1R activation promotes natriuresis and may reduce intraglomerular pressure, partially through afferent arteriolar vasodilation and interaction with tubulo-glomerular feedback. In the tubulo-interstitial compartment, GLP-1 signalling dampens inflammatory cytokine production, inhibits NF-κB activation and reduces oxidative stress, thereby limiting tubulo-interstitial fibrosis. GLP-1RAs also improve endothelial function in renal microvasculature, protect podocytes from injury and reduce albuminuria by strengthening the glomerular filtration barrier. GIP’s renal actions appear to intersect with haemodynamic and inflammatory pathways. Experimental models suggest that GIPR activation may influence natriuresis, alter renal vascular tone and interact with sympathetic nervous system output, potentially explaining the small increases in heart rate and variable bloodpressure changes seen during GIP infusion studies. In the context of dual agonism, these renal effects likely integrate with improvements in adipose inflammation, dyslipidaemia and systemic haemodynamics to yield net renoprotection, but more mechanistic work in humans is required. Weight, Appetite and Energy Balance Central control of appetite and energy intake GLP-1 is a key regulator of appetite and energy balance. GLP-1 receptors are expressed in the arcuate nucleus, paraventricular nucleus and nucleus tractus solitarius, where GLP-1signalling modulates orexigenic and anorexigenic neuronal populations. Activation of GLP-1R reduces hunger, enhances satiety and modifies reward valuation of palatable foods, leading to reduced energy intake and healthier food choice. Peripheral GLP-1RAs, although large peptides, reach the brain via circumventricular organs and by activating vagal afferent pathways; chronic administration produces dose-dependent, durable weight loss in people with obesity, often exceeding 15–20% of baseline weight with high-dose preparations. GIP’s role in appetite regulation is more context-dependent. Some early studies suggested that GIP might promote weight gain by stimulating adipose tissue blood flow and triglyceride storage, particularly in overnutrition. However, more recent work shows that chronic, pharmacological GIPR agonism, especially when combined with GLP-1R activation, can enhance anorectic signalling, increase energy expenditure and augment weight loss. In tirzepatide trials, dual GIP/GLP-1 agonism produced significantly greater weight loss than semaglutide at comparable or higher doses, indicating that the net effect of combined receptor stimulation is strongly anti-obesity. Adipose biology and ectopic fat: Adipose tissue is a central site where GIP and GLP-1 exert non-glycaemic actions. GLP-1R activation improves insulin sensitivity in adipocytes, reduces lipolysis and may modestly enhance adiponectin levels, contributing to improvements in systemic insulin sensitivity and lipid profiles. GIP receptors are highly expressed in white adipose tissue, particularly in endothelial cells, macrophages and adipocytes. Chronic GIPR agonism increases adipose tissue blood flow and lipoprotein lipase activity, thereby facilitating uptake and storage of triglyceride-rich lipoproteins into subcutaneous fat depots. In atherosclerosis-prone mice, acyl-GIP therapy increased the proportion of small, insulin-sensitive adipocytes and reduced expression of complement and coagulation genes linked to inflamed, pro-thrombotic adipose tissue, changes associated with lower plasma triglycerides and reduced atherosclerotic lesion burden. These adipose effects are clinically important because ectopic lipid deposition in liver, skeletal muscle and heart is a key driver of insulin resistance, NAFLD/NASH and cardiomyopathy. GLP-1RAs and tirzepatide reduce hepatic fat content measured by MRI-PDFF and improve NASH histology, often with resolution of steatohepatitis and regression of fibrosis in a subset of patients. Dual GIP/GLP-1 agonism may further enhance these effects by improving adipose buffering capacity and more aggressively depleting visceral and ectopic fat depots. Lipid Metabolism and Systemic Inflammation GLP-1 and GIP influence lipid metabolism and inflammatory state in ways that extend beyond changes in body weight. GLP-1RAs reduce fasting triglycerides, post-prandial lipaemia and modestly lower LDL-cholesterol, effects that appear partly mediated by delayed gastric emptying and reduced chylomicron secretion but may also involve direct hepatic actions on de novo lipogenesis and VLDL production. Clinical studies in NAFLD/NASH demonstrate reductions in intrahepatic triglyceride content, inflammatory cell infiltration and stellate-cell activation with GLP-1RA therapy, suggesting a favourable impact on liver-related drivers of cardiovascular and kidney disease. Systemically, GLP1R activation reduces markers of inflammation such as -high sensitivity -Creactive- protein, interleukin-6 and tumour necrosis factor-α in both experimental models and human studies. Mechanistic work shows that GLP1 dampens -NF-κB activation, reduces macrophage infiltration into vascular and renal tissues and may modulate Tcell responses, thereby exerting broad -anti-inflammatory- and antiatherogenic effects. GIP’s immunomodulatory footprint is more complex. Depending on the cellular context and metabolic environment, GIPR signalling in macrophages and T cells can either amplify or restrain inflammation. This duality has stimulated interest in both GIPR agonists and antagonists as potential treatments for obesity, NAFLD and cardiovascular disease, with the ultimate direction likely to depend on the balance between -adipose tissue- remodeling and direct immune cell effects in specific patient populations. Central Nervous System and Neuroprotection: GLP-1 is increasingly recognized as a neuropeptide with important roles in cognition, neuroprotection and mood regulation. GLP-1 receptors are expressed in the hippocampus, cortex and other brain regions involved in learning and memory. In animal models of neurodegeneration, GLP-1R agonists enhance synaptic plasticity, promote neuronal survival, reduce amyloid-β deposition and attenuate tau phosphorylation, collectively suggesting disease-modifying potential in Alzheimer’s disease and related disorders. These preclinical findings motivated large phase-3 trials of GLP-1RAs, including oral semaglutide, in early Alzheimer’s disease. Although the EVOKE and EVOKE+ trials did not demonstrate significant slowing of cognitive decline despite favourable biomarker shifts, they confirm that GLP-1-based therapies engage brain pathways involved in neurodegeneration and may yet find a role in prevention or in mixed vascular-degenerative phenotypes. Beyond cognition, GLP-1 modulates mesolimbic reward circuits, reducing the hedonic drive for palatable foods and possibly influencing addiction pathways and mood. Clinically, some patients receiving GLP-1RAs report improvements in food cravings, emotional eating and quality of life that cannot be fully explained by weight loss alone, suggesting central psychobehavioural effects that contribute to long-term adherence and cardiometabolic benefit. GIP can cross the blood–brain barrier to a limited degree, and GIP receptors are expressed in hypothalamic and brainstem nuclei involved in autonomic and cardiovascular regulation. Human infusion studies report modest increases in heart rate and changes in blood pressure during acute GIP exposure, consistent with direct central or autonomic effects. How these CNS actions integrate with those of GLP1 during chronic dual agonist therapy remains an active area of research, particularly with regard to potential neuroprotective synergy, mood effects and longterm autonomic adaptations. Dual GIP/GLP1 Agonism: Integrated Non-Glycemic Actions Tirzepatide represents the first clinically approved dual GIP/GLP-1 receptor co-agonist and provides a powerful human proof of concept for harnessing the complementary non-glycaemic biology of both hormones. Pharmacologically, tirzepatide is an “imbalanced” agonist with near-native potency at the GIP receptor and somewhat lower affinity for the GLP-1 receptor, yet it produces superior HbA1c lowering and roughly 1.5–2-fold greater weight loss compared with high-dose GLP-1RAs in head-to-head trials like SURPASS-2. Beyond glycaemia, tirzepatide induces larger reductions in blood pressure, triglycerides, hepatic fat content and systemic inflammatory markers than GLP-1RAs alone. Many of these benefits correlate more strongly with weight loss and improvements in body-composition— particularly reductions in visceral and ectopic fat—than with changes in HbA1c. Mechanistic studies suggest that dual GIP/GLP-1 agonism reprogrammes adipose tissue towards a more insulin-sensitive, anti-inflammatory phenotype, enhances mitochondrial function and increases energy expenditure, thereby promoting deeper and more sustained weight loss. In β-cells, tirzepatide appears to restore responsiveness to GIP, which is often blunted in long-standing type 2 diabetes, and enhances insulin secretory capacity and insulin-to-glucagon balance beyond what is observed with GLP-1RAs alone. Although these actions clearly improve glycaemic control, their downstream effects on cardiovascular and renal risk are likely mediated through parallel improvements in adiposity, lipid profiles, inflammation and organ haemodynamics. Ongoing cardiovascular and renal outcome trials are expected to clarify whether dual agonism confers incremental reductions in MACE and kidney events compared with GLP-1RAs, and whether particular patient subgroups—such as those with severe obesity, NAFLD/NASH or high inflammatory burden—derive disproportionate benefit. Conclusion: The accumulated evidence over the past two decades has fundamentally transformed understanding of GLP-1 and GIP from narrow incretin hormones into broad-spectrum regulators of cardiovascular, renal, hepatic, adipose and central-nervous-system physiology. In large cardiovascular outcome trials, long-acting GLP-1RAs consistently reduce major adverse cardiovascular events and cardiovascular mortality, with relative risk reductions of around 20–26% that cannot be fully explained by modest improvements in HbA1c alone. Parallel analyses in chronic kidney disease demonstrate that GLP-1RAs slow eGFR decline, reduce progression to kidney failure and lower albuminuria across a wide range of baseline kidney function, again in a largely glycaemia-independent manner. Mechanistic studies attribute these benefits to an integrated set of non-glycaemic actions, including improved endothelial function, attenuation of oxidative stress, suppression of vascular and renal inflammation, natriuresis and reductions in intraglomerular pressure. Beyond organ protection, GLP-1 and GIP orchestrate powerful effects on appetite, body weight and adipose-tissue quality. GLP-1RAs have emerged as highly effective anti-obesity agents, delivering sustained 10–20% weight loss alongside improvements in blood pressure, lipids, obstructive sleep apnoea and musculoskeletal symptoms. GIP, once considered largely obesogenic, is now recognised as a context-dependent adipose modulator; chronic GIP-receptor activation can rehabilitate white adipose tissue, enhance subcutaneous lipid buffering, reduce visceral and ectopic fat and improve plasma lipid profiles in preclinical models. Both hormones directly impact liver fat, inflammation and fibrogenesis, contributing to improvements in NAFLD and NASH that are increasingly seen as central mediators of cardiovascular and kidney disease. At the level of systemic inflammation and immune regulation, GLP-1 dampens NF-κB signalling, reduces pro-inflammatory cytokines and limits macrophage infiltration in vascular and renal tissues, with consistent reductions in high-sensitivity C-reactive protein observed in clinical studies. GIP’s immunomodulatory effects are more nuanced, but growing evidence indicates that carefully tuned GIP-receptor engagement can support anti-inflammatory, anti-atherogenic adipose remodeling in appropriate metabolic contexts. In the CNS, GLP-1 receptors in hippocampal and cortical regions support synaptic plasticity and neuronal survival, while mesolimbic GLP-1 pathways modulate reward and hedonic eating, contributing to durable behavior change and potential neuroprotection. Dual GIP/GLP-1 agonism with tirzepatide represents the current pinnacle of this evolving field. By simultaneously targeting two complementary incretin pathways, tirzepatide delivers deeper HbA1c reduction, greater weight loss and more pronounced improvements in blood pressure, triglycerides, hepatic fat and inflammatory markers than high-dose GLP-1RAs alone. Mechanistic work suggests that co-activation of GIP and GLP-1 receptors reconfigures adipose tissue, restores GIP responsiveness in β-cells, enhances energy expenditure and exerts more comprehensive effects on organ haemodynamics and inflammation than single-receptor agonism. Ongoing cardiovascular and renal outcome trials will define the full extent of these benefits, but existing evidence strongly indicates that non-glycaemic mechanisms are central to tirzepatide’s therapeutic profile. From a clinical perspective, these insights support reframing GLP-1RAs and dual GIP/GLP-1 agonists as cardio-renal-metabolic and neuroendocrine agents rather than simply glucose-lowering drugs. Guidelines already recommend GLP-1RAs in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease or high cardiovascular risk, independent of baseline HbA1c, and the same logic increasingly applies to patients with obesity, NAFLD/NASH and chronic kidney disease. Future therapeutic strategies are likely to involve multi-agonist combinations—for example GLP-1/GIP/glucagon or GLP-1/GIP/amylin— engineered specifically to exploit complementary non-glycaemic actions on weight, lipids, liver, heart and kidney. Key research priorities include defining the optimal pattern and magnitude of GIP receptor engagement in humans, clarifying the longterm cardiovascular consequences of chronic GIP agonism or antagonism, delineating neurocognitive and mood effects, and understanding how genetic variation in GLP1R and GIPR pathways shapes individual response profiles. As cardio renal metabolic medicine shifts towards organ protective, diseasemodifying approaches, the ability to harness the nonglycemic biology of GLP1 and GIP will be central to designing therapies that not only normalise HbA1c but also prevent heart failure, myocardial infarction, stroke, kidney failure and neurodegeneration across the spectrum of diabetes and obesity. References: 1. Coskun, T. et al. (2022) ‘Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes’, Reviews in Endocrine and Metabolic Disorders, 23(5), pp. 745–762. 2. Gupta, V. et al. (2025) ‘Effects of GLP1 receptor agonists on kidney and cardiovascular disease outcomes: a metaanalysis of randomized trials’, The Lancet Diabetes & Endocrinology, 13(1), pp. 15–28. 3. Kristensen, S.L. et al. (2019) ‘Cardiovascular, mortality, and kidney outcomes with GLP1 receptor agonists in type 2 diabetes: a systematic review and metaanalysis of CVOTs’, The Lancet Diabetes & Endocrinology, 7(10), pp. 776–785. 4. Müller, T.D. et al. (2023) ‘GIP receptor agonism improves dyslipidaemia and atherosclerosis independently of body weight loss in a preclinical mouse model’, Cardiovascular Diabetology, 22, 167. 5. Nørregaard, R. et al. (2024) ‘Updated evidence on cardiovascular and renal effects of GLP1 receptor agonists’, Current Opinion in Nephrology and Hypertension, 33(6), pp. 421–430. 6. Pottegård, A. et al. (2025) ‘Impact of GLP1 receptor agonist–based therapies on cardiovascular and renal outcomes across baseline kidney function groups: a systematic review and metaanalysis’, Clinical Kidney Journal, 17(9), pp. 1923–1936. 7. Sørensen, H.B. et al. (2024) ‘GIP receptor pharmacology in adipose tissue and the cardiovascular system: a review’, Trends in Endocrinology & Metabolism, 35(11), pp. 845–859.

Published

2025-12-15

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Vol. 3 No. 4 (2025): Evolutionary Role of GIP & GLP-1 Beyond Glycaemia Review: non-glycemic role of GIP and GLP1 in current clinical practice

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Articles

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Evolutionary Role of GIP & GLP-1 Beyond Glycaemia Review: non-glycaemic role of GIP and GLP1 in current clinical practice. (2025). Diabzen, 3(4), 111-119. https://www.thediabzen.com/index.php/d/article/view/33

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