Impact of Incretin analogues on lipid and lipoprotein metabolism in obesity and diabetes

Incretin-based therapies are gaining momentum as a key strategy for reducing cardiovascular risk in individuals with obesity and/or type 2 diabetes (T2D). As therapeutic approaches extend beyond classical GLP-1 agonism, it remains unclear whether the cardiovascular benefits primarily reflect direct reductions in atherogenic lipoproteins—namely LDL, VLDL, and triglycerides—or broader effects mediated by weight loss, improved insulin sensitivity, and reduced ectopic adiposity. This review examines these relationships in depth. We summarize molecular, cellular, and physiological evidence describing how GLP-1, GIP, glucagon, and amylin signaling regulate intestinal lipid absorption, hepatic apoB-lipoprotein assembly, and peripheral lipoprotein catabolism. These mechanistic insights are integrated with available clinical data on single, dual, and triple incretin-based agonists and related compounds. Overall, incretin-based therapies predominantly reduce triglycerides and VLDL cholesterol, with these changes closely linked to reductions in hepatic ectopic adiposity and paralleling improvements in glycemic control, insulin sensitivity, and body weight. Agents that additionally activate glucagon or amylin pathways consistently produce greater lipid-lowering effects, supporting the concept that lipid benefits scale with global metabolic reprogramming rather than isolated receptor activation. Despite consistent lipid improvements, the short duration of most clinical trials limits assessment of long-term cardiovascular risk reduction. Moreover, the absence of apolipoprotein B data precludes definitive conclusions regarding changes in atherogenic lipoprotein burden. Uncertainty also remains regarding the preservation of lean mass during substantial weight loss. This review provides an up-to-date synthesis linking incretin pharmacology to lipid metabolism and identifies priorities for future cardiometabolic research. Impact of Incretin analogues on lipid and lipoprotein metabolism in obesity and diabetes Baragetti A 1, Norata GD 1 Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, Milan, Italy Correspondence to: Prof. Giuseppe Danilo Norata, PhD Department of Pharmacological Sciences “Rodolfo Paoletti”, University of Milan 3rd floor Via G. Balzaretti, 9, 20133, Milan, Italy Phone: +39 02503184313 Email: [email protected] or Prof. Andrea Baragetti, PhD Department of Pharmacological Sciences “Rodolfo Paoletti”, University of Milan 3rd floor Via G. Balzaretti, 9, 20133, Milan, Italy Phone: +39 0250318401 Email: [email protected]

Incretins; lipid metabolism; cardiovascular risk Wordcount: 7,650

Incretin-based therapies are gaining momentum as a key strategy for reducing cardiovascular risk in individuals with obesity and/or type 2 diabetes (T2D). As therapeutic approaches extend beyond classical GLP-1 agonism, it remains unclear whether the cardiovascular benefits primarily reflect direct reductions in atherogenic lipoproteins—namely LDL, VLDL, and triglycerides—or broader effects mediated by weight loss, improved insulin sensitivity, and reduced ectopic adiposity. This review examines these relationships in depth. We summarize molecular, cellular, and physiological evidence describing how GLP-1, GIP, glucagon, and amylin signaling regulate intestinal lipid absorption, hepatic apoB-lipoprotein assembly, and peripheral lipoprotein catabolism. These mechanistic insights are integrated with available clinical data on single, dual, and triple incretin-based agonists and related compounds. Overall, incretin-based therapies predominantly reduce triglycerides and VLDL cholesterol, with these changes closely linked to reductions in hepatic ectopic adiposity and paralleling improvements in glycemic control, insulin sensitivity, and body weight. Agents that additionally activate glucagon or amylin pathways consistently produce greater lipid-lowering effects, supporting the concept that lipid benefits scale with global metabolic reprogramming rather than isolated receptor activation. Despite consistent lipid improvements, the short duration of most clinical trials limits assessment of long-term cardiovascular risk reduction. Moreover, the absence of apolipoprotein B data precludes definitive conclusions regarding changes in atherogenic lipoprotein burden. Uncertainty also remains regarding the preservation of lean mass during substantial weight loss. This review provides an up-to-date synthesis linking incretin pharmacology to lipid metabolism and identifies priorities for future cardiometabolic research. ApoB-containing lipoproteins, Incretins, and the residual cardiovascular risk of obesity and in diabetes Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in patients with obesity and type 2 diabetes (T2D). In patients affected by these pathologies, the dysregulation of lipid and lipoprotein metabolism represents a dominant and causative mechanism underlying this excess risk. Central to atherogenesis are the hepatic overproduction and the delayed peripheral catabolism of the apolipoprotein B (apoB)–containing lipoproteins(Romeo et al., 2025). These include the spectrum of very low-density lipoproteins (VLDL), their remnants (generated through peripheral lipase–mediated hydrolysis of VLDL triglycerides), and low-density lipoproteins (LDL). Although LDL is the principal target of contemporary strategies to reduce CVD risk because of its cholesterol content, VLDL and the other apoB-containing remnants are intrinsically atherogenic as well. This is not attributable to their triglyceride content, but rather to the fact that each particle carries a substantial cholesterol load—generally greater than that of LDL—and, despite its larger diameter, remains capable of infiltrating and accumulating within the arterial wall(Norata et al., 2007; Baragetti, 2022). In metabolically unhealthy obesity and T2D, the hepatic intracellular lipid accumulation results into insulin resistance which, in turn, disrupts the tightly coordinated Golgi–endoplasmic reticulum (ER) hepatic machinery and accelerates the secretion of the microsomal triglyceride transfer protein (MTP)–dependent apoB100 lipidation and secretion. As a result, this leads to excessive secretion of cholesterol-enriched, VLDL, a phenotypic trait unique of the diabetic dyslipidemia that aggravates the residual cardiovascular risk factor in patients treated with glucose-lowering therapies (Romeo et al., 2025). Within this pathophysiological framework, incretin signaling—mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)—has emerged as a key axis linking nutrient sensing to lipid handling. Indeed, beyond its canonical role in nutrient-stimulated insulin secretion, incretin signaling influences intestinal lipid absorption, hepatic lipoprotein assembly, and peripheral lipoprotein clearance, thus playing a key role in apoB-lipoprotein homeostasis ( Figure 1 ). In the gastrointestinal tract, nutrients stimulate the release of GLP-1 from the enterochromaffin L-cells (located in the distal gut) and GIP from the K-cells (located in the upper gut). More specifically, GIP secretion is rapidly induced by carbohydrate absorption via SGLT1 and K-ATP channel modulation (Gorboulev et al., 2012), whereas GLP-1 release is preferentially stimulated by the binding of long-chain fatty acids to FFAR1/FFAR4 receptors (Hirasawa et al., 2005). In pancreatic β-cells, both incretins activate Gαs–adenylate cyclase signaling, increase cAMP, PKA, and Epac2 activity to potentiate glucose-dependent insulin secretion (Light et al., 2002). GLP-1 additionally suppresses glucagon secretion in α-cell via direct binding to GLP-1 receptor (GLP-1R) and somatostatin-mediated inhibition of the voltage-dependent calcium channels (Ramracheya et al., 2018).In contrast GIP stimulates α-cells under low or normal glycemia and promotes glucagon releases a feedback mechanism(El and Campbell, 2020) ( Figure 1 ). Incretin pathways also intersect glucagon receptor (GCGR) signaling, with evidence for functional crosstalk that influences glucose and lipid metabolism (Wicik et al., 2025). Moreover, amylin, co-secreted with insulin by pancreatic beta cells and acting in the brain through three receptors (AMY 1-3; composed of a calcitonin core receptor (CTR) and associated receptor-activity modifying proteins (RAMPs) 1-3), complements GLP-1 action (Coester et al., 2020). Indeed, amylin restrains postprandial glucagon and modulates gastric emptying and satiety. GLP-1 enhances amylin secretion, reinforcing this integrated regulatory network (Volčanšek et al., 2025)( Figure 1 ). In obesity and T2D, the blunted incretin effect, due to impaired GLP-1R and GIPR responsiveness in β-cells, results into α-cell hyperresponsiveness, and this collectively contributes to the disturbed islet hormone dynamics characteristic of metabolic disease. The control of lipid metabolism by incretins Incretin hormones contribute to lipid handling and the production and clearance of apoB-containing lipoproteins across the intestine, liver, and peripheral tissues, acting in close integration with insulin, glucagon, and amylin signaling (Hoffman and Adeli, 2024). In addition to ectopic adiposity and insulin resistance, also incretin “resistance”, a condition where pancreatic beta cells fail to respond adequately to incretin hormones, profoundly alters insulin–glucagon crosstalk and downstream cAMP-dependent signaling contribute to the development of diabetic/obesogenic dyslipidemia. Intestinal regulation of lipid and lipoprotein metabolism by incretins. Dietary triglycerides undergo enzymatic hydrolysis within the intestinal lumen, generating absorbable lipid species that cross the epithelial barrier through mechanisms involving multiple transporters and lipid-binding proteins, such as CD36 and FABP5, or dietary sterol binding proteins (NPC1L1). Within the endoplasmic reticulum of enterocytes, monoacylglycerols and long-chain fatty acids are re-esterified by via MTP, MGAT2 and DGAT1, assembled into apoB48-containing chylomicrons, and subsequently secreted from the basolateral surface. FFAR1 and FFAR4 are localized at the basolateral membrane of enterochromaffin cells and are thought to sense long-chain fatty acids present in the interstitial environment of the lymphatics, following the hydrolysis of triglycerides derived from chylomicrons (Gribble and Reimann, 2019) ( Figure 1 ). GLP1, once released by L-cells via the cellular influx of calcium mediated by voltage-dependent channels that are opened by the activation of the cAMP and PLC/IP 3 pathways (Ables et al., 2012), lowers the postprandial plasma levels of ApoB48, by either reducing chylomicrons secretion(Hsieh et al., 2010) or delaying the gastric emptying (Dash et al., 2015). The potential impact of GIP on enteral chylomicron secretion is counterintuitive. GIP administration in dogs reduces chylomicron concentration by promoting their peripheral catabolism (Wasada et al., 1981), other observations propose that GIP may enhance enterocyte lipoprotein synthesis, via cAMP–PI3K signaling and inducing MTP and DGAT1 activity (Coon et al., 2015; Lyons et al., 2025). While the net effect of GLP1 and GIP on chylomicron secretion is not clear (Dash et al., 2015), the field is further complicated by the observation that GLP-2, which shares approximately 35–40% sequence identity with GLP-1, promotes intestinal fat absorption and chylomicron assembly in a CD36-dependent manner (Hsieh et al., 2009). This effect was appreciated after an equimolar co-administration of GLP-1 and GLP-2 following an intragastric gavage (Hein et al., 2013). Amylin has an indirect impact on chylomicrons production/secretion by affecting eating behavior and promoting an anorectic effect on the long-term (Lutz et al., 1998; Potes et al., 2010; Züger et al., 2013; Boyle et al., 2018). The activity of amylin on the brain-gut axis complements that of incretins on nutrients absorption which is still a topic of intensive investigation (Hoffman and Adeli, 2024) ( Figure 1 ). Interestingly specific brain-gut axis pathways that innervate L-cells have been described to promote further release of GLP-1 postprandially (Farr et al., 2015). Additionally, a central crosstalk between GLP-1 and glucagon receptor signaling reduces intestinal lipid absorption via parasympathetic signaling (Patel et al., 2018). Hepatic regulation of lipid and lipoprotein metabolism by incretins. Incretins can modulate hepatic lipid and lipoprotein metabolism at multiple level, either by regulating lipogenesis, cholesterol biosynthesis and lipoprotein secretion, or interfering with entero-hepatic bile acids recycling. Although GLP-1 should reasonably promote lipogenesis, by virtue of its main insulinotropic action in the pancreas, sparse information indicates that it vice versa attenuates this pathway in the liver. Yet, GLP-1 may either increase the phosphorylation of cAMP-activated protein kinase (AMPK) (Ben-Shlomo et al., 2011), or indirectly promote the activity of proliferator-activated receptorα (PPARα), through the promotion of the protein kinase A (PKA), thus suppressing the Sterol regulatory element-binding protein1c (SREBP-1c)–dependent lipogenesis (Sugden and Holness, 2004), or, by promoting mitochondrial oxidative metabolism, jointly with the hepatic activity of glucagon(Boland et al., 2020). Anyhow, deciphering if a direct impact of GLP-1 on lipogenesis exists, and stands beyond its overall impact on body weight reduction is complicated. It should be noted that also the activation of central GLP-1R, following intracerebroventricular delivery of GLP-1 during insulin euglycemic clamp, favored the suppression of hepatic gluconeogenesis by insulin and resulted in lower hepatic fat content(Burmeister et al., 2012). The impact of GIP on hepatic lipogenesis is more complex to elucidate; Yet, GIP is expected to reduce lipogenesis, given its impact on the pancreatic secretion of glucagon that, in turn, reduces lipogenesis, promote fatty acids oxidation (through inactivation of key enzymes like acetyl-CoA carboxylase (ACC)) and limits apoB lipidation (Galsgaard et al., 2019) ( Figure 1 ). However, GIP agonist did not limit the development of hepatic steatosis, nor reduced the expression of SREBP-1c and other genes involved in the hepatic uptake of fatty acids (CD36), fatty acids synthesis (FASN) and in lipid metabolism (DGAT1, ACACA, PPARα) in a humanized model for diabetic dyslipidemia and NAFLD (APOE∗3-Leiden.CETP mice) (Ying et al., 2023). By contrast, the expression of the genes above and of hepatic steatosis was reduced by treating APOE∗3-Leiden.CETP mice with GLP-1 and with dual GLP-1+GIP agonists, suggesting a more relevant effect of GLP-1 signaling in hepatic lipid handling. This observation may reflect the hypothesis that continuous activation of GIP in obesity, while altering the balance between lipid storage/mobilization in the adipose tissue (Getty-Kaushik et al., 2006), it impacts the development of liver steatosis on the long-term, by interfering in the oxidative metabolism of hepatic ectopic adipose depots (Thondam et al., 2020). Glucagon signaling intersects this network, by promoting hepatic fatty acid oxidation and by modulating the hepatic secretion of VLDL through GCGR–cAMP pathways (Guettet et al., 1988; Longuet et al., 2008a; Galsgaard et al., 2019). Amylin indirectly influences hepatic lipid handling through central regulation of satiety and glucagon suppression (Volčanšek et al., 2025). The fraction of apoB100 containing lipoproteins produced by the liver predominates by two to six hours over the postprandial state, determining the largest peripheral mobilization of triglycerides and cholesterol (Baragetti, 2022). GLP-1 mimetics reduced, while GIP mimetics increased, plasma triglycerides levels two hours after an intragastric administration of fats together with the injection of inhibitors of peripheral lipases (Hsieh et al., 2010), suggesting that GLP-1 signaling could modulate hepatic lipoprotein secretion. Whether this effect results in an upregulation of key players involved in apoB degradation (e.g. ubiquitination), or in reducing its lipidation and secretion through the Golgi–endoplasmic reticulum (ER) system, is plausible but not sufficiently described to date. In the liver, GLP-1enhances PI3K–Akt–mediated apoB100 ubiquitination through sortilin–FBXO2 pathways (Bu et al., 2024) ( Figure 1 ). In APOE∗3-Leiden.CETP mice, nor single, neither dual GLP-1+GIP agonist impacted hepatic gene expression of MTP and APOB, while only the dual agonism resulted into increased expression of HMG-CoA reductase, a key enzyme involved in cholesterol biosynthesis (Ying et al., 2023). Moreover GLP-1 could promote hepatic LDL receptor expression, by suppressing PCSK9 activity (Yang et al., 2018), with the consequent hepatic uptake of apoB containing residual lipoproteins (so called as “remnants”(Chait et al., 2020)), could reduce cholesterol synthesis and limit hepatic cholesterol accumulation ( Figure 1 ). At the same time, GLP-1 signaling can also directly modulate hepatic cholesterol handling and reverse cholesterol transport. In hepatocytes, GLP-1 enhances intracellular cholesterol efflux by activating liver X receptor α (LXRα)–dependent pathways (Li et al., 2021) and by inducing ATP-binding cassette transporter A1 (ABCA1) expression (Yao et al., 2018) through Ca²⁺/calmodulin-dependent kinase signaling, thereby promoting apolipoprotein A-I synthesis and secretion ( Figure 1 ). Notably, the increased expression of HMG-CoA reductase in the APOE∗3-Leiden.CETP mice also coupled with increased expression of Cyp7b1 oxysterol 7-alpha-hydroxylase, a crucial enzyme for breaking down cholesterol and divert it into bile acids in the liver(Ying et al., 2023). This observation supports the concept that GLP-1 acts as a key player within the entero-hepatic system of cholesterol re-cycling. Indeed, while TGR5 signaling critically regulates the secretion of GLP-1(Thomas et al., 2009), suggesting a bile acid sensing controls glucose homeostasis, GLP-1 itself is also actively involved in the FXR/FGF15/FGFR4/CYP7A1 hepato–enteral pathway, modulating bile acid–responsive gene expression (Bozadjieva-Kramer et al., 2024) ( Figure 1 ). Whether this results in increased cholesterol catabolism through bile acids transport is still not fully clear. Liraglutide has shown to attenuate negative feedback inhibition of bile acids by inhibiting intestinal FXR activity and ultimately reducing bile acid synthesis in the liver (Zhang et al., 2021). On the other hand, it has been also shown that the GLP-1/FXR interaction (Trabelsi et al., 2015) is mediated by the thyroid receptor β (THRβ) signaling, which downstream impacts the incretin activity (Yan et al., 2022). Indeed, the activation of T4 thyroid hormone via DIO2 promotes the generation of T3 which by binding THRβ inhibits lipogenesis and lipoprotein assembly and promotes FXR activity ( Figure 1 ). FXR therefore participate to an entero-hepatic feedback loop regulating bile acids secretion and enhancing GLP-1 production in the intestine, thus potentiating the insulinotropic effect and the inhibition of chylomicron secretion (Yan et al., 2022) ( Figure 1 ). This FXR–thyroid hormone axis provides a metabolic feedback loop linking bile acid flux to incretin secretion and hepatic lipid handling. In insulin resistant conditions, impaired AMPK and Akt signaling weaken both incretin and FXR-dependent control, thus stabilizing apoB100, sustaining MTP activity, and driving VLDL overproduction. Through these coordinated actions, incretin signaling contributes to the integration of hepatic cholesterol efflux, bile acid metabolism, and lipoprotein homeostasis. Incretin signaling in the peripheral catabolism of apoB-containing lipoproteins and remnants In diabetic dyslipidemia, catabolism of apoB-containing lipoproteins is impaired due to defective lipoprotein lipase–mediated triglyceride hydrolysis in adipose and skeletal muscle capillaries. As a result, long-lived apoB particles accumulate and undergo progressive triglyceride depletion and size reduction relative to their liver derived VLDL precursors, becoming cholesterol-enriched remnants with enhanced arterial wall penetration, prolonged retention, and increased propensity to promote atherogenesis (Chait et al., 2020; Baragetti, 2022). On the long-term, this chronic lipid flux promotes adipocyte hypertrophy, attenuates LPL responsiveness and impairs the clearance of remnant particles (Romeo et al., 2025). There is evidence regarding the role of GLP-1 as a regulator of adipogenesis, an effect achieved in part through activation of ERK, PKC, and AKT signaling pathways both in 3T3-L1 pre-adipocytes incubated in vitro and in visceral adipose tissue explanted from mice treated with liraglutide (Challa et al., 2012), brown adipose tissue thermogenesis and browning, via the activation of AMPK(Beiroa et al., 2014). While these effects are likely driven predominantly by the systemic fraction of GLP-1, there is also evidence that the GLP-1 interaction on its receptors localized in the brain can interfere in adipose tissue remodeling (Lockie et al., 2012; Kooijman et al., 2015). Also, GIP facilitates triglyceride storage by upregulating LPL, via PI3K/PKB/AMPK-dependent CREB/TORC2 activation (Kim et al., 2010). Glucagon vice versa inhibits adipogenesis, by activating AMPK, which phosphorylates Acetyl-CoA carboxylase 1 (ACC1), that ultimately reduces fatty acid synthesis (Peng et al., 2012). Anyhow, the regulation of glucagon is critically interconnected with the PPARs system. Yet, in the liver the activation of the glucagon receptor promotes the activity of PPARα, that in turn favors the flux of fats storage to the mitochondria for energetic utilization (Longuet et al., 2008b). By contrast, the activity of glucagon in extra-hepatic sites of energetic storage is countereacted by PPARγ, that promotes adipogenesis (Schinner et al., 2002); this response can be indirectly supported by PPARδ activation, that promotes fatty acids uptake by adipose tissue and oxidation in skeletal muscle (de Lange et al., 2008). Additionally, amylin impacts systemic energetic handling (Lutz, 2012) and, although the mechanisms are not well characterized, it is possible that amylin counteracts weight gain, promotes the sensitization of leptin and increases energy expenditure, via the activation of specific brain circuits (Meek et al., 2013) ( Figure 1 ). Effects of incretin analogues on plasma lipids and lipoproteins: evidence from clinical trials Incretin-based therapies are rapidly surpassing the efficacy of traditional glucose-lowering agents and, for the first time, are providing a pharmacological solution capable of inducing clinically meaningful and sustained weight loss. What began as a therapeutic approach centered on enhancing endogenous incretin physiology has evolved into a diverse pipeline of peptide and non-peptide molecules that target complementary metabolic pathways with unprecedented potency. The earliest class comprises the single GLP-1 receptor peptide agonists—such as liraglutide, semaglutide (administered subcutaneously or orally), dulaglutide, exenatide, and efpeglenatide—which stimulate glucose-dependent insulin secretion, suppress inappropriate glucagon release, slow gastric emptying, and engage central appetite-regulating circuits, thereby improving glycaemia and reducing body weight ( Figure 2 ). Building upon these foundations, dual GLP-1/GIP receptor agonists like tirzepatide harness synergistic incretin biology, amplifying insulinotropic actions while enhancing satiety and energy deficit ( Figure 2 ). More recently, triple agonists that co-activate GLP-1, GIP, and the glucagon receptor—exemplified by retatrutide—have emerged, integrating controlled glucagon-mediated increases in energy expenditure with the established anorectic and insulinotropic effects of GLP-1 and GIP ( Figure 2 ). Parallel strategies include dual GLP-1/glucagon receptor agonists such as survodutide, mazdutide, and cotadutide, which combine strong appetite suppression with mild glucagon-driven lipid mobilization and hepatic fat reduction ( Figure 2 ). Other innovations employ antibody-conjugated molecules that unite GLP-1 receptor agonism with GIP receptor antagonism, as in maridebart cafraglutide (“maritide”), aiming to simultaneously blunt adipose insulin sensitivity and reinforce satiety pathways. Single-molecule co-agonists targeting the GLP-1 and amylin receptors, such as amycretin, emulate the physiological co-secretion of these hormones, providing potent gastric-emptying delay and central appetite inhibition. Complementary to this, formulations pairing distinct agents—such as semaglutide with the amylin analogue cagrilintide (“CagriSema”)—seek additive or supra-additive weight-reducing effects. The development of non-peptide small-molecule GLP-1 receptor agonists, including orally administered orforglipron, represents an additional layer in administration modality, overcoming the structural limitations of injectable peptides. Finally, fixed-ratio combinations of GLP-1 agonists with basal insulins, such as insulin degludec–liraglutide (IDegLira) and insulin icodec–semaglutide (IcoSema), aim to optimize glycaemic control while mitigating insulin-associated weight gain ( Figure 2 ). Across all these approaches, the glucose-lowering and weight-reducing effects are well established. Yet the extent to which their cardiovascular benefits arise also from direct modulation of lipid profiles, lipoprotein metabolism, and intra-/extra-cellular ectopic adiposity remains to be established. A detailed analysis of the impact of the different classes of drugs on plasma lipids and lipoproteins is presented below. Single GLP-1 Receptor agonists Across the clinical programs evaluating single GLP-1 receptor peptide agonists—including liraglutide, semaglutide (s.c. and oral formulations), dulaglutide, exenatide, and efpeglenatide—a coherent pattern emerges linking their glucose-lowering actions to improvements in specific lipid parameters ( Figure 3 and Supplemental Tables 1–6), which highlights the gluco-metabolic and lipid-lowering efficacy of these compounds. In T2D subjects, clinical trials with liraglutide, SCALE Diabetes(Davies et al., 2015), semaglutide, SUSTAIN (Marso et al., 2016; Sorli et al., 2017; Zinman et al., 2019b; McGowan et al., 2024; Lingvay et al., 2025b) and PIONEER (Aroda et al., 2019; Husain et al., 2019; Mosenzon et al., 2019; Pieber et al., 2019; Pratley et al., 2019; Rodbard et al., 2019; Rosenstock et al., 2019; Zinman et al., 2019a; Yabe et al., 2020; Yamada et al., 2020), dulaglutide, AWARD (Dungan et al., 2014; Wysham et al., 2014; Blonde et al., 2015; Giorgino et al., 2015; Ludvik et al., 2018; Frias et al., 2021; Arslanian et al., 2022), exenatide, DURATION trials (Buse et al., 2010, 2013; Diamant et al., 2010; Blevins et al., 2011; Wysham et al., 2011; Frías et al., 2016; Guja et al., 2018), and efpeglenatide AMPLITUDE/BALANCE (Gerstein et al., 2021, 2023; Lam et al., 2022; Pratley et al., 2022) showed that, greater reductions in HbA1c or fasting glucose consistently coincided with more pronounced decreases in plasma triglycerides and VLDL cholesterol, while the effect on total cholesterol, LDL-C, HDL-C and non-HDL-C were small in magnitude even though statistical significant. The observation that the reduction in VLDL-C was more robust in the study arms achieving ≥1% HbA1c reduction, is in line with the concept that improved glycemic control decreases hepatic VLDL synthesis and fatty acid flux. At the same time, the lack of a robust association between glycemic control and LDL- or HDL-cholesterol changes, supports the hypothesis that in T2D patients alterations in lipoprotein cholesterol-rich fractions are partially related to glycemic control, and often secondary to broader metabolic changes. In clinical studies enrolling overweight or obese participants without diabetes, such as SCALE Obesity & Prediabetes with liraglutide (Pi-Sunyer et al., 2015; Wadden et al., 2020) and STEP-1 (Wilding et al., 2021), -3 (Wadden et al., 2021), -4 (Rubino et al., 2021), -5 (Garvey et al., 2022)and -6 with semaglutide (Kadowaki et al., 2022), the pattern is even clearer. Triglycerides, VLDL cholesterol, and fatty-acid indices show the strongest and most consistent reduction, tightly mirroring the degree of weight loss rather than glycemic change (which is minimal in these non-diabetic cohorts). In the trials with liraglutide 3.0 mg or semaglutide 2.4 mg the magnitude of reduction in BMI, triglycerides, and VLDL cholesterol tended to increase with longer duration of follow-up. While more modest effects were generally observed in shorter trials of 26–56 weeks with liraglutide (e.g., LEAD-4, SCALE-Diabetes) and SUSTAIN-1 and -9 with semaglutide (30 weeks long); By contrast, larger and more sustained reductions were reported in the SCALE Obesity and Prediabetes NN8022-1839 studies with the follow-up extending to 56 and 160 weeks, as well as in the 68-week STEP program, the 104-week SELECT trial, the SUSTAIN trials with follow-up ranging from 30 to 109 weeks, and the more recent ESSENCE trial with 72 weeks of observation. These observations may suggest that negative energy balance and reduced adipose-tissue lipolysis result in suppressed hepatic secretion of VLDL particles. Like what observed in the studies with T2D patients, total cholesterol and LDL-C reductions were small, further stressing that weight-induced improvements preferentially target triglyceride-related pathways rather than cholesterol metabolism. Furthermore, while the previous study showed that the decline in free fatty acids and in the cholesterol content of VLDL parallel weight loss and triglyceride reductions mainly due to improved systemic insulin sensitivity and reduced adipose-tissue lipid spillover, the recent phase 3 ESSENCE study demonstrated that semaglutide (2.4mg/week) reduced hepatic ectopic adiposity and improved metabolic dysfunction-associated steatohepatitis (MASLD) in patients with biopsy-proven hepatic steatosis (Sanyal et al., 2025). This however remains up to date the only study showing the effect of GLP1-RA on ectopic adiposity. Taken together, for single-agent GLP-1 receptor agonists, reduction in triglycerides and VLDL cholesterol are the most robust and reproducible lipid effects which are tightly aligned with improvements in both glucose control (in T2D patients) and weight loss (in obese subjects). In contrast, changes in total cholesterol, LDL-C, HDL-C, and non-HDL-C remain comparatively modest, suggesting that the principal cardiometabolic impact of these agents arises from their integrated effects on adiposity, insulin sensitivity, and VLDL metabolism, rather than from strong direct modulation of cholesterol fractions ( Figure 3 ). Within this class, orally administered GLP1RAs deserve special consideration. Oral semaglutide, a peptide co-formulated with an absorption enhancer (sodium;8-[(2-hydroxybenzoyl)amino]octanoate, “SNAC”) which broadly reproduces the metabolic profile of injectable semaglutide: in T2D and obesity PIONEER program trials and in OASIS-1(Knop et al., 2023), -2 (Kadowaki et al., 2025) and -4 (Wharton et al., 2025a) produced clinically relevant reductions in HbA1c and body weight. This effect was also associated with clear improvements in triglycerides and VLDL cholesterol but only modest effects on LDL-C and total cholesterol. Despite the main practical limitations for its posology, including the strict fasting and water-intake conditions required for dosing, FDA recently approved this oral option at the dose of 25 mg for weight management. Orforglipron is a novel non-peptide, small-molecule GLP-1 receptor agonist designed for once-daily oral administration without food or water restrictions (Cong et al., 2021) (Pratt et al., 2023; Ma et al., 2024). In the phase 2 obesity trial in adults without diabetes (GZGI; Supplemental Table 7 ), weight reductions of roughly −8.6 to −12.6% at 36 weeks vs about −2% with placebo were accompanied by ≈10–26% decreases in triglycerides and VLDL cholesterol and ≈8–26% reductions in LDL-C, whereas HbA1c changes were small (≈−0.3 to −0.4 percentage points) (Wharton et al., 2023). This pattern mirrors that seen with injectable GLP-1 analogues: in non-diabetic obesity, lipid benefits—especially on the levels of triglycerides and of cholesterol in VLDL—track closely with weight loss, with modest additional effects on total cholesterol and LDL-C. In the phase 2, dose-response, T2D ACHIEVE-1 study, orforglipron 12–36 mg once daily reduced HbA1c by about −1.5 to −1.7 percentage points and body weight by ≈−6–8%, with triglyceride and VLDL cholesterol reductions in the order of ≈10–15% versus placebo and a smaller reduction in total cholesterol and LDL-C (Rosenstock et al., 2025). Orforglipron was more effective than dulaglutide in lipid lowering Phase 2 NCT05048719 trial(Frias et al., 2023b) and in the ACHIEVE-3 trial lead to a larger HbA1c and weight reductions compared to oral semaglutide (up to −2.2% vs −1.4% in HbA1c and ≈−9.2% vs −5.3% in body weight) coupled to clinically meaningful improvements in non-HDL cholesterol and triglycerides(Johnson et al., 2020). Finally, orforglipron also significantly lowered triglycerides, and cholesterol content in VLDL, along with reducing non-HDL cholesterol the Phase 3 ATTAIN-2 trial(Horn et al., 2025). Overall, orforglipron reproduces the characteristic effects of GLP-1 receptor agonism on lipid parameters (robust effects on triglycerides, cholesterol content in VLDL), while leads to modest effects on the other cholesterol fractions ( Figure 3 )—but offers two potential advantages over peptide-based oral semaglutide: (i) greater potency in glucose and weight lowering at tested doses, and (ii) a more convenient pharmacokinetic and administration profile (true once-daily pill without prandial restrictions). These features suggest that small-molecule GLP-1 receptor agonists may extend the cardiometabolic benefits of the class to a broader population — not only by improving convenience and adherence but also by maintaining previously achieved weight loss when patients switch from injectable incretins to oral therapy, as shown in the ATTAIN-MAINTAIN trial, a part of the ongoing ATTAIN investigation programme with orforglipron(Eli Lilly, 2025). Dual modulators of GLP-1 and GIP Receptors Tirzepatide is the first compound which can simultaneously activate both GLP1 receptor as well as the GIP receptor. Across studies in patients with diabetes or obesity, tirzepatide resulted in a pronounced metabolic improvement ( Supplemental Table 8 ). In the SURPASS program, HbA1c reductions routinely exceed −2.0%, which was paralleled by substantial declines in triglycerides and VLDL cholesterol levels. This dose-dependent pattern—seen across SURPASS-1 through SURPASS-5 (Del Prato et al., 2021; Frías et al., 2021; Rosenstock et al., 2021; Dahl et al., 2022; Gastaldelli et al., 2022) —reflects enhanced insulin sensitivity, reduced hepatic lipid synthesis, and diminished excretion of VLDL particles. By contrast, changes in total cholesterol, LDL-C, HDL-C, and non-HDL-C are modest, indicating that also tirzepatide acts on lipoprotein metabolism primarily through pathways governing the production of VLDL particles, and/or the clearance of remnant particles ( Figure 3 ). In the SURMOUNT program too (Jastreboff et al., 2022; Garvey et al., 2023; Hankosky et al., 2023; Wadden et al., 2023; Aronne et al., 2024, 2025; Look et al., 2025; Mamas et al., 2025), which involved obese individuals without diabetes, extensive and dose-dependent weight losses coincided with marked reductions in triglycerides, and in the cholesterol content of VLDL. Changes in plasma lipid profile were consistent with reduced adipose-tissue lipolysis, improved insulin sensitivity, and diminished hepatic production of VLDL particles. Like what observed in the SURPASS program, also in the SURMONT trials, LDL-C and HDL-C were minimally affected, despite the robust weight reduction achieved. These effects on lipid profile are also associated with a significant reduction in ectopic visceral adiposity, at least as analyzed in the dedicated SURMOUNT-1 (Look et al., 2025) and SURPASS-3 MRI (Gastaldelli et al., 2022) post-hoc lipid-focused analyses. Maridebart cafraglutide (Maritide) is an antibody–peptide conjugate that combines GLP-1 receptor agonism with GIP receptor antagonism. Whereas tirzepatide enhances GIP signaling to exploit its insulinotropic and potentially weight-modulating actions, maritide is developed on the hypothesis that chronic GIP signaling may favor adipose lipid storage and insulin-sensitive fat retention; therefore, blocking the GIP receptor while activating GLP-1 might further reduce adiposity and impact lipid partitioning. The long-acting antibody backbone provides sustained exposure and preferential targeting of GIP-rich tissues such as adipose depots, and it has been to date tested in a phase 2 obesity trial enrolling both in obese, non-diabetic patients as well as in obese and diabetic patients (NCT05669599; Supplemental Table 9 ). Once-weekly subcutaneous injection of maritide in individuals with obesity produced a robust weight loss (≈−13–16%), but only modest changes in glycaemia (Jastreboff et al., 2025). Weight reduction was accompanied by ≈13–18% decrease in plasma triglycerides and ≈11–18% reduction in VLDL/remnant cholesterol. Interestingly, maritide also promoted a ≈7–9% reductions in total cholesterol, ≈8–9% in LDL-C, and a modest increase in HDL-C. in the obese-nondiabetic patients. In patients with diabetes and obesity, maritide produced combined HbA1c lowering (around −2%), ≈8–12% weight loss followed by a ≈25–28% reduction in triglycerides and ≈25–26% in the cholesterol content of VLDL. Besides, changes in total cholesterol and non-HDL-C were minimal and more variable. Across both cohorts, measures of ectopic adiposity (total fat mass and liver fat content) showed substantial reductions, clearly exceeding those seen with placebo. Compared with tirzepatide, maritide shares a similar qualitative profile—very large effects on weight and robust improvements in triglycerides and in cholesterol content of VLDL, with more modest changes in LDL-C and total cholesterol ( Figure 3 ). Quantitatively, the available phase 2 data suggest that maritide’s lipid-lowering effects, particularly on triglycerides and remnants, are at least comparable to those of tirzepatide at similar degrees of weight loss, although direct comparisons are not yet possible. Both strategies therefore support the concept that potentiating GLP-1 signaling while modulating GIP pathways—either by agonism or antagonism—primarily improves the levels of cholesterol in VLDL and ectopic adiposity, with only secondary, modest effects on the cholesterol content in other lipoprotein fractions. Triple GLP-1, GIP and glucagon receptor peptide agonists Triple GLP-1/GIP/glucagon receptor agonists such as retatrutide are designed to activate three complementary hormonal signals via a single molecule ( Supplemental Table 10 ). GLP-1 and GIP agonism jointly enhance glucose-dependent insulin secretion, suppress inappropriate glucagon release, and reduce appetite, while glucagon receptor activation increases energy expenditure, promotes hepatic fatty-acid oxidation, and mobilizes lipid stores. The key driving mechanism is that the hyperglycemic potential of glucagon signaling is counterbalanced by GLP-1/GIP–mediated insulinotropic effects, allowing the glucagon component to be used therapeutically to drive additional weight loss and hepatic lipid utilization. Data from a phase 2 trial of retatrutide injected subcutaneously (NCT04881760 (Jastreboff et al., 2023)) in overweight or obese individuals without diabetes showed a robust effect on weight and plasma lipid profile. Across doses from 1 to 12 mg once a week, body weight reductions ranged from −8.7% to −24.2%. Triglycerides fall by was observed. Interestingly in these trials also a reduction in total cholesterol (5–18%) and LDL-C (5–22%) was appreciated, while HDL-cholesterol levels were unaffected. In patients with diabetes (NCT04867785 (Coskun et al., 2025)) retatrutide produced dose-dependent reductions in total body mass and fat mass compared with placebo, indicating potent effects on adiposity. Unfortunately, data on plasma lipids were not reported. Compared to single GLP-1 receptor agonists and the dual GLP-1/GIP agonist, retatrutide exert a similar pattern of beneficial effects but with more robust response ( Figure 3 ). This suggests that adding calibrated glucagon receptor agonism may confer incremental lipid-lowering efficacy, particularly on VLDL/remnant and LDL fractions, on top of already substantial benefits on adiposity. Dual GLP-1, and glucagon receptor peptide agonists Dual GLP-1/glucagon receptor agonists such as mazdutide, survodutide, and cotadutide are built on the idea that GLP-1–mediated appetite suppression and glucose-dependent insulin secretion can safely “unmask” the beneficial metabolic actions of glucagon. While GLP-1 reduces energy intake, slows gastric emptying, and improves glycaemia, glucagon receptor activation increases energy expenditure, stimulates hepatic fatty-acid oxidation, and promotes mobilisation of lipid stores. On its own, glucagon agonism would raise glucose, but in the dual constructs, this is counterbalanced by GLP-1, allowing the glucagon signal to be exploited therapeutically to enhance weight loss and target hepatic and visceral fat. Multiple trials showed lipid lowering effects of both cotadutide (Parker et al., 2020, 2023; Nahra et al., 2021; Selvarajah et al., 2024) and survodutide (le Roux et al., 2024), although the most complete set of information is currently available for mazdutide ( Supplemental Tables 11-13 ). In obese individuals without diabetes (phase 2 (Ji et al., 2023) and GLORY-1(Ji et al., 2025b)), mazdutide administered once-a week induced dose-dependent weight reductions from −7% to −14% with a modest effect on fasting glucose and HbA1c levels. Interestingly, plasma triglycerides decreased by 25–36%, accompanied by 7–14% reductions in total cholesterol and 6–14% reductions in LDL-C, whereas changes in HDL-C levels were minimal. In the diabetes studies (NCT04965506 (Zhang et al., 2024), the very recent DREAMS-1, and the DREAMS-2(Zhu et al., 2025) that compared the effect with that of dulaglutide), mazdutide also produced substantial dual effects on glycaemia and lipids. In NCT04965506 trial, for instance, HbA1c reductions of about −1.4 to −1.6 percentage points are accompanied by weight loss of ~4–7% and very large triglyceride reductions (≈−25% to −54%), together with 12–21% decreases in total cholesterol and 11–22% in LDL-C versus placebo. Here, both glucose lowering and weight reduction co-segregate with lipid changes, and, in contrast to single GLP-1 agonists and tirzepatide, the reductions in LDL-C and total cholesterol are quantitatively more impressive, indicating a strong direct or indirect impact on hepatic cholesterol. Importantly, dual GLP-1/glucagon agonism also shows clear effects on ectopic adiposity. In GLORY-1, mazdutide reduced total fat mass by ~14–25% versus a small increase with placebo, and liver fat content falls by roughly 66–80%, even in participants with relatively low baseline hepatic fat (Ji et al., 2025b), indicating a powerful de-fatting effect on the liver and visceral depots. Survodutide also demonstrated even more pronounced effects in reducing steatohepatitis in T2D, by significantly reducing surrogate markers of hepatic steatosis, fibrosis and local inflammation in a dose-dependent manner, both compared to placebo (Sanyal et al., 2024) and to semaglutide (Blüher et al., 2024). In summary, dual GLP-1/glucagon receptor agonists out-perform GLP-1 RA and dual GLP-1/GIP RA in terms of triglyceride and LDL-C lowering as well as on hepatic fat reduction, suggesting that glucagon receptor engagement is critically involved in the effect on lipid profile and ectopic adiposity ( Figure 3 ). Dual GLP-1 receptor and amylin receptor agonists. The integration of amylin signaling into incretin-based pharmacotherapy is motivated by the complementary biology of GLP-1 and amylin. Amylin, by interacting with its constitutive receptors (AMYs), that are composed of the calcitonin core-receptor (CTR) and one of the 3 receptor activity modifying protein (RAMP1-3), physiologically slows gastric emptying, suppresses post-prandial glucagon, enhances satiation, and reduces food reward in the area postrema and other hindbrain structures (Volčanšek et al., 2025). Engagement of the CTR pathway adds a second, mechanistically distinct satiety axis to GLP-1 signaling and promotes deeper negative energy balance with downstream reductions in adipose-tissue lipolysis, hepatic lipid influx, and hepatic VLDL production. GLP-1 agonism also buffers the potential glycemic liability of isolated amylin agonism, setting favorable conditions for combined or unimolecular GLP-1/amylin therapy. Amycretin, a single-molecule GLP-1/amylin receptor agonist, is designed to co-activate the GLP-1 receptor and the CTR pathway with balanced potency and once-weekly pharmacokinetics(Gasiorek et al., 2025). In phase 1b–2a studies in obese nondiabetic patients ( Supplemental Table 14 ), amycretin induced large, dose-dependent reductions in body weight (≈−16% to −24%), with only modest changes in glycaemia (Dahl et al., 2025). Across doses, lipid changes were reported predominantly as estimated treatment ratios (ETRs) and showed a characteristic pattern: triglycerides and the cholesterol content of VLDL decreased most robustly (ETR ≈0.7), while total cholesterol and LDL-C showed more modest reductions (ETR ≈0.8) and a modest increase in HDL-C was observed. This profile indicates that the metabolic effects are primarily mediated through profound energy deficit and reduced adipose and hepatic lipid flux, rather than through a direct modulation of cholesterol metabolism. CagriSema, the co-formulation of semaglutide 2.4 mg with the long-acting amylin analogue cagrilintide 2.4 mg, leverages the same mechanistic complementarity but through two separate agents. In obese individuals without diabetes ( Supplemental Table 15 ), CagriSema produced greater weight loss than either component alone (≈−15–20%), with glucose lowering of smaller magnitude (Lau et al., 2021; Frias et al., 2023a; Garvey et al., 2025). Changes in plasma lipid profile were observed mainly in the triglyceride–VLDL compartment, with ≈−25–28% reduction in both triglycerides and cholesterol content of VLDL, while total cholesterol and LDL-C fell modestly. HDL-C levels increased more consistently in the amylin-containing arms. CagriSema clearly outperformed the data obtained in the trials with semaglutide alone in both reducing total body weight, body adiposity, plasma triglycerides and the cholesterol content of VLDL both in the REDEFINE-1 (Garvey et al., 2025), in REDEFINE-2 (Davies et al., 2025) and in the very recent data released regarding the REIMAGINE program(Novo Nordisk A/S, 2026). Data on ectopic adiposity is available for total whole-body analysis and changes in hepatic steatosis still need to be explored. Interestingly amycretin and cagriSema present a similar effect on metabolic profile, as both produce large reductions in weight, plasma triglycerides and cholesterol content of VLDL, while lead modest effects on LDL-C and total cholesterol ( Figure 3 ). Recent data with eloralintide, a selective amylin receptor agonist (Billings et al., 2025) showed modest reductions in body weight with minimal effects on fasting glucose, HbA1c, and triglycerides. These findings indicate that while amylin receptor agonism alone influences appetite and energy intake, this does not translate into robust metabolic and lipid effects while those achieved with dual GLP-1/amylin strategies are more robust, underscoring the importance of concurrent amylin and GLP-1 pathways to appreciate cardiometabolic benefits. Beyond these molecules, additional GLP-1/amylin multiagonists and related constructs are under development and include different combinations of GLP-1, amylin, and calcitonin-receptor agonists. Advances in GLP-1 Receptor Pharmacology and Next-Generation Multi-Agonist Therapeutics The pipeline of incretin-based therapeutics is rapidly expanding with the aim of improving delivery convenience, extending pharmacokinetics and broadening metabolic actions. One major area of innovation involves small-molecule, orally bioavailable GLP-1 receptor agonists—including ASC30 (Jason Wu Vanessa Wang Ascletis Pharma), AZD5004 (AstraZeneca, 2024b), CT-996(Roche, 2024), GSBR-1290 (Structure Therapeutics, 2024), KAI-7535 (Kailera, 2025), RGT-075 (Pirner et al., 2022; Regor, 2025), and TERN-601(Terns Pharmaceuticals, 2024)—which are designed to overcome the administration constraints inherent to injectable or absorption-dependent peptide formulations. Several molecules exhibit substantially greater oral exposure compared with existing oral GLP-1 agents, with marked improvements in AUC and stable once-daily pharmacokinetics. Parallel to these molecules, longer-acting peptide GLP-1 analogues, such as MET-097(VESPER, 2025), ecnoglutide, GZR18 (bofanglutide) (Li et al., 2025), incorporate technologies to extend half-life and to achieve prolonged systemic exposure with a potential monthly dosing schedule. Ecnoglutide which possesses a half-life of 124–138 hours (far higher compared to exenatide, dulaglutide and liraglutide), also promotes a robust reduced cholesterol and triglycerides over a 40-week follow-up, administered once weekly at the doses of 1.8-2.4 mg (Ji et al., 2025a). Interestingly a nanoportal implantable device for long-term release of a GLP-1 analogue (MPM-115) is under testing (Vivani Medical, 2024). Mechanistic diversification is also occurring with new dual GLP-1/GIP agonists such as VK2735 (Viking Therapeutics, 2025), HRS-9531(Zhao et al., 2024), CT-868 (Roche, 2025), and BGM0504(Fan et al., 2025), which explore the possibility of increasing GIP activation to potentiate insulinotropic and satiety pathways. Early clinical observations showed favorable effects on body weight and glycaemia, and early signals of triglyceride reduction. Amylin-based strategies are advancing in parallel, including AZD6234 and the triple amylin–GLP-1/glucagon receptor agonist. (AstraZeneca, 2024a). Additional dual-receptor approaches such as pemvidutide (ALT-801) show promising activity in weight reduction and hepatic steatosis (Altimmune, 2025). Furthermore, wider hormone-receptor targeting is under development. The first, is illustrated by bioglutide (NA-931), an oral quadruple GLP-1/GIP/glucagon/Insulin-like Growth Factor 1 (IGF-1) receptor agonist which showed an earlier weight-loss effects and a potential benefit on lean-mass preservation (Biomed Industries Inc., 2024). The rationale for integrating IGF-1 receptor agonism to GLP-1/GIP/glucagon strategy is to counterbalance the lean-mass loss that often accompanies profound weight reduction. IGF-1 promotes muscle protein synthesis and preserves anabolic tone, allowing weight loss driven by incretin and glucagon pathways to occur with better maintenance of skeletal muscle mass. The second approach that is preclinically underway is the GLP-1/GIP/PPARα/δ/γ quintuple agonist, a unimolecular compound designed with the rationale of combining the benefit on weight-loss by GLP-1R:GIP-R co-agonism with the insulin-sensitizing properties of a panPPAR activation (Liskiewicz et al., 2025). Together, the ongoing research highlights how the next generation of incretin-related agents is studied to amplify potency, simplify dosing, diversify receptor engagement and broaden metabolic benefits beyond those achieved by current single, dual and triple agonists. Specifically, no data on lipid-lowering effects is not available yet for most of these prototypes.

and perspectives Cardiovascular outcome trials (CVOTs) with incretin-based therapies have consistently demonstrated reductions in major adverse cardiovascular events across different populations. In obese patients with established CVD, LEADER (liraglutide) (Marso et al., 2016), REWIND (dulaglutide) (Gerstein et al., 2019), EXSCEL (exenatide QW) (Holman et al., 2017), PIONEER-6 (semaglutide s.c.)(Husain et al., 2019), AMPLITUDE-O (efpeglenatide) (Lam et al., 2022; Gerstein et al., 2023), and SELECT (semaglutide 2.4 mg (Deanfield et al., 2025) ) have all reported clinically meaningful reductions in MACE (Nicholls et al., 2025b). The recent SURPASS-CVOT showed that tirzepatide reduced body weight and glycated hemoglobin compared to dulaglutide, but it led to similar cardiovascular protection to dulaglutide (Nicholls et al., 2025a). Being tirzepatide non-inferior in reducing the occurrence of new events in people with T2D and established cardiovascular disease at baseline, this trial provides the first head-to-head evidence that substantial protection occurs irrespectively from the type of modulation of the incretin activity, and that improved metabolic efficacy—particularly greater weight loss and broader improvements in insulin sensitivity—unequivocally translates into incremental cardiovascular benefit. These trial-level observations are further supported by a recent large meta-analysis, which evaluated cardiovascular outcomes across randomized trials of semaglutide and tirzepatide in T2Dpatients (Krüger et al., 2025). The analysis confirmed a robust and consistent reduction in major cardiovascular events with both agents, while also indicating numerically but not significantly greater risk reductions with tirzepatide compared with semaglutide. Importantly, this meta-analysis supports the hypothesis that cardiovascular benefit closely follows the magnitude of metabolic improvement, including body-weight reduction and glycemic control. Yet, it is unclear how changes in lipid profile, particularly those in triglycerides and VLDL/remnant cholesterol, contribute to risk reduction. Importantly, the field is now extending to agents with broader receptor profiles: the SYNCHRONIZE-CVOT trial (NCT06077864; (Kosiborod et al., 2024)) will determine the cardiovascular safety and efficacy of survodutide in people with obesity and increased cardiovascular risk, while the phase III SYNCHRONIZE-1 (le Roux et al., 2026) and SYNCHRONIZE-2 (Wharton et al., 2025b) trials will evaluate long-term safety and tolerability in individuals with obesity with or without diabetes. These studies will clarify whether the cardioprotective signals observed with GLP-1–based agents extend to dual GLP-1/glucagon agonism. Across completed trials, larger relative reductions in triglycerides and VLDL/remnant lipoproteins, along with modest improvements in LDL-C, tend to align with effect sizes at the upper end of the trial with GLP-1 receptor agonists. However, if the extent to which these lipid modifications directly mediates the reduction in cardiovascular risk remains uncertain at this level of investigation. Dedicated meta-regression analyses incorporating changes in triglycerides, remnants, non-HDL-C, weight loss, and glycaemia will be essential to delineate the relative cardioprotective contributions of each parameter. Fixed-ratio combinations of GLP-1 receptor agonists with insulin, such as IDegLira and IcoSema, will further broaden the therapeutic landscape (Gough et al., 2014; Lingvay et al., 2025a). Although variations in lipid fractions were not presented in these trials, the mechanistic balance—reduced insulin dose requirements combined with preserved GLP-1RA effects—suggests a neutral-to-favourable impact on triglycerides and VLDL. It is important to stress that compared to CVOT trials with lipid lowering therapies, those with incretins were shorter. As such it is possible that longer exposure to GLP-1–based or dual/triple agonists will yield additional cardiovascular benefits, partly through continued improvements in plasma lipid profile or affecting hepatic lipid flux yet we have to wait data from real word evidence study. Nevertheless, the dominant lipid signature across incretin-based therapies—strong reductions in triglycerides, in the cholesterol content in the VLDL lipoprotein fraction, while modest changes in LDL-C and HDL-C—appears largely attributable to improvements in systemic metabolism, including weight loss, normalization of insulin sensitivity, and reduction of hepatic and visceral adiposity. Yet none of the trials with incretin analogues reported data on apoB, the most comprehensive metric of atherogenic particle burden(Sniderman et al., 2019), nor the levels of lipoprotein(a), a genetically determined ASCVD risk factor that is inversely associates with risk of T2D but acts as a risk multiplier when superimposed on obesity, insulin resistance, and dyslipidemia (Lamina and Ward, 2022). Additional important gaps refer to body composition and liver steatosis. Profound weight loss raises legitimate concerns about lean and muscle mass preservation. Emerging trials combining incretin analogues with myostatin/activin pathway inhibitors, such as EMBRAZE (tirzepatide + apitegromab), COURAGE (semaglutide + trevogrumab ± garetosmab), and NCT05616013 (semaglutide + bimagrumab), suggest that preservation or enhancement of lean mass may be feasible. These combinations aim to uncouple weight loss from skeletal muscle loss, potentially altering lipid flux, fatty-acid oxidation, and ectopic fat mobilization in ways not yet captured by standard cardiometabolic markers. Regarding liver steatosis, incretin analogues demonstrate consistent improvements in hepatic steatosis and fibrosis surrogates, raising the possibility that they may favorably influence MASLD/MASH progression. Whether these hepatic benefits arise purely from weight loss or also relate to GLP-1–regulated hepatocellular pathways, including interactions with THR-β signaling (implicated in MASLD resolution and targeted by agents such as resmetirom), remains an open and clinically relevant question. Understanding how incretin therapies might complement or synergise with THR-β agonists could meaningfully expand future therapeutic frameworks. In summary, incretin-based therapies deliver powerful cardiometabolic improvements, but the specific contribution of lipid remodeling and ectopic fat reduction to cardiovascular benefit remains incompletely defined. Longer-duration trials incorporating apoB, Lp(a), detailed lipoprotein subclass analyses, and standardized body-composition endpoints will be essential to determine how much of the cardiovascular benefit can be ascribed to improvements in lipid metabolism versus other metabolic pathways. Fundings This work of GDN is supported by Progetti di Rilevante Interesse Nazionale (PRIN 2022 7KTSAT), PNRR Missione 4 (Progetto CN3 - National Center for Gene Therapy and Drugs based on RNA Technology), PNRR Missione 4 (Progetto MUSA- Multilayered Urban Sustainability Action to GDN), PNRR Missione 6 (PNRR-MAD-2022-12375913), CARDINNOV. The work of AB received funding by Ministry of Research and University under the umbrella of the Partnership Fostering a European Research Area for Health (ERA4Health) (GA N° 101095426 of the EU Horizon Europe Research and Innovation Programme), Progetti di Rilevante Interesse Nazionale (PRIN-PNRR 2022 P202294PHK). Figure legends Figure 1 – Primary incretin effects and impact on systemic lipid and lipoprotein metabolism The figure is scheduled in boxes resuming the primary incretin effects in the pancreas (top, left), in the brain (top, right), and the impact on systemic lipid and lipoprotein metabolism in the liver (center) and in the intestine (bottom). Sharp-headed arrows indicate pathways/effects promoted, while t-shaped head arrows indicate pathways/effects inhibited or reduced. Red question marks indicate information that is not present in literature. “ABCA1”= ATP binding cassette transporter 1; “AMPK”= AMP-activated protein kinase;; “apoAI”= apolipoprotein A-I; “apoB”= apolipoprotein B; “ATP”= Adenosine Triphosphate; “CAMKIV”= Calcium/calmodulin-dependent protein kinase type IV; “Ca2+”= Calcium ion; “CAMKK”= Calcium/Calmodulin-dependent Protein Kinase Kinase; “Carbs”= Carbohydrates; “cAMP”= cyclic adenosine monophosphate; “CD36”= Cluster of Differentiation 36; “ChREBP2”= Carbohydrate-response element-binding protein 2; CTR= Calcitonin receptor; “Cyp7a1”= Cholesterol 7α-hydroxylase; “DGAT”= Diacylglycerol O-acyltransferase; “DIO2”= Deiodinase type 2; “ER”= Endoplasmic Reticulum”; “FABP5”= Fatty Acid Binding Protein 5; “FAO”= Fatty Acids Oxidation; “FFAR1/4”= Free Fatty Acid Receptors 1/4; “ΔΨ”= electrical potential difference; “FGF15”= Fibroblast Growth Factor 5; “FGFR4”= Fibroblast Growth Factor Receptor type 4; “FXR”= Farnesoid X Receptor; “GCR”= Glucagon receptor; “GIP”= Glucose-dependent Insulinotropic Polypeptide; “GIPR”= GIP receptor; “GLP-1”= Glucagon-like Peptide-1; “GLP1-R”= GLP-1 receptor; “INSR”= Insulin receptor; “K+”= potassium ion; “IP3”= inositol 1,4,5-trisphosphate; “LDLR”= Low-Density Lipoprotein receptor; “LPL”= Lipoprotein lipase; “MTP”= Microsomal triglyceride transfer protein; “PCSK9”= Proprotein Convertase Subtilisin Kexin Type-9; “PI3K”= Phosphoinositide 3-kinase; “PKA”= Protein Kinase K; “PLC”= Phospholipase C; “PPARalpha”= Peroxisome proliferator-activated receptor alpha; “PREB”= Preb transcription factor; RAMP1/3= receptor-activity modifying protein 1/3; “SGLT1”= Sodium-glucose cotransporter 1; “SREBP1c”= Sterol Regulatory Element Binding Protein 1c; “T3”= Triiodothyronine; “T4”= Thyroxine; “THRβ”= Thyroid Hormone Receptor beta; “VDCC”= Voltage-dependent calcium channel. Figure 2 - Current pipeline of molecules targeting incretin related pathways. The figure resumes the currently available incretin analogues and the strategies currently under development. These are divided according to their receptor target as: (1) Single GLP-1 receptor agonists, (2) Dual modulators of GLP-1 and GIP receptors, where “modulators” includes both those with only agonistic activity and those with partial antagonistic activity; (3) Triple GLP-1, GIP and Glucagon receptor agonists; (4) Dual GLP-1 and Amylin receptor agonists; (5) Combination of GLP-1 receptor agonists and insulin formulations. Green arrows indicate agonistic activity while red line indicates antagonistic activity. “SNAC”= N-(8-[2-hydroxybenzoyl]-amino) caprylic acid, embedded with the oral formulation of semaglutide to enhance the intestinal absorption. “INSR”= Insulin receptor. Figure 3 – Effect of incretin analogues on lipids and lipoproteins. The figure summarizes graphically the evidence from clinical trials with incretin analogues on lipids and lipoproteins along with their primary effects on body weight reduction and improvement of gluco-metabolic profile. Double downward or upward green arrows indicate the reduction or the increase of the specific parameter in most or in all the clinical trials. Single downward or upward green arrows indicate the reduction or the increase of the specific parameter in less than half of the clinical trials. Yellow horizonal bidirectional arrows indicate any or neutral effect on the specific parameter in the clinical trials available. A red trait indicates that the information is missing in the clinical trials. “HbA1c”= glycated hemoglobin; “LDL-C”= cholesterol in Low Density Lipoproteins; “HDL-C”= cholesterol in High-Density lipoproteins; “VLDL-C”= cholesterol in Very-Low Density Lipoproteins; “TGs”= triglycerides; “FAs”= fatty acids; “non-HDL-C”= sum of the cholesterol in all the lipoproteins except of HDL; “ApoB”= apolipoprotein B. Supplemental Tables legends Supplemental Tables 1-15 The tables list the clinical trials testing the efficacy of (1) liraglutide, (2) semaglutide (subcutaneous administration), (3) semaglutide (oral administration), (4) exenatide, (5) dulaglutide, (6) epfeglenantide, (7) orforglipron, (8) tirzepatide, (9) maritide, (10) retatutride, (11) mazdutide, (12) cotadutide, (13) survodutide, (14) amycretin and (15) CagriSema on body weight, ectopic adiposity, gluco-metabolic parameters, and lipid profile. Data are obtained by from the original trials and are stratified by the dose arm of the compound in the trial. “NA”= information not available.

Ables, G.P., Yang, K.J.Z., Vogel, S., Hernandez-Ono, A., Yu, S., Yuen, J.J., et al. (2012). Intestinal DGAT1 deficiency reduces postprandial triglyceride and retinyl ester excursions by inhibiting chylomicron secretion and delaying gastric emptying. J. Lipid Res. 53 : 2364–79. Altimmune (2025). Results from the IMPACT Phase 2b Trial of Pemvidutide in the Treatment of MASH. Aroda, V.R., Rosenstock, J., Terauchi, Y., Altuntas, Y., Lalic, N.M., Villegas, E.C.M., et al. (2019). PIONEER 1: Randomized clinical trial of the efficacy and safety of oral semaglutide monotherapy in comparison with placebo in patients with type 2 diabetes. Diabetes Care 42 : 1724–1732. Aronne, L.J., Horn, D.B., Roux, C.W. le, Ho, W., Falcon, B.L., Gomez Valderas, E., et al. (2025). Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N. Engl. J. Med. 393 : 26–36. Aronne, L.J., Sattar, N., Horn, D.B., Bays, H.E., Wharton, S., Lin, W.-Y., et al. (2024). Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA 331 : 38–48. Arslanian, S.A., Hannon, T., Zeitler, P., Chao, L.C., Boucher-Berry, C., Barrientos-Pérez, M., et al. (2022). Once-Weekly Dulaglutide for the Treatment of Youths with Type 2 Diabetes. New England Journal of Medicine 387 : 433–443. AstraZeneca (2024a). APRICUS study. AstraZeneca (2024b). Meet the Management: Weight Management Virtual Event Webinar for investors and analysts. Baragetti, A. (2022). Liver-derived lipoproteins and inflammation: from pathophysiology to pharmacological targets in metabolic liver disease. Metabolism and Target Organ Damage 2 :. Beiroa, D., Imbernon, M., Gallego, R., Senra, A., Herranz, D., Villarroya, F., et al. (2014). GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 63 : 3346–58. Ben-Shlomo, S., Zvibel, I., Shnell, M., Shlomai, A., Chepurko, E., Halpern, Z., et al. (2011). Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase. J. Hepatol. 54 : 1214–23. Billings, L.K., Hsia, S., Bays, H., Tidemann-Miller, B., O’Hagan, J., Tham, L.S., et al. (2025). Eloralintide, a selective amylin receptor agonist for the treatment of obesity: a 48-week phase 2, multicentre, double-blind, randomised, placebo-controlled trial. The Lancet. Biomed Industries Inc. (2024). NA-931 oral quadruple receptor agonist Biomed. Blevins, T., Pullman, J., Malloy, J., Yan, P., Taylor, K., Schulteis, C., et al. (2011). DURATION-5: Exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. Journal of Clinical Endocrinology and Metabolism 96 : 1301–1310. Blonde, L., Jendle, J., Gross, J., Woo, V., Jiang, H., Fahrbach, J.L., et al. (2015). Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority study. Blüher, M., Rosenstock, J., Hoefler, J., Manuel, R., and Hennige, A.M. (2024). Dose–response effects on HbA1c and bodyweight reduction of survodutide, a dual glucagon/GLP-1 receptor agonist, compared with placebo and open-label semaglutide in people with type 2 diabetes: a randomised clinical trial. Diabetologia 67 : 470–482. Boland, M.L., Laker, R.C., Mather, K., Nawrocki, A., Oldham, S., Boland, B.B., et al. (2020). Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis. Nat. Metab. 2 : 413–431. Boyle, C.N., Lutz, T.A., and Foll, C. Le (2018). Amylin - Its role in the homeostatic and hedonic control of eating and recent developments of amylin analogs to treat obesity. Mol. Metab. 8 : 203–210. Bozadjieva-Kramer, N., Shin, J.H., Li, Z., Rupp, A.C., Miller, N., Kernodle, S., et al. (2024). Intestinal FGF15 regulates bile acid and cholesterol metabolism but not glucose and energy balance. JCI Insight 9 :. Bu, T., Sun, Z., Pan, Y., Deng, X., and Yuan, G. (2024). Glucagon-Like Peptide-1: New Regulator in Lipid Metabolism. Diabetes Metab. J. 48 : 354–372. Burmeister, M.A., Ferre, T., Ayala, J.E., King, E.M., Holt, R.M., and Ayala, J.E. (2012). Acute activation of central GLP-1 receptors enhances hepatic insulin action and insulin secretion in high-fat-fed, insulin resistant mice. American Journal of Physiology-Endocrinology and Metabolism 302 : E334–E343. Buse, J.B., Drucker, D.J., Taylor, K.L., Kim, T., Walsh, B., Hu, H., et al. (2010). DURATION-1: Exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care 33 : 1255–1261. Buse, J.B., Nauck, M., Forst, T., Sheu, W.H.H., Shenouda, S.K., Heilmann, C.R., et al. (2013). Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): A randomised, open-label study. The Lancet 381 : 117–124. Chait, A., Ginsberg, H.N., Vaisar, T., Heinecke, J.W., Goldberg, I.J., and Bornfeldt, K.E. (2020). Remnants of the Triglyceride-Rich Lipoproteins, Diabetes, and Cardiovascular Disease. Diabetes 69 : 508–516. Challa, T.D., Beaton, N., Arnold, M., Rudofsky, G., Langhans, W., and Wolfrum, C. (2012). Regulation of adipocyte formation by GLP-1/GLP-1R signaling. J. Biol. Chem. 287 : 6421–30. Coester, B., Pence, S.W., Arrigoni, S., Boyle, C.N., Foll, C. Le, and Lutz, T.A. (2020). RAMP1 and RAMP3 Differentially Control Amylin’s Effects on Food Intake, Glucose and Energy Balance in Male and Female Mice. Neuroscience 447 : 74–93. Cong, Z., Chen, L.-N., Ma, H., Zhou, Q., Zou, X., Ye, C., et al. (2021). Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor. Nat. Commun. 12 : 3763. Coon, S.D., Rajendran, V.M., Schwartz, J.H., and Singh, S.K. (2015). Glucose-dependent insulinotropic polypeptide-mediated signaling pathways enhance apical PepT1 expression in intestinal epithelial cells. Am. J. Physiol. Gastrointest. Liver Physiol. 308 : G56-62. Coskun, T., Wu, Q., Schloot, N.C., Haupt, A., Milicevic, Z., Khouli, C., et al. (2025). Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial. Lancet Diabetes Endocrinol. 13 : 674–684. Dahl, D., Onishi, Y., Norwood, P., Huh, R., Bray, R., Patel, H., et al. (2022). Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients with Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial. JAMA 327 : 534–545. Dahl, K., Toubro, S., Dey, S., Duque do Vale, R., Flint, A., Gasiorek, A., et al. (2025). Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist administered subcutaneously: results from a phase 1b/2a randomised controlled study. The Lancet 406 : 149–162. Dash, S., Xiao, C., Morgantini, C., and Lewis, G.F. (2015). New Insights into the Regulation of Chylomicron Production. Annu. Rev. Nutr. 35 : 265–294. Davies, M.J., Bajaj, H.S., Broholm, C., Eliasen, A., Garvey, W.T., Roux, C.W. le, et al. (2025). Cagrilintide–Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. New England Journal of Medicine 393 : 648–659. Davies, M.J., Bergenstal, R., Bode, B., Kushner, R.F., Lewin, A., Skjøth, T.V., et al. (2015). Efficacy of liraglutide for weight loss among patients with type 2 diabetes: The SCALE diabetes randomized clinical trial. JAMA - Journal of the American Medical Association 314 : 687–699. Deanfield, J., Lincoff, A.M., Kahn, S.E., Emerson, S.S., Lingvay, I., Scirica, B.M., et al. (2025). Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial. Lancet 406 : 2257–2268. Diamant, M., Gaal, L. Van, Stranks, S., Northrup, J., Cao, D., Taylor, K., et al. (2010). Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. The Lancet 375 : 2234–2243. Dungan, K.M., Povedano, S.T., Forst, T., González, J.G.G., Atisso, C., Sealls, W., et al. (2014). Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): A randomised, open-label, phase 3, non-inferiority trial. The Lancet 384 : 1349–1357. El, K., and Campbell, J.E. (2020). The role of GIP in α-cells and glucagon secretion. Peptides (N.Y.). 125 : 170213. Eli Lilly (2025). Orforglipron ATTAIN clinical trial program. Fan, Y., Yuan, J., Dong, L., Yu, C., Ding, H., Xie, D., et al. (2025). The safety, tolerability, pharmacokinetics and pharmacodynamics of an optimized dual GLP-1/GIP receptor agonist (BGM0504) in healthy volunteers: A dose-escalation Phase I study. Diabetes Obes. Metab. 27 : 2110–2119. Farr, S., Baker, C., Naples, M., Taher, J., Iqbal, J., Hussain, M., et al. (2015). Central Nervous System Regulation of Intestinal Lipoprotein Metabolism by Glucagon-Like Peptide-1 via a Brain-Gut Axis. Arterioscler. Thromb. Vasc. Biol. 35 : 1092–100. Frias, J.P., Bonora, E., Ruiz, L.N., Li, Y.G., Yu, Z., Milicevic, Z., et al. (2021). Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (award-11). Diabetes Care 44 : 765–773. Frías, J.P., Davies, M.J., Rosenstock, J., Pérez Manghi, F.C., Fernández Landó, L., Bergman, B.K., et al. (2021). Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. New England Journal of Medicine 385 : 503–515. Frias, J.P., Deenadayalan, S., Erichsen, L., Knop, F.K., Lingvay, I., Macura, S., et al. (2023a). Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. The Lancet 402 : 720–730. Frías, J.P., Guja, C., Hardy, E., Ahmed, A., Dong, F., Öhman, P., et al. (2016). Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 4 : 1004–1016. Frias, J.P., Hsia, S., Eyde, S., Liu, R., Ma, X., Konig, M., et al. (2023b). Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study. The Lancet 402 : 472–483. Galsgaard, K.D., Pedersen, J., Knop, F.K., Holst, J.J., and Wewer Albrechtsen, N.J. (2019). Glucagon Receptor Signaling and Lipid Metabolism. Front. Physiol. 10 : 413. Garvey, W.T., Batterham, R.L., Bhatta, M., Buscemi, S., Christensen, L.N., Frias, J.P., et al. (2022). Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat. Med. 28 : 2083–2091. Garvey, W.T., Blüher, M., Osorto Contreras, C.K., Davies, M.J., Winning Lehmann, E., Pietiläinen, K.H., et al. (2025). Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine 393 : 635–647. Garvey, W.T., Frias, J.P., Jastreboff, A.M., Roux, C.W. le, Sattar, N., Aizenberg, D., et al. (2023). Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. The Lancet 402 : 613–626. Gasiorek, A., Heydorn, A., Gabery, S., Hjerpsted, J.B., Kirkeby, K., Kruse, T., et al. (2025). Safety, tolerability, pharmacokinetics, and pharmacodynamics of the first-in-class GLP-1 and amylin receptor agonist, amycretin: a first-in-human, phase 1, double-blind, randomised, placebo-controlled trial. Lancet 406 : 135–148. Gastaldelli, A., Cusi, K., Fernández Landó, L., Bray, R., Brouwers, B., and Rodríguez, Á. (2022). Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol. 10 : 393–406. Gerstein, H.C., Branch, K., Heenan, L., Prato, S. Del, Khurmi, N.S., Lam, C.S.P., et al. (2021). Design and baseline characteristics of the AMPLITUDE-O cardiovascular outcomes trial of efpeglenatide, a weekly glucagon-like peptide-1 receptor agonist. Diabetes Obes. Metab. 23 : 318–323. Gerstein, H.C., Colhoun, H.M., Dagenais, G.R., Diaz, R., Lakshmanan, M., Pais, P., et al. (2019). Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. The Lancet 394 : 121–130. Gerstein, H.C., Li, Z., Ramasundarahettige, C., Baek, S., Branch, K.R.H., Prato, S. Del, et al. (2023). Exploring the Relationship between Efpeglenatide Dose and Cardiovascular Outcomes in Type 2 Diabetes: Insights from the AMPLITUDE-O Trial. Circulation 147 : 1004–1013. Getty-Kaushik, L., Song, D.H., Boylan, M.O., Corkey, B.E., and Wolfe, M.M. (2006). Glucose-dependent insulinotropic polypeptide modulates adipocyte lipolysis and reesterification. Obesity (Silver Spring). 14 : 1124–31. Giorgino, F., Benroubi, M., Sun, J.H., Zimmermann, A.G., and Pechtner, V. (2015). Efficacy and safety of once- weekly dulaglutide versus insulin glargine in patients with type 2 Diabetes on metformin and glimepiride (AWARD-2). Diabetes Care 38 : 2241–2249. Gorboulev, V., Schürmann, A., Vallon, V., Kipp, H., Jaschke, A., Klessen, D., et al. (2012). Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 61 : 187–96. Gough, S.C.L., Bode, B., Woo, V., Rodbard, H.W., Linjawi, S., Poulsen, P., et al. (2014). Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: Results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2 : 885–893. Gribble, F.M., and Reimann, F. (2019). Function and mechanisms of enteroendocrine cells and gut hormones in metabolism. Nat. Rev. Endocrinol. 15 : 226–237. Guettet, C., Mathe, D., Riottot, M., and Lutton, C. (1988). Effects of chronic glucagon administration on cholesterol and bile acid metabolism. Biochim. Biophys. Acta 963 : 215–23. Guja, C., Frías, J.P., Somogyi, A., Jabbour, S., Wang, H., Hardy, E., et al. (2018). Effect of exenatide QW or placebo, both added to titrated insulin glargine, in uncontrolled type 2 diabetes: The DURATION-7 randomized study. Diabetes Obes. Metab. 20 : 1602–1614. Hankosky, E.R., Wang, H., Neff, L.M., Kan, H., Wang, F., Ahmad, N.N., et al. (2023). Tirzepatide reduces the predicted risk of developing type 2 diabetes in people with obesity or overweight: Post hoc analysis of the SURMOUNT-1 trial. Diabetes Obes. Metab. 25 : 3748–3756. Hein, G.J., Baker, C., Hsieh, J., Farr, S., and Adeli, K. (2013). GLP-1 and GLP-2 as yin and yang of intestinal lipoprotein production: evidence for predominance of GLP-2-stimulated postprandial lipemia in normal and insulin-resistant states. Diabetes 62 : 373–81. Hirasawa, A., Tsumaya, K., Awaji, T., Katsuma, S., Adachi, T., Yamada, M., et al. (2005). Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat. Med. 11 : 90–4. Hoffman, S., and Adeli, K. (2024). Glucagon-like peptide (GLP)-1 regulation of lipid and lipoprotein metabolism. Medical Review (2021) 4 : 301–311. Holman, R.R., Bethel, M.A., Mentz, R.J., Thompson, V.P., Lokhnygina, Y., Buse, J.B., et al. (2017). Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine 377 : 1228–1239. Horn, D.B., Ryan, D.H., Kis, S.G., Alves, B., Mu, Y., Kim, S.G., et al. (2025). Orforglipron, an oral small-molecule GLP-1 receptor agonist, for the treatment of obesity in people with type 2 diabetes (ATTAIN-2): a phase 3, double-blind, randomised, multicentre, placebo-controlled trial. The Lancet. Hsieh, J., Longuet, C., Baker, C.L., Qin, B., Federico, L.M., Drucker, D.J., et al. (2010). The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice. Diabetologia 53 : 552–61. Hsieh, J., Longuet, C., Maida, A., Bahrami, J., Xu, E., Baker, C.L., et al. (2009). Glucagon-like peptide-2 increases intestinal lipid absorption and chylomicron production via CD36. Gastroenterology 137 : 997–1005, 1005.e1–4. Husain, M., Birkenfeld, A.L., Donsmark, M., Dungan, K., Eliaschewitz, F.G., Franco, D.R., et al. (2019). Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine 381 : 841–851. Jason Wu Vanessa Wang Ascletis Pharma, J. ASC30, an Oral GLP-1R Biased Small Molecule Agonist Demonstrated Superior Weigh Loss in Participants with Obesity: A 28-Day Multiple Ascending Dose Study. Jastreboff, A.M., Aronne, L.J., Ahmad, N.N., Wharton, S., Connery, L., Alves, B., et al. (2022). Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine 387 : 205–216. Jastreboff, A.M., Kaplan, L.M., Frías, J.P., Wu, Q., Du, Y., Gurbuz, S., et al. (2023). Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine 389 : 514–526. Jastreboff, A.M., Ryan, D.H., Bays, H.E., Ebeling, P.R., Mackowski, M.G., Philipose, N., et al. (2025). Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity — A Phase 2 Trial. New England Journal of Medicine 393 : 843–857. Ji, L., Gao, L., Xue, H., Tian, J., Wang, K., Jiang, H., et al. (2025a). Efficacy and safety of a biased GLP-1 receptor agonist ecnoglutide in adults with overweight or obesity: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 13 : 777–789. Ji, L., Jiang, H., Bi, Y., Li, H., Tian, J., Liu, D., et al. (2025b). Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight. New England Journal of Medicine 392 : 2215–2225. Ji, L., Jiang, H., Cheng, Z., Qiu, W., Liao, L., Zhang, Y., et al. (2023). A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity. Nat. Commun. 14 :. Johnson, E.L., Feldman, H., Butts, A., Chamberlain, J., Collins, B., Doyle-Delgado, K., et al. (2020). Standards of medical care in diabetes—2020 abridged for primary care providers. Clinical Diabetes 38 : 10–38. Kadowaki, T., Heftdal, L.D., Ko, H.-J., Overvad, M., Shimomura, I., Thamattoor, U.K., et al. (2025). Oral Semaglutide in an East Asian Population With Overweight or Obesity, With or Without Type 2 Diabetes: The OASIS 2 Randomized Clinical Trial. JAMA Intern. Med. 185 : 1206–1217. Kadowaki, T., Isendahl, J., Khalid, U., Lee, S.Y., Nishida, T., Ogawa, W., et al. (2022). Semaglutide once a week in adults with overweight or obesity, with or without type 2 diabetes in an east Asian population (STEP 6): a randomised, double-blind, double-dummy, placebo-controlled, phase 3a trial. Lancet Diabetes Endocrinol. 10 : 193–206. Kailera (2025). KAI-7535 Phase 1, Open-Label, Randomized, Crossover Study in Healthy Participants Living With Obesity or Overweight. Kim, S.-J., Nian, C., and McIntosh, C.H.S. (2010). GIP increases human adipocyte LPL expression through CREB and TORC2-mediated trans-activation of the LPL gene. J. Lipid Res. 51 : 3145–57. Knop, F.K., Aroda, V.R., Vale, R.D. do, Holst-Hansen, T., Laursen, P.N., Rosenstock, J., et al. (2023). Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet 402 : 705–719. Kooijman, S., Wang, Y., Parlevliet, E.T., Boon, M.R., Edelschaap, D., Snaterse, G., et al. (2015). Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice. Diabetologia 58 : 2637–46. Kosiborod, M.N., Platz, E., Wharton, S., Roux, C.W. le, Brueckmann, M., Ajaz Hussain, S., et al. (2024). Survodutide for the Treatment of Obesity: Rationale and Design of the SYNCHRONIZE Cardiovascular Outcomes Trial. JACC Heart Fail. 12 : 2101–2109. Krüger, N., Schneeweiss, S., Desai, R.J., Sreedhara, S.K., Kehoe, A.R., Fuse, K., et al. (2025). Cardiovascular outcomes of semaglutide and tirzepatide for patients with type 2 diabetes in clinical practice. Nat. Med. Lam, C.S.P., Ramasundarahettige, C., Branch, K.R.H., Sattar, N., Rosenstock, J., Pratley, R., et al. (2022). Efpeglenatide and Clinical Outcomes With and Without Concomitant Sodium-Glucose Cotransporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial. Circulation 145 : 565–574. Lamina, C., and Ward, N.C. (2022). Lipoprotein (a) and diabetes mellitus. Atherosclerosis 349 : 63–71. Lange, P. de, Lombardi, A., Silvestri, E., Goglia, F., Lanni, A., and Moreno, M. (2008). Peroxisome Proliferator-Activated Receptor Delta: A Conserved Director of Lipid Homeostasis through Regulation of the Oxidative Capacity of Muscle. PPAR Res. 2008 : 172676. Lau, D.C.W., Erichsen, L., Francisco, A.M., Satylganova, A., Roux, C.W. le, McGowan, B., et al. (2021). Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial. The Lancet 398 : 2160–2172. Li, R., Sun, X., Li, P., Li, W., Zhao, L., Zhu, L., et al. (2021). GLP-1-Induced AMPK Activation Inhibits PARP-1 and Promotes LXR-Mediated ABCA1 Expression to Protect Pancreatic β-Cells Against Cholesterol-Induced Toxicity Through Cholesterol Efflux. Front. Cell Dev. Biol. 9 : 646113. Li, W., Liu, M., Dong, R., Wang, X., Zhao, J., Zhao, L., et al. (2025). 769-P: Bofanglutide (GZR18), a Novel GLP-1RA, Improved Glycemic Control and Cardiometabolic Risk Factors in Chinese Patients with T2D. Light, P.E., Manning Fox, J.E., Riedel, M.J., and Wheeler, M.B. (2002). Glucagon-like peptide-1 inhibits pancreatic ATP-sensitive potassium channels via a protein kinase A- and ADP-dependent mechanism. Mol. Endocrinol. 16 : 2135–44. Lingvay, I., Benamar, M., Chen, L., Fu, A., Jódar, E., Nishida, T., et al. (2025a). Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial. Diabetologia 68 : 739–751. Lingvay, I., Bergenheim, S.J., Buse, J.B., Freitas, P., Garvey, W.T., Harder-Lauridsen, N.M., et al. (2025b). Once-weekly semaglutide 7·2 mg in adults with obesity and type 2 diabetes (STEP UP T2D): a randomised, controlled, phase 3b trial. Lancet Diabetes Endocrinol. Liskiewicz, D., Novikoff, A., Khalil, A., Campbell, J., Serrano, A.C., Douros, J., et al. (2025). An unimolecular GLP-1R/GIPR/Pan-PPAR quintuple agonist eliminates obesity and insulin resistance in miceAn unimolecular GLP-1R/GIPR/Pan-PPAR quintuple agonist eliminates obesity and insulin resistance in mice. Lockie, S.H., Heppner, K.M., Chaudhary, N., Chabenne, J.R., Morgan, D.A., Veyrat-Durebex, C., et al. (2012). Direct Control of Brown Adipose Tissue Thermogenesis by Central Nervous System Glucagon-Like Peptide-1 Receptor Signaling. Diabetes 61 : 2753–2762. Longuet, C., Sinclair, E.M., Maida, A., Baggio, L.L., Maziarz, M., Charron, M.J., et al. (2008a). The glucagon receptor is required for the adaptive metabolic response to fasting. Cell Metab. 8 : 359–71. Longuet, C., Sinclair, E.M., Maida, A., Baggio, L.L., Maziarz, M., Charron, M.J., et al. (2008b). The glucagon receptor is required for the adaptive metabolic response to fasting. Cell Metab. 8 : 359–71. Look, M., Dunn, J.P., Kushner, R.F., Cao, D., Harris, C., Gibble, T.H., et al. (2025). Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study of adults with obesity or overweight. Diabetes Obes. Metab. 27 : 2720–2729. Ludvik, B., Frías, J.P., Tinahones, F.J., Wainstein, J., Jiang, H., Robertson, K.E., et al. (2018). Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 6 : 370–381. Lutz, T.A. (2012). Control of energy homeostasis by amylin. Cell. Mol. Life Sci. 69 : 1947–65. Lutz, T.A., Senn, M., Althaus, J., Prete, E. Del, Ehrensperger, F., and Scharrer, E. (1998). Lesion of the area postrema/nucleus of the solitary tract (AP/NTS) attenuates the anorectic effects of amylin and calcitonin gene-related peptide (CGRP) in rats. Peptides (N.Y.). 19 : 309–17. Lyons, S.A., Lea, M.B.S., Parikh, M., Guo, Z., Kagdi, S., Bisnauth, A.R., et al. (2025). Acute exogenous acyl-GIP treatment enhances lipid handling and fatty acid oxidation by involving brown fat. EMBO Rep. 26 : 5154–5171. Ma, X., Liu, R., Pratt, E.J., Benson, C.T., Bhattachar, S.N., and Sloop, K.W. (2024). Effect of Food Consumption on the Pharmacokinetics, Safety, and Tolerability of Once-Daily Orally Administered Orforglipron (LY3502970), a Non-peptide GLP-1 Receptor Agonist. Diabetes Therapy 15 : 819–832. Mamas, M.A., Bays, H., Li, R., Upadhyay, N., Irani, T., Senyucel, C., et al. (2025). Tirzepatide compared with semaglutide and 10-year cardiovascular disease risk reduction in obesity: post-hoc analysis of the SURMOUNT-5 trial. European Heart Journal Open 5 :. Marso, S.P., Bain, S.C., Consoli, A., Eliaschewitz, F.G., Jódar, E., Leiter, L.A., et al. (2016). Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine 375 : 1834–1844. McGowan, B.M., Bruun, J.M., Capehorn, M., Pedersen, S.D., Pietiläinen, K.H., Muniraju, H.A.K., et al. (2024). Efficacy and safety of once-weekly semaglutide 2·4 mg versus placebo in people with obesity and prediabetes (STEP 10): a randomised, double-blind, placebo-controlled, multicentre phase 3 trial. Lancet Diabetes Endocrinol. 12 : 631–642. Meek, T.H., Matsen, M.E., Dorfman, M.D., Guyenet, S.J., Damian, V., Nguyen, H.T., et al. (2013). Leptin action in the ventromedial hypothalamic nucleus is sufficient, but not necessary, to normalize diabetic hyperglycemia. Endocrinology 154 : 3067–76. Mosenzon, O., Blicher, T.M., Rosenlund, S., Eriksson, J.W., Heller, S., Hels, O.H., et al. (2019). Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 7 : 515–527. Nahra, R., Wang, T., Gadde, K.M., Oscarsson, J., Stumvoll, M., Jermutus, L., et al. (2021). Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or obesity and type 2 diabetes: A 54-week randomized phase 2b study. Diabetes Care 44 : 1433–1442. Nicholls, S.J., Pavo, I., Bhatt, D.L., Buse, J.B., Prato, S. Del, Kahn, S.E., et al. (2025a). Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes. New England Journal of Medicine 393 : 2409–2420. Nicholls, S.J., Ryan, D.H., Deanfield, J., Ferreira, D., Lang, C.C., Lincoff, A.M., et al. (2025b). Semaglutide and Hospitalizations in Patients With Obesity and Established Cardiovascular Disease. JAMA Cardiol. Norata, G.D., Grigore, L., Raselli, S., Redaelli, L., Hamsten, A., Maggi, F., et al. (2007). Post-prandial endothelial dysfunction in hypertriglyceridemic subjects: Molecular mechanisms and gene expression studies. Atherosclerosis 193 : 321–327. Novo Nordisk A/S (2026). REIMAGINE 2 trial. Parker, V.E.R., Robertson, D., Erazo-Tapia, E., Havekes, B., Phielix, E., Ligt, M. de, et al. (2023). Cotadutide promotes glycogenolysis in people with overweight or obesity diagnosed with type 2 diabetes. Nat. Metab. 5 : 2086–2093. Parker, V.E.R., Robertson, D., Wang, T., Hornigold, D.C., Petrone, M., Cooper, A.T., et al. (2020). Efficacy, Safety, and Mechanistic Insights of Cotadutide, a Dual Receptor Glucagon-Like Peptide-1 and Glucagon Agonist. Journal of Clinical Endocrinology and Metabolism 105 :. Patel, V., Joharapurkar, A., Kshirsagar, S., Sutariya, B., Patel, M., Patel, H., et al. (2018). Central administration of coagonist of GLP-1 and glucagon receptors improves dyslipidemia. Biomed. Pharmacother. 98 : 364–371. Peng, I.-C., Chen, Z., Sun, W., Li, Y.-S., Marin, T.L., Hsu, P.-H., et al. (2012). Glucagon regulates ACC activity in adipocytes through the CAMKKβ/AMPK pathway. Am. J. Physiol. Endocrinol. Metab. 302 : E1560-8. Pieber, T.R., Bode, B., Mertens, A., Cho, Y.M., Christiansen, E., Hertz, C.L., et al. (2019). Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 7 : 528–539. Pirner, M.A., Lin, J., Liu, F., Yao, L., Zettler, M.E., and Valacer, D.J. (2022). A Phase 1, Double-Blind, Placebo-Controlled Multiple Escalating Dose Study of RGT-075, a Novel Small-Molecule Oral GLP-1 Receptor Agonist in Adults with Type 2 Diabetes. Pi-Sunyer, X., Astrup, A., Fujioka, K., Greenway, F., Halpern, A., Krempf, M., et al. (2015). A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. New England Journal of Medicine 373 : 11–22. Potes, C.S., Turek, V.F., Cole, R.L., Vu, C., Roland, B.L., Roth, J.D., et al. (2010). Noradrenergic neurons of the area postrema mediate amylin’s hypophagic action. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299 : R623-31. Pratley, R., Amod, A., Hoff, S.T., Kadowaki, T., Lingvay, I., Nauck, M., et al. (2019). Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet 394 : 39–50. Pratley, R.E., Jacob, S., Baek, S., Trautmann, M.E., Hompesch, M., Han, O., et al. (2022). Efficacy and safety of efpeglenatide in key patient subgroups from the BALANCE randomized trial, stratified by pre-diabetes status, BMI, and age at baseline. BMJ Open Diabetes Res. Care 10 :. Prato, S. Del, Kahn, S.E., Pavo, I., Weerakkody, G.J., Yang, Z., Doupis, J., et al. (2021). Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. The Lancet 398 : 1811–1824. Pratt, E., Ma, X., Liu, R., Robins, D., Haupt, A., Coskun, T., et al. (2023). Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1a, blinded, placebo-controlled, randomized, single- and multiple-ascending-dose study in healthy participants. Diabetes Obes. Metab. 25 : 2634–2641. Ramracheya, R., Chapman, C., Chibalina, M., Dou, H., Miranda, C., González, A., et al. (2018). GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca2+ channels. Physiol. Rep. 6 : e13852. Regor (2025). Phase 2a Topline Results for RGT-075. Roche (2024). CT-996 development and initial data. Roche (2025). CT-868 Corporate Presentation. Rodbard, H.W., Rosenstock, J., Canani, L.H., Deerochanawong, C., Gumprecht, J., Lindberg, S.Ø., et al. (2019). Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: The PIONEER 2 trial. Diabetes Care 42 : 2272–2281. Romeo, S., Vidal-Puig, A., Husain, M., Ahima, R., Arca, M., Bhatt, D.L., et al. (2025). Clinical staging to guide management of metabolic disorders and their sequelae: a European Atherosclerosis Society consensus statement. Eur. Heart J. 46 : 3685–3713. Rosenstock, J., Allison, D., Birkenfeld, A.L., Blicher, T.M., Deenadayalan, S., Jacobsen, J.B., et al. (2019). Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults with Type 2 Diabetes Uncontrolled with Metformin Alone or with Sulfonylurea: The PIONEER 3 Randomized Clinical Trial. JAMA - Journal of the American Medical Association 321 : 1466–1480. Rosenstock, J., Hsia, S., Nevarez Ruiz, L., Eyde, S., Cox, D., Wu, W.-S., et al. (2025). Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes. New England Journal of Medicine 393 : 1065–1076. Rosenstock, J., Wysham, C., Frías, J.P., Kaneko, S., Lee, C.J., Fernández Landó, L., et al. (2021). Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. The Lancet 398 : 143–155. Roux, C.W. le, Steen, O., Lucas, K.J., Startseva, E., Unseld, A., and Hennige, A.M. (2024). Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial. Lancet Diabetes Endocrinol. 12 : 162–173. Roux, C.W. le, Wharton, S., Bozkurt, B., Platz, E., Bleckert, G., Ajaz Hussain, S., et al. (2026). Survodutide for treatment of obesity: Baseline characteristics of participants in a randomized, double-blind, placebo-controlled, phase 3 trial (SYNCHRONIZE TM -1). Diabetes Obes. Metab. 28 : 337–346. Rubino, D., Abrahamsson, N., Davies, M., Hesse, D., Greenway, F.L., Jensen, C., et al. (2021). Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults with Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA - Journal of the American Medical Association 325 : 1414–1425. Sanyal, A.J., Bedossa, P., Fraessdorf, M., Neff, G.W., Lawitz, E., Bugianesi, E., et al. (2024). A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. New England Journal of Medicine 391 : 311–319. Sanyal, A.J., Newsome, P.N., Kliers, I., Østergaard, L.H., Long, M.T., Kjær, M.S., et al. (2025). Phase 3 Trial of Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis. New England Journal of Medicine 392 : 2089–2099. Schinner, S., Dellas, C., Schroder, M., Heinlein, C.A., Chang, C., Fischer, J., et al. (2002). Repression of glucagon gene transcription by peroxisome proliferator-activated receptor gamma through inhibition of Pax6 transcriptional activity. J. Biol. Chem. 277 : 1941–8. Selvarajah, V., Robertson, D., Hansen, L., Jermutus, L., Smith, K., Coggi, A., et al. (2024). A randomized phase 2b trial examined the effects of the glucagon-like peptide-1 and glucagon receptor agonist cotadutide on kidney outcomes in patients with diabetic kidney disease. Kidney Int. 106 : 1170–1180. Sniderman, A.D., Thanassoulis, G., Glavinovic, T., Navar, A.M., Pencina, M., Catapano, A., et al. (2019). Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review. JAMA Cardiol. 4 : 1287–1295. Sorli, C., Harashima, S. ichi, Tsoukas, G.M., Unger, J., Karsbøl, J.D., Hansen, T., et al. (2017). Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 5 : 251–260. Structure Therapeutics (2024). GSBR-1290 Obesity Topline Data Presentation. Sugden, M.C., and Holness, M.J. (2004). Potential role of peroxisome proliferator-activated receptor-alpha in the modulation of glucose-stimulated insulin secretion. Diabetes 53 Suppl 1 : S71-81. Terns Pharmaceuticals (2024). Terns Pharmaceuticals Announces Positive Phase 1 Clinical Trial Results with TERN-601 Once-Daily Oral GLP-1R Agonist for the Treatment of Obesity. Thomas, C., Gioiello, A., Noriega, L., Strehle, A., Oury, J., Rizzo, G., et al. (2009). TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 10 : 167–77. Thondam, S.K., Cuthbertson, D.J., and Wilding, J.P.H. (2020). The influence of Glucose-dependent Insulinotropic Polypeptide (GIP) on human adipose tissue and fat metabolism: Implications for obesity, type 2 diabetes and Non-Alcoholic Fatty Liver Disease (NAFLD). Peptides (N.Y.). 125 : 170208. Trabelsi, M.-S., Daoudi, M., Prawitt, J., Ducastel, S., Touche, V., Sayin, S.I., et al. (2015). Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat. Commun. 6 : 7629. VESPER (2025). Phase 2b Study to Evaluate the Efficacy and Safety of Once-Monthly MET097 in Adults With Obesity or Overweight. Viking Therapeutics (2025). VK-2735 Corporate Presentation. Vivani Medical (2024). Vivani Medical Announces Positive NPM115 Preclinical Weight Loss Data. Volčanšek, Š., Koceva, A., Jensterle, M., Janež, A., and Muzurović, E. (2025). Amylin: From Mode of Action to Future Clinical Potential in Diabetes and Obesity. Diabetes Ther. 16 : 1207–1227. Wadden, T.A., Bailey, T.S., Billings, L.K., Davies, M., Frias, J.P., Koroleva, A., et al. (2021). Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults with Overweight or Obesity: The STEP 3 Randomized Clinical Trial. JAMA - Journal of the American Medical Association 325 : 1403–1413. Wadden, T.A., Chao, A.M., Machineni, S., Kushner, R., Ard, J., Srivastava, G., et al. (2023). Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat. Med. 29 : 2909–2918. Wadden, T.A., Tronieri, J.S., Sugimoto, D., Lund, M.T., Auerbach, P., Jensen, C., et al. (2020). Liraglutide 3.0 mg and Intensive Behavioral Therapy (IBT) for Obesity in Primary Care: The SCALE IBT Randomized Controlled Trial. Obesity 28 : 529–536. Wasada, T., McCorkle, K., Harris, V., Kawai, K., Howard, B., and Unger, R.H. (1981). Effect of gastric inhibitory polypeptide on plasma levels of chylomicron triglycerides in dogs. J. Clin. Invest. 68 : 1106–7. Wharton, S., Blevins, T., Connery, L., Rosenstock, J., Raha, S., Liu, R., et al. (2023). Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. New England Journal of Medicine 389 : 877–888. Wharton, S., Lingvay, I., Bogdanski, P., Duque do Vale, R., Jacob, S., Karlsson, T., et al. (2025a). Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity. New England Journal of Medicine 393 : 1077–1087. Wharton, S., Roux, C.W. le, Bozkurt, B., Platz, E., Bleckert, G., Ajaz Hussain, S., et al. (2025b). Baseline characteristics in the SYNCHRONIZE TM -2 randomized phase 3 trial of survodutide, a glucagon receptor/GLP-1 receptor dual agonist, for obesity in people with type 2 diabetes. Diabetes Obes. Metab. Wicik, Z., Nowak-Szwed, A., Eyileten, C., Sourij, H., Lewinski, D. von, Kistkins, S., et al. (2025). Integrative gene-metabolite network analysis of GLP-1 receptor agonists and related incretin pathways in cardiometabolic health. NPJ Syst. Biol. Appl. 11 : 144. Wilding, J.P.H., Batterham, R.L., Calanna, S., Davies, M., Gaal, L.F. Van, Lingvay, I., et al. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine 384 : 989–1002. Wysham, C., Bergenstal, R., Malloy, J., Yan, P., Walsh, B., Malone, J., et al. (2011). DURATION-2: Efficacy and safety of switching from maximum daily sitagliptin or pioglitazone to once-weekly exenatide. Diabetic Medicine 28 : 705–714. Wysham, C., Blevins, T., Arakaki, R., Colon, G., Garcia, P., Atisso, C., et al. (2014). Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care 37 : 2159–2167. Yabe, D., Nakamura, J., Kaneto, H., Deenadayalan, S., Navarria, A., Gislum, M., et al. (2020). Safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes (PIONEER 10): an open-label, randomised, active-controlled, phase 3a trial. Lancet Diabetes Endocrinol. 8 : 392–406. Yamada, Y., Katagiri, H., Hamamoto, Y., Deenadayalan, S., Navarria, A., Nishijima, K., et al. (2020). Dose-response, efficacy, and safety of oral semaglutide monotherapy in Japanese patients with type 2 diabetes (PIONEER 9): a 52-week, phase 2/3a, randomised, controlled trial. Yan, Y., Niu, Z., Sun, C., Li, P., Shen, S., Liu, S., et al. (2022). Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism. Nat. Commun. 13 : 6408. Yang, S.-H., Xu, R.-X., Cui, C.-J., Wang, Y., Du, Y., Chen, Z.-G., et al. (2018). Liraglutide downregulates hepatic LDL receptor and PCSK9 expression in HepG2 cells and db/db mice through a HNF-1a dependent mechanism. Cardiovasc. Diabetol. 17 : 48. Yao, Y., Li, Q., Gao, P., Wang, W., Chen, L., Zhang, J., et al. (2018). Glucagon-like peptide-1 contributes to increases ABCA1 expression by downregulating miR-758 to regulate cholesterol homeostasis. Biochem. Biophys. Res. Commun. 497 : 652–658. Ying, Z., Eenige, R. van, Ge, X., Marwijk, C. van, Lambooij, J.M., Guigas, B., et al. (2023). Combined GIP receptor and GLP1 receptor agonism attenuates NAFLD in male APOE∗3-Leiden.CETP mice. EBioMedicine 93 : 104684. Zhang, B., Cheng, Z., Chen, J., Zhang, X., Liu, D., Jiang, H., et al. (2024). Efficacy and safety of mazdutide in chinese patients with type 2 diabetes: A randomized, double-blind, placebo-controlled phase 2 trial. Diabetes Care 47 : 160–168. Zhang, Z., Du, Z., Liu, Q., Wu, T., Tang, Q., Zhang, J., et al. (2021). Glucagon-like peptide 1 analogue prevents cholesterol gallstone formation by modulating intestinal farnesoid X receptor activity. Metabolism 118 : 154728. Zhao, J., Zhao, M., Song, W., Wang, D., Zhang, X., Hui, Y., et al. (2024). Efficacy and safety of HRS9531, a novel dual GLP-1/GIP receptor agonist, in patients with type 2 diabetes mellitus (T2DM): a randomized, double-blind, placebo-controlled phase 2 trial. Zhu, D., Zhao, J., Cai, H., Chu, X., Xiu, S., Song, C., et al. (2025). Mazdutide versus placebo in Chinese adults with type 2 diabetes. Nature. Zinman, B., Aroda, V.R., Buse, J.B., Cariou, B., Harris, S.B., Hoff, S.T., et al. (2019a). Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: The PioNEER 8 trial. Diabetes Care 42 : 2262–2271. Zinman, B., Bhosekar, V., Busch, R., Holst, I., Ludvik, B., Thielke, D., et al. (2019b). Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 7 : 356–367. Züger, D., Forster, K., Lutz, T.A., and Riediger, T. (2013). Amylin and GLP-1 target different populations of area postrema neurons that are both modulated by nutrient stimuli. Physiol. Behav. 112–113 : 61–9. Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Authors Metrics & Citations Metrics Article Usage 380views 159downloads Citations Download citation Baragetti A, Danilo Norata. Impact of Incretin analogues on lipid and lipoprotein metabolism in obesity and diabetes. Authorea. 07 February 2026. DOI: https://doi.org/10.22541/au.177050005.57383776/v1 DOI: https://doi.org/10.22541/au.177050005.57383776/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.