Superior metabolic improvement of polycystic ovary syndrome traits after GLP1-based multi-agonist therapy.

Polycystic ovary syndrome (PCOS) is a heterogeneous condition, defined by oligo-/anovulation, hyper-androgenism and/or polycystic ovaries. Metabolic complications are common in patients suffering PCOS, including obesity, insulin resistance and type-2 diabetes, which severely compromise the clinical course of affected women. Yet, therapeutic options remain mostly symptomatic and of limited efficacy for the metabolic and reproductive alterations of PCOS. We report here the hormonal, metabolic and gonadal responses to the glucagon-like peptide-1 (GLP1)-based multi-agonists, GLP1/Estrogen (GLP1/E), GLP1/gastric inhibitory peptide (GLP1/GIP) and GLP1/GIP/Glucagon, in two mouse PCOS models, with variable penetrance of metabolic and reproductive traits, and their comparison with metformin. Our data illustrate the superior efficacy of GLP1/E vs. other multi-agonists and metformin in the management of metabolic complications of PCOS; GLP1/E ameliorates also ovarian cyclicity in an ovulatory model of PCOS, without direct estrogenic uterotrophic effects. In keeping with GLP1-mediated brain targeting, quantitative proteomics reveals changes in common and distinct hypothalamic pathways in response to GLP1/E between the two PCOS models, as basis for differential efficiency. Altogether, our data set the basis for the use of GLP1-based multi-agonists, and particularly GLP1/E, in the personalized management of PCOS.

Glucose-dependent insulinotropic polypeptide (GIP) alleviates ferroptosis in aging-induced brain damage through the Epac/Rap1 signaling pathway.

Glucose-dependent insulinotropic polypeptide (GIP), a 42-aminoacid hormone, exerts multifaceted effects in physiology, most notably in metabolism, obesity, and inflammation. Its significance extends to neuroprotection, promoting neuronal proliferation, maintaining physiological homeostasis, and inhibiting cell death, all of which play a crucial role in the context of neurodegenerative diseases. Through intricate signaling pathways involving its cognate receptor (GIPR), a member of the G protein-coupled receptors, GIP maintains cellular homeostasis and regulates a defense system against ferroptosis, an essential process in aging. Our study, utilizing GIP-overexpressing mice and in vitro cell model, elucidates the pivotal role of GIP in preserving neuronal integrity and combating age-related damage, primarily through the Epac/Rap1 pathway. These findings shed light on the potential of GIP as a therapeutic target for the pathogenesis of ferroptosis in neurodegenerative diseases and aging. [BMB Reports 2024; 57(9): 417-423].

Lead-in calorie restriction enhances the weight-lowering efficacy of incretin hormone-based pharmacotherapies in mice.

OBJECTIVES: The potential benefits of combining lifestyle changes with weight loss pharmacotherapies for obesity treatment are underexplored. Building on recent clinical observations, this study aimed to determine whether "lead-in" calorie restriction before administering clinically approved weight loss medications enhances the maximum achievable weight loss in preclinical models. METHODS: Diet-induced obese mice (DIO) were exposed to 7 or 14 days of calorie restriction before initiating treatment with semaglutide (a glucagon-like peptide-1 receptor (GLP-1R) agonist), tirzepatide (a GLP-1R/glucose insulinotropic peptide receptor (GIPR) co-agonist), or setmelanotide (a melanocortin-4 receptor (MC4R) agonist). Follow-up assessments using indirect calorimetry determined the contributions of energy intake and expenditure linked to consecutive exposure to dieting followed by pharmacotherapy. RESULTS: Calorie restriction prior to treatment with semaglutide or tirzepatide enhanced the weight loss magnitude of both incretin-based therapies in DIO mice, reflected by a reduction in fat mass and linked to reduced energy intake and a less pronounced adaptive drop in energy expenditure. These benefits were not observed with the MC4R agonist, setmelanotide. CONCLUSIONS: Our findings provide compelling evidence that calorie restriction prior to incretin-based therapy enhances the achievable extent of weight loss, as reflected in a weight loss plateau at a lower level compared to that of treatment without prior calorie reduction. This work suggests that more intensive lifestyle interventions should be considered prior to pharmacological treatment, encouraging further exploration and discussion of the current standard of care.

GLP-1, GIP, and Glucagon Agonists for Obesity Treatment: A Hunger Perspective.

For centuries, increasingly sophisticated methods and approaches have been brought to bear to promote weight loss. Second only to the Holy Grail of research on aging, the idea of finding a single and simple way to lose weight has long preoccupied the minds of laymen and scientists alike. The effects of obesity are far-reaching and not to be minimized; the need for more effective treatments is obvious. Is there a single silver bullet that addresses this issue without effort on the part of the individual? The answer to this question has been one of the most elusive and sought-after in modern history. Now and then, a miraculous discovery propagates the illusion that a simple solution is possible. Now there are designer drugs that seem to accomplish the task: we can lose weight without effort using mono, dual, and triple agonists of receptors for glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon. There are, however, fundamental biological principles that raise intriguing questions about these therapies beyond the currently reported side-effects. This perspective reflects upon these issues from the angle of complex goal-oriented behaviors, and systemic and cellular metabolism associated with satiety and hunger.

[A new era for incretins : from GLP-1 receptor agonists to co-agonists and poly-agonists]. / Une nouvelle ère pour les incrétines : des agonistes des récepteurs du GLP-1 aux co-agonistes et poly-agonistes.

Incretin gut hormones, especially glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), raise a huge interest in diabetology. GLP-1 receptor agonists have gained a privileged role in the management of type 2 diabetes (T2D). They improve glucose control without inducing hypoglycaemia, while promoting weight loss. Furthermore, they protect people with T2D against atherosclerotic cardiovascular disease and contribute to reduce the risk of heart failure and chronic kidney disease, two other common complications of T2D. A recent innovation consists in the development of co-agonists that target both GIP and GLP-1 receptors. Whereas the co-infusion of GIP and GLP-1 failed to further reduce hyperglycaemia of T2D compared to GLP-1 single infusion, tirzepatide, an original dual unimolecular biaised GIP/GLP-1 agonist, showed a remarkable improvement of glucose control in the SURPASS programme in patients with T2D. Consequently, it is now commercialized in many countries for the management of T2D. GLP-1/glucagon (GCG) co-agonists and GIP/GLP-1/GCG poly-agonists are currently in development, aiming to benefit from the favourable effects of GCG on energy expenditure and liver lipid metabolism, while mitigating the hyperglycaemic effects of this hormone thanks to balanced effects of GLP-1 and/or GIP. They might occupy in the future an interesting place in the management of obesity and its metabolic complications among which T2D and liver steatosis.

Les hormones digestives à effet incrétine, en particulier le «glucagon-like peptide-1¼ (GLP-1) et le «glucose-dependent insulinotropic polypeptide¼ (GIP) suscitent un intérêt considérable en diabétologie. Les agonistes des récepteurs du GLP-1 ont acquis une place de choix dans la prise en charge des patients avec un diabète de type 2 (DT2). Ils améliorent le contrôle glycémique, sans provoquer des hypoglycémies, tout en faisant perdre du poids. De plus, ils protègent contre les maladies cardiovasculaires athéromateuses. Enfin, ils contribuent à réduire le risque d'insuffisance cardiaque et de maladie rénale chronique, deux autres complications fréquentes du DT2. Une innovation récente consiste dans le développement de co-agonistes ciblant à la fois les récepteurs du GLP-1 et du GIP. Alors que la co-infusion de GIP et de GLP-1 ne réduit pas davantage l'hyperglycémie du DT2 qu'une perfusion isolée de GLP-1, le tirzépatide, un agoniste biaisé unimoléculaire original à effet double sur les récepteurs GIP/GLP-1, a montré une amélioration remarquable du contrôle glycémique, tout en favorisant l'amaigrissement, dans le programme SURPASS chez le patient avec DT2. Ce médicament est maintenant commercialisé dans de nombreux pays. Des co-agonistes GLP-1/glucagon (GCG) et des poly-agonistes GIP/GLP-1/GCG sont actuellement développés, profitant des effets favorables du glucagon sur les dépenses énergétiques et le métabolisme lipidique hépatique, tout en maîtrisant les effets hyperglycémiants de cette hormone grâce aux actions balancées du GLP-1 et/ou du GIP. Ils pourraient occuper à l'avenir une place intéressante dans le traitement de l'obésité et ses complications métaboliques dont le DT2 et la stéatopathie hépatique.

Glucose-Dependent Insulinotropic Polypeptide Inhibits AGE-Induced NADPH Oxidase-Derived Oxidative Stress Generation and Foam Cell Formation in Macrophages Partly via AMPK Activation.

Glucose-dependent insulinotropic polypeptide (GIP) of the incretin group has been shown to exert pleiotropic actions. There is growing evidence that advanced glycation end products (AGEs), senescent macromolecules formed at an accelerated rate under chronic hyperglycemic conditions, play a role in the pathogenesis of atherosclerotic cardiovascular disease in diabetes. However, whether and how GIP could inhibit the AGE-induced foam cell formation of macrophages, an initial step of atherosclerosis remains to be elucidated. In this study, we address these issues. We found that AGEs increased oxidized low-density-lipoprotein uptake into reactive oxygen species (ROS) generation and Cdk5 and CD36 gene expressions in human U937 macrophages, all of which were significantly blocked by [D-Ala2]GIP(1-42) or an inhibitor of NADPH oxidase activity. An inhibitor of AMP-activated protein kinase (AMPK) attenuated all of the beneficial effects of [D-Ala2]GIP(1-42) on AGE-exposed U937 macrophages, whereas an activator of AMPK mimicked the effects of [D-Ala2]GIP(1-42) on foam cell formation, ROS generation, and Cdk5 and CD36 gene expressions in macrophages. The present study suggests that [D-Ala2]GIP(1-42) could inhibit the AGE-RAGE-induced, NADPH oxidase-derived oxidative stress generation in U937 macrophages via AMPK activation and subsequently suppress macrophage foam cell formation by reducing the Cdk5-CD36 pathway.

Achieving normoglycaemia with tirzepatide: Post hoc exploratory analysis of the SURPASS J-mono and J-combo studies.

AIM: Normoglycaemia was achieved in a significant proportion of Japanese participants with type 2 diabetes in two phase 3 studies of tirzepatide. This post hoc exploratory analysis aimed to identify predictive factors associated with normoglycaemia achievement. MATERIALS AND METHODS: SURPASS J-mono and SURPASS J-combo study data were pooled for this analysis. Characteristics of participants in whom normoglycaemia [glycated haemoglobin (HbA1c) <5.7%] was achieved were summarized. Logistic regression analyses were performed with HbA1c <5.7% achievement as the target variable. RESULTS: Of 912 participants, normoglycaemia was achieved in 553 (60.6%) following 52 weeks of tirzepatide treatment. Overall, the mean (SD) age was 56.7 (10.6) years and mean diabetes duration was 7.7 (6.0) years, and 76% of participants were men. Mean (SD) change from baseline in HbA1c and bodyweight was -2.87% (0.95) versus -2.47% (1.1) and -10.30 (5.8) kg versus -3.75 (4.3) kg for participants in whom normoglycaemia was and was not reached, respectively. Multivariate regression analyses showed that lower baseline body mass index, shorter disease duration and lower baseline HbA1c were significantly associated with higher rates of normoglycaemia achievement (p = 0.009, p = 0.008, p < 0.001, respectively) as was a tirzepatide dose of 10 or 15 mg compared with 5 mg (p < 0.001). The highest percentage of participants in whom normoglycaemia (94%) was achieved were those with lower baseline HbA1c (<8%) and the greatest weight reduction (≥15%). CONCLUSIONS: Baseline HbA1c and body mass index, disease duration and the tirzepatide treatment group were shown to be predictive factors for achieving normoglycaemia. A lower baseline HbA1c was most strongly associated with normoglycaemia achievement.

Anti-Obesity Medications in Patients With Heart Failure: Current Evidence and Practical Guidance.

Obesity is a significant risk factor for heart failure (HF) development, particularly HF with preserved ejection fraction and as a result, many patients with HF also have obesity. There is growing clinical interest in optimizing strategies for the management of obesity in patients with HF across the spectrums of both ejection fraction and disease severity. The emergence of anti-obesity medications with cardiovascular outcomes benefits, principally glucagon-like peptide-1 receptor agonists, has made it possible to study the impact of anti-obesity medications for patients with baseline cardiovascular conditions, including HF. However, clinical trials data supporting the safety and efficacy of treating obesity in patients with HF is currently limited to patients with HF with preserved ejection fraction, but do confirm safety and weight loss efficacy in this patient population as well as improvements in HF functional status, biomarkers of inflammation and HF stability. Here, we review the current data available surrounding the management of obesity for patients with HF, including the limitations of this evidence and ongoing areas for investigation, summarize the next phase of emerging anti-obesity medications and provide practical clinical advice for the multidisciplinary management of patients with both HF and obesity.

The dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist tirzepatide effects on body weight evolution, adiponectin, insulin and leptin levels in the combination of obesity, type 2 diabetes and menopause in mice.

AIM: Tirzepatide (Tzp), a novel dual agonist glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1, is approved for treating insulin resistance and obesity, and menopausal women consuming a high-calorie diet are a target to study the Tzp effect. Therefore, we aimed to allometrically scale body weight (BW) in Tzp-treated obese diabetic menopausal mice. MATERIALS AND METHODS: Three-month-old C57BL/6 female mice had bilateral ovariectomy (Ovx) or a sham procedure and for 12 weeks were fed a control diet or a high-fat and high sucrose diet (n = 120/each group [control (C), obese diabetic (Od), Ovx (O), sham (S), Tzp (T)]). Tzp was subcutaneously administered (10 nmol/kg) or vehicle once a day for an additional 4 weeks. The analysis considered log-transformed data and the allometric equation log y = log a + b log x. RESULTS: Od and OdO showed more upward slopes than C and CO. In C, BW was non-allometric by T administration. Od and OdO showed slightly positive slopes (more prominent in OdO than Od). OdT and OdOT showed negative slopes, significant intercepts, and more robust Pearson coefficients than untreated ones. A potent drug effect was seen with BW allometric decline. Interactions between diet versus Ovx and diet versus Tzp affected weight gain. Diet versus Ovx versus Tzp affected food intake. CONCLUSIONS: A model was developed to show three usual factors observed in mature women. Notably, Tzp improved the metabolism and weight loss of OdO mice. Tzp-treated mice showed negative allometric BW across treatment time, which is a quantitative assessment that allows better comparison between results.

Gut-derived appetite hormones do not explain energy intake differences in humans following low-carbohydrate versus low-fat diets.

OBJECTIVE: The objective of this study was to explore how dietary macronutrient composition influences postprandial appetite hormone responses and subsequent energy intake. METHODS: A total of 20 adults (mean [SEM], age 30 [1] years, BMI 27.8 [1.3] kg/m2, n = 8 with normal weight, n = 6 with overweight, n = 6 with obesity) consumed a low-fat (LF) diet (10% fat, 75% carbohydrate) and a low-carbohydrate (LC) diet (10% carbohydrate, 75% fat) for 2 weeks each in an inpatient randomized crossover design. At the end of each diet, participants consumed isocaloric macronutrient-representative breakfast test meals, and 6-h postprandial responses were measured. Ad libitum energy intake was measured for the rest of the day. RESULTS: The LC meal resulted in greater mean postprandial plasma active glucagon-like peptide-1 (GLP-1; LC: 6.44 [0.78] pg/mL, LF: 2.46 [0.26] pg/mL; p < 0.0001), total glucose-dependent insulinotropic polypeptide (GIP; LC: 578 [60] pg/mL, LF: 319 [37] pg/mL; p = 0.0004), and peptide YY (PYY; LC: 65.6 [5.6] pg/mL, LF: 50.7 [3.8] pg/mL; p = 0.02), whereas total ghrelin (LC: 184 [25] pg/mL, LF: 261 [47] pg/mL; p = 0.0009), active ghrelin (LC: 91 [9] pg/mL, LF: 232 [28] pg/mL; p < 0.0001), and leptin (LC: 26.9 [6.5] ng/mL, LF: 35.2 [7.5] ng/mL; p = 0.01) were lower compared with LF. Participants ate more during LC at lunch (244 [85] kcal; p = 0.01) and dinner (193 [86] kcal; p = 0.04), increasing total subsequent energy intake for the day compared with LF (551 [103] kcal; p < 0.0001). CONCLUSIONS: In the short term, endogenous gut-derived appetite hormones do not necessarily determine ad libitum energy intake.

Adipose Tissue: A Novel Target of the Incretin Axis? A Paradigm Shift in Obesity-Linked Insulin Resistance.

Adipose tissue (AT) represents a plastic organ that can undergo significant remodeling in response to metabolic demands. With its numerous checkpoints, the incretin system seems to play a significant role in controlling glucose homeostasis and energy balance. The importance of the incretin hormones, namely the glucagon-like peptide-1 (GLP-1) and the glucose-dependent insulinotropic peptide (GIP), in controlling the function of adipose cells has been brought to light by recent studies. Notably, a "paradigm shift" in reevaluating the role of the incretin system in AT as a potential target to treat obesity-linked metabolic disorders resulted from the demonstration that a disruption of the GIP and GLP-1 signaling axis in fat is associated with adiposity-induced insulin-resistance (IR) and/or type 2 diabetes mellitus (T2D). We will briefly discuss the (patho)physiological functions of GLP-1 and GIP signaling in AT in this review, emphasizing their potential impacts on lipid storage, adipogenesis, glucose metabolism and inflammation. We will also address the conundrum with the perturbation of the incretin axis in white or brown fat tissue and the emergence of metabolic disorders. In order to reduce or avoid adiposity-related metabolic complications, we will finally go over a potential scientific rationale for suggesting AT as a novel target for GLP-1 and GIP receptor agonists and co-agonists.

Potassium voltage-gated channel subfamily H member 2 (KCNH2) is a promising target for incretin secretagogue therapies.

Derived from enteroendocrine cells (EECs), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are pivotal incretin hormones crucial for blood glucose regulation. Medications of GLP-1 analogs and GLP-1 receptor activators are extensively used in the treatment of type 2 diabetes (T2D) and obesity. However, there are currently no agents to stimulate endogenous incretin secretion. Here, we find the pivotal role of KCNH2 potassium channels in the regulation of incretin secretion. Co-localization of KCNH2 with incretin-secreting EECs in the intestinal epithelium of rodents highlights its significance. Gut epithelial cell-specific KCNH2 knockout in mice improves glucose tolerance and increases oral glucose-triggered GLP-1 and GIP secretion, particularly GIP. Furthermore, KCNH2-deficient primary intestinal epithelial cells exhibit heightened incretin, especially GIP secretion upon nutrient stimulation. Mechanistically, KCNH2 knockdown in EECs leads to reduced K+ currents, prolonged action potential duration, and elevated intracellular calcium levels. Finally, we found that dofetilide, a KCNH2-specific inhibitor, could promote incretin secretion in enteroendocrine STC-1 cells in vitro and in hyperglycemic mice in vivo. These findings elucidate, for the first time, the mechanism and application of KCNH2 in regulating incretin secretion by EECs. Given the therapeutic promise of GLP-1 and GIP in diabetes and obesity management, this study advances our understanding of incretin regulation, paving the way for potential incretin secretagogue therapies in the treatment of diabetes and obesity.

Clinical Outcomes of Tirzepatide or GLP-1 Receptor Agonists in Individuals With Type 2 Diabetes.

Importance: Despite its demonstrated benefits in improving cardiovascular risk profiles, the association of tirzepatide with mortality and cardiovascular and kidney outcomes compared with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) remains unknown. Objective: To investigate the association of tirzepatide with mortality and adverse cardiovascular and kidney outcomes compared with GLP-1 RAs in patients with type 2 diabetes. Design, Setting, and Participants: This retrospective cohort study used US Collaborative Network of TriNetX data collected on individuals with type 2 diabetes aged 18 years or older initiating tirzepatide or GLP-1 RA between June 1, 2022, and June 30, 2023; without stage 5 chronic kidney disease or kidney failure at baseline; and without myocardial infarction or ischemic or hemorrhagic stroke within 60 days of drug initiation. Exposures: Treatment with tirzepatide compared with GLP-1 RA. Main Outcomes and Measures: The primary outcome was all-cause mortality, and secondary outcomes included major adverse cardiovascular events (MACEs), the composite of MACEs and all-cause mortality, kidney events, acute kidney injury, and major adverse kidney events. All outcomes were analyzed using Cox proportional hazards regression models. Results: There were 14 834 patients treated with tirzepatide (mean [SD] age, 55.4 [11.8] years; 8444 [56.9%] female) and 125 474 treated with GLP-1 RA (mean [SD] age, 58.1 [13.3] years; 67 474 [53.8%] female). After a median (IQR) follow-up of 10.5 (5.2-15.7) months, 95 patients (0.6%) in the tirzepatide group and 166 (1.1%) in the GLP-1 RA group died. Tirzepatide treatment was associated with lower hazards of all-cause mortality (adjusted hazard ratio [AHR], 0.58; 95% CI, 0.45-0.75), MACEs (AHR, 0.80; 95% CI, 0.71-0.91), the composite of MACEs and all-cause mortality (AHR, 0.76; 95% CI, 0.68-0.84), kidney events (AHR, 0.52; 95% CI, 0.37-0.73), acute kidney injury (AHR, 0.78; 95% CI, 0.70-0.88), and major adverse kidney events (AHR, 0.54; 95% CI, 0.44-0.67). Treatment with tirzepatide was associated with greater decreases in glycated hemoglobin (treatment difference, -0.34 percentage points; 95% CI, -0.44 to -0.24 percentage points) and body weight (treatment difference, -2.9 kg, 95% CI, -4.8 to -1.1 kg) compared with GLP-1 RA. An interaction test for subgroup analysis revealed consistent results stratified by estimated glomerular filtration rate, glycated hemoglobin level, body mass index, comedications, and comorbidities. Conclusions and Relevance: In this study, treatment with tirzepatide was associated with lower hazards of all-cause mortality, adverse cardiovascular events, acute kidney injury, and adverse kidney events compared with GLP-1 RA in patients with type 2 diabetes. These findings support the integration of tirzepatide into therapeutic strategies for this population.

Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic ß-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.

Incretin-mediated control of cardiac energy metabolism.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) are incretin hormones that stimulate insulin secretion and improve glycemic control in individuals with type 2 diabetes (T2D). Data from several cardiovascular outcome trials for GLP-1 receptor (GLP-1R) agonists have demonstrated significant reductions in the occurrence of major adverse cardiovascular events in individuals with T2D. Although the cardiovascular actions attributed to GLP-1R agonism have been extensively studied, little is known regarding the cardiovascular consequences attributed to GIP receptor (GIPR) agonism. As there is now an increasing focus on the development of incretin-based co-agonist therapies that activate both the GLP-1R and GIPR, it is imperative that we understand the mechanism(s) through which these incretins impact cardiovascular function. This is especially important considering that cardiovascular disease represents the leading cause of death in individuals with T2D. With increasing evidence that perturbations in cardiac energy metabolism are a major contributor to the pathology of diabetes-related cardiovascular disease, this may represent a key component through which GLP-1R and GIPR agonism influence cardiovascular outcomes. Not only do GIP and GLP-1 increase the secretion of insulin, they may also modify glucagon secretion, both of which have potent actions on cardiac substrate utilization. Herein we will discuss the potential direct and indirect actions through which GLP-1R and GIPR agonism impact cardiac energy metabolism while interrogating the evidence to support whether such actions may account for incretin-mediated cardioprotection in T2D.