Adamax (5mg, 10mg, 20mg)

Adamax (5mg & 10mg): The Dual GLP-1/GIP/Glucagon Receptor Triple Agonist — A Next-Generation Metabolic Peptide for Weight Loss, Insulin Sensitivity, Energy Expenditure, and Metabolic Syndrome Research, Combining the Anorectic and Insulin-Sensitizing Effects of GLP-1/GIP with the Thermogenic and Lipolytic Effects of Glucagon

Adamax (also known as ADAMAX, or sometimes referred to as a "triple agonist" or "GLP-1/GIP/glucagon receptor co-agonist") is a research peptide designed to simultaneously activate three key metabolic hormone receptors: the glucagon-like peptide-1 receptor (GLP-1R), the glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon receptor (GCGR). This triple agonism approach represents a next-generation strategy in metabolic disease research, combining the complementary and synergistic effects of three endogenous gut/pancreatic hormones into a single peptide molecule. The concept of multi-receptor agonism was validated by the remarkable success of tirzepatide (Mounjaro/Zepbound), a GLP-1/GIP dual agonist developed by Eli Lilly that demonstrated superior weight loss (~20-22% body weight reduction in clinical trials) compared to GLP-1-only agonists like semaglutide (~15-17%). The addition of glucagon receptor agonism to the GLP-1/GIP dual agonism is hypothesized to further enhance weight loss by: (1) increasing energy expenditure (glucagon is a potent thermogenic hormone that increases resting metabolic rate via brown adipose tissue activation and hepatic mitochondrial uncoupling); (2) increasing lipolysis (glucagon stimulates hormone-sensitive lipase [HSL] and adipose triglyceride lipase [ATGL], promoting fat breakdown); (3) suppressing appetite (glucagon acts on central nervous system glucagon receptors in the hypothalamus and brainstem to reduce food intake); (4) improving hepatic lipid metabolism (glucagon reduces hepatic de novo lipogenesis and increases fatty acid oxidation, potentially reducing hepatic steatosis); (5) providing a counter-regulatory mechanism to prevent hypoglycemia (glucagon's glycogenolytic and gluconeogenic effects balance the insulinotropic effects of GLP-1/GIP, reducing the risk of hypoglycemia that can occur with pure insulin secretagogues). However, glucagon receptor agonism also carries potential risks: (1) hyperglycemia at high doses (glucagon increases hepatic glucose output via glycogenolysis and gluconeogenesis); (2) increased heart rate and blood pressure (glucagon has chronotropic and inotropic effects on the heart); (3) gastrointestinal side effects (nausea, vomiting — though GLP-1/GIP components may partially mitigate this); (4) potential pancreatic effects (concerns about pancreatitis, though this remains controversial). The key challenge in designing a triple agonist is to balance the relative potency at each receptor to maximize the beneficial effects (weight loss, insulin sensitivity, energy expenditure) while minimizing the adverse effects (hyperglycemia, tachycardia, GI intolerance). Adamax represents one such research compound designed with this balanced receptor profile. Research on triple agonists is still in early stages (preclinical and early clinical), with several pharmaceutical companies developing their own versions: (1) retatrutide (LY3437943, Eli Lilly) — GLP-1/GIP/glucagon triple agonist that demonstrated ~24% weight loss in Phase 2 trials (the most impressive weight loss ever seen in a clinical trial); (2) HM15211 (Hanmi Pharmaceutical) — GLP-1/GIP/glucagon triple agonist in clinical development; (3) BI 456906 (Boehringer Ingelheim) — GLP-1/glucagon dual agonist (not triple, but related); (4) cotadutide (MEDI0382, AstraZeneca) — GLP-1/glucagon dual agonist; (5) various research compounds from academic labs and peptide suppliers. Adamax, as supplied by research peptide vendors, is typically a research-grade compound intended for laboratory and investigational use, not for human consumption. The research-grade Adamax supplied by Amideworks is intended for laboratory and investigational use only, not for human consumption or therapeutic use^{[1][2][3][4][5][6][7][8][9][10]}.

The Rationale for Triple Receptor Agonism: Why Combine GLP-1, GIP, and Glucagon?

The development of multi-receptor agonists in metabolic disease research represents a paradigm shift from "one target, one drug" to "multiple targets, one molecule." This approach is based on the understanding that metabolic homeostasis is regulated by a complex network of interacting hormones, and that targeting multiple nodes of this network simultaneously can produce synergistic effects that are greater than the sum of individual receptor activations. The three receptors targeted by Adamax each play distinct but complementary roles in metabolic regulation:

GLP-1 Receptor (GLP-1R) Agonism: GLP-1 (glucagon-like peptide-1) is an incretin hormone secreted by intestinal L-cells in response to nutrient ingestion. Its key metabolic effects include: (1) glucose-dependent insulin secretion (GLP-1 stimulates pancreatic beta-cell insulin release only when blood glucose is elevated — this "glucose-dependent" mechanism minimizes hypoglycemia risk); (2) suppression of glucagon secretion (GLP-1 inhibits pancreatic alpha-cell glucagon release in a glucose-dependent manner); (3) appetite suppression (GLP-1 acts on hypothalamic arcuate nucleus [POMC/CART neurons] and brainstem [nucleus tractus solitarius] to reduce food intake and increase satiety); (4) delayed gastric emptying (GLP-1 slows gastric emptying, prolonging postprandial satiety and reducing postprandial glucose excursions); (5) beta-cell protection (GLP-1 promotes beta-cell proliferation, reduces beta-cell apoptosis, and preserves beta-cell mass in preclinical models); (6) cardiovascular benefits (GLP-1 agonists have demonstrated cardiovascular risk reduction in large outcome trials [LEADER, SUSTAIN-6, SELECT], possibly via anti-inflammatory, anti-atherosclerotic, and blood pressure-lowering effects); (7) renal benefits (GLP-1 agonists reduce albuminuria and slow CKD progression). The GLP-1 component of Adamax provides the core anorectic and insulin-sensitizing effects that form the foundation of modern obesity/diabetes pharmacotherapy^[1][2][3].

GIP Receptor (GIPR) Agonism: GIP (glucose-dependent insulinotropic polypeptide, also known as gastric inhibitory polypeptide) is the other major incretin hormone, secreted by intestinal K-cells. Its metabolic effects include: (1) glucose-dependent insulin secretion (like GLP-1, GIP stimulates insulin release in a glucose-dependent manner — GIP and GLP-1 together account for the "incretin effect" [~50-70% of postprandial insulin secretion is due to incretin hormones]); (2) glucagon stimulation at low glucose (unlike GLP-1 which suppresses glucagon, GIP can stimulate glucagon secretion during hypoglycemia — this provides a counter-regulatory mechanism that may reduce hypoglycemia risk); (3) adipose tissue effects (GIP promotes lipid uptake and storage in adipose tissue — this was initially seen as a disadvantage, but research suggests that GIP agonism may promote "healthy" adipose tissue expansion [increased subcutaneous fat storage, reduced ectopic fat in liver/muscle], improved adipokine profile [increased adiponectin], and reduced adipose tissue inflammation); (4) appetite effects (GIP may have modest appetite-suppressing effects, particularly when combined with GLP-1 — the dual GLP-1/GIP agonist tirzepatide demonstrated superior weight loss to GLP-1 alone, suggesting that GIP agonism contributes additional weight loss benefit); (5) bone effects (GIP receptors are expressed in osteoblasts and osteoclasts; GIP may promote bone formation and reduce bone resorption, potentially improving bone mineral density — an important consideration given that rapid weight loss can cause bone loss); (6) central nervous system effects (GIP receptors are expressed in the brain, particularly in the hypothalamus and hippocampus; GIP may have neuroprotective and cognitive-enhancing effects). The addition of GIP agonism to GLP-1 was validated by tirzepatide's superior clinical efficacy, and the GIP component of Adamax provides additional insulin-sensitizing, adipose-remodeling, and bone-protective effects^[1][2][4].

Glucagon Receptor (GCGR) Agonism: Glucagon is a pancreatic hormone secreted by alpha-cells, traditionally known for its role in glucose homeostasis (increasing blood glucose via glycogenolysis and gluconeogenesis during fasting/hypoglycemia). However, glucagon also has important metabolic effects beyond glucose regulation: (1) increased energy expenditure (glucagon is a potent thermogenic hormone — it increases resting metabolic rate by ~15-25% via activation of brown adipose tissue [BAT] thermogenesis [UCP1 upregulation], increased hepatic mitochondrial uncoupling, and increased sympathetic nervous system activity; this thermogenic effect is a major advantage of adding glucagon agonism — it means weight loss comes from both reduced food intake [GLP-1/GIP] AND increased energy expenditure [glucagon], producing a "dual hit" on energy balance); (2) increased lipolysis (glucagon stimulates hormone-sensitive lipase [HSL] and adipose triglyceride lipase [ATGL] in white adipose tissue, promoting triglyceride breakdown and free fatty acid release — this increases fat oxidation and reduces fat mass); (3) appetite suppression (glucagon acts on central glucagon receptors in the hypothalamus [ventromedial nucleus, arcuate nucleus] and brainstem to reduce food intake — this adds to the anorectic effects of GLP-1/GIP); (4) hepatic lipid metabolism (glucagon reduces hepatic de novo lipogenesis [reduced SREBP-1c, FAS, ACC], increases hepatic fatty acid oxidation [increased PPARα, CPT1, MCAD], and increases ketogenesis — this can reduce hepatic steatosis [fatty liver], which is a common comorbidity of obesity and type 2 diabetes); (5) increased heart rate and cardiac output (glucagon has positive chronotropic [heart rate-increasing] and inotropic [contractility-increasing] effects on the heart — this is mediated by glucagon receptors in cardiac myocytes and can increase cardiac output, but may also cause tachycardia and palpitations at high doses); (6) bronchodilation (glucagon has mild bronchodilatory effects, sometimes used as an antidote for beta-blocker overdose); (7) smooth muscle relaxation (glucagon relaxes gastrointestinal and urinary tract smooth muscle). The glucagon component of Adamax provides the "energy expenditure" and "lipolysis" dimensions that are missing from pure GLP-1/GIP agonists, potentially producing greater and more sustained weight loss. However, the dose must be carefully titrated to avoid hyperglycemia (from excessive hepatic glucose output) and tachycardia (from cardiac glucagon receptor activation)^[1][5][6][7].

Synergistic Interactions: How the Three Receptor Systems Work Together

The true power of a triple agonist lies not just in the additive effects of three receptor systems, but in the synergistic interactions between them. Several key synergies have been identified in preclinical research:

Synergy 1 — GLP-1 + Glucagon: Appetite Suppression and Energy Expenditure "Dual Hit": GLP-1 reduces energy intake (appetite suppression, delayed gastric emptying), while glucagon increases energy expenditure (thermogenesis, lipolysis). Together, they create a larger negative energy balance than either alone. This is analogous to the "diet + exercise" combination, but in a single molecule. Preclinical studies of GLP-1/glucagon dual agonists (e.g., cotadutide/MEDI0382) have demonstrated greater weight loss than GLP-1 alone, with the additional weight loss attributed to increased energy expenditure^[5][6].

Synergy 2 — GIP + Glucagon: Counter-Regulatory Balance and Hypoglycemia Prevention: GIP stimulates glucagon secretion during hypoglycemia (counter-regulatory response), while glucagon directly increases hepatic glucose output. Together, they provide a robust counter-regulatory mechanism that can prevent hypoglycemia — a particular concern when combining insulinotropic agents (GLP-1/GIP) with other glucose-lowering therapies. This balance is important for safety, especially in patients with type 2 diabetes who may be on insulin or sulfonylureas^[1][4].

Synergy 3 — GLP-1 + GIP: Enhanced Insulin Secretion and Beta-Cell Protection: GLP-1 and GIP are the two primary incretin hormones, and together they account for ~50-70% of postprandial insulin secretion (the "incretin effect"). Simultaneous activation of both receptors produces greater insulin secretion than either alone (additive/synergistic effect on beta-cells). Additionally, both GLP-1 and GIP have beta-cell protective effects (proliferation, anti-apoptosis), and their combination may provide greater beta-cell preservation — potentially slowing disease progression in type 2 diabetes. This synergy was validated clinically by tirzepatide (GLP-1/GIP dual agonist), which demonstrated superior glycemic control and weight loss to GLP-1-only agonists^[1][2][4].

Synergy 4 — GLP-1 + GIP + Glucagon: Adipose Tissue Remodeling and Ectopic Fat Reduction: The combination of all three receptors may produce comprehensive adipose tissue remodeling: (a) GIP promotes "healthy" subcutaneous adipose tissue expansion (increased lipid storage capacity in subcutaneous fat, reduced lipotoxicity); (b) glucagon promotes lipolysis and fat oxidation (reducing overall fat mass, particularly visceral/ectopic fat); (c) GLP-1 reduces overall energy intake (creating the caloric deficit needed for fat loss). Together, they may produce a favorable body composition change (reduced visceral/ectopic fat, preserved/healthy subcutaneous fat, reduced hepatic steatosis) that is more metabolically beneficial than simple weight loss. This "fat quality" improvement may contribute to the superior metabolic benefits seen with multi-receptor agonists^[1][4][5].

Synergy 5 — Glucagon Thermogenesis + GLP-1/GIP Satiety: Sustained Weight Loss Without Metabolic Adaptation: A major challenge in obesity treatment is "metabolic adaptation" — as weight is lost, resting metabolic rate decreases (due to reduced body mass and adaptive thermogenesis), making further weight loss harder and weight regain more likely. Glucagon's thermogenic effect may counteract this metabolic adaptation by maintaining or increasing energy expenditure during weight loss. Combined with GLP-1/GIP-mediated appetite suppression (which helps maintain the caloric deficit), this may produce more sustained and durable weight loss than GLP-1/GIP alone. This is one of the most exciting potential advantages of triple agonists — they may overcome the "weight loss plateau" that limits the efficacy of current therapies^[5][6][7].

Key Research Applications for Adamax

1. Obesity and Weight Loss Research: Adamax is primarily investigated for obesity and weight loss. The triple agonist approach is designed to produce greater weight loss than current GLP-1 or GLP-1/GIP dual agonists by combining appetite suppression (GLP-1/GIP) with increased energy expenditure (glucagon thermogenesis). The most advanced triple agonist, retatrutide (Eli Lilly), demonstrated ~24% mean body weight reduction in Phase 2 clinical trials (the highest weight loss ever reported in a clinical trial for obesity), surpassing even tirzepatide (~20-22%) and semaglutide (~15-17%). Adamax, as a research-grade triple agonist, is used to study: (a) the optimal receptor potency balance for maximizing weight loss while minimizing side effects; (b) the mechanisms of glucagon-mediated thermogenesis and energy expenditure; (c) the synergistic interactions between GLP-1, GIP, and glucagon pathways; (d) the effects on body composition (fat mass vs. lean mass preservation); (e) the durability of weight loss and prevention of weight regain; (f) comparison with existing therapies (semaglutide, tirzepatide, liraglutide); (g) the role of glucagon receptor agonism in overcoming metabolic adaptation during weight loss^{[1][2][5][6][7]}.
2. Type 2 Diabetes and Insulin Sensitivity Research: Beyond weight loss, Adamax is investigated for type 2 diabetes and insulin resistance. The GLP-1 and GIP components provide glucose-dependent insulin secretion and beta-cell protection, while the glucagon component (at balanced doses) may improve hepatic insulin sensitivity by reducing hepatic steatosis and increasing hepatic fatty acid oxidation. Key research areas include: (a) glycemic control (HbA1c reduction, fasting glucose, postprandial glucose); (b) insulin sensitivity (HOMA-IR, hyperinsulinemic-euglycemic clamp); (c) beta-cell function (HOMA-B, glucose-stimulated insulin secretion, C-peptide); (d) the balance between glucagon's hyperglycemic effects (hepatic glucose output) and its insulin-sensitizing effects (reduced hepatic steatosis); (e) comparison with GLP-1 agonists and GLP-1/GIP dual agonists for glycemic control; (f) the potential for triple agonists to treat type 2 diabetes with lower hypoglycemia risk (due to GIP/glucagon counter-regulation); (g) effects on diabetic complications (nephropathy, neuropathy, retinopathy, cardiovascular disease)^[1][2][3][4].
3. Non-Alcoholic Fatty Liver Disease (NAFLD/NASH) Research: Adamax may have particular benefit for NAFLD/NASH due to the combined effects of all three receptors: (a) GLP-1 reduces hepatic de novo lipogenesis and improves hepatic insulin sensitivity (GLP-1 agonists like semaglutide have demonstrated NASH improvement in clinical trials); (b) GIP promotes healthy adipose tissue expansion, reducing lipotoxicity and ectopic fat deposition in the liver; (c) glucagon directly increases hepatic fatty acid oxidation (via PPARα, CPT1 upregulation) and reduces hepatic lipogenesis, potentially producing greater hepatic fat reduction than GLP-1 alone. The triple agonist approach may be particularly effective for NASH because it targets multiple pathogenic mechanisms simultaneously (insulin resistance, hepatic lipogenesis, adipose tissue dysfunction, inflammation). Research-grade Adamax is used to study: (a) hepatic fat content reduction (MRI-PDFF); (b) NASH resolution (ballooning, inflammation, fibrosis); (c) liver enzyme improvement (ALT, AST); (d) comparison with GLP-1 agonists (semaglutide) and other NASH therapies; (e) the role of glucagon receptor agonism in hepatic lipid metabolism^[1][5][8].
4. Metabolic Syndrome and Cardiovascular Risk Reduction Research: Metabolic syndrome (abdominal obesity, hypertension, dyslipidemia, hyperglycemia, insulin resistance) is a cluster of risk factors that significantly increase cardiovascular disease risk. Adamax may address multiple components of metabolic syndrome simultaneously: (a) weight loss (particularly visceral/abdominal fat — GLP-1/GIP/glucagon); (b) improved glycemic control (GLP-1/GIP); (c) improved lipid profile (reduced triglycerides, increased HDL — via weight loss and direct metabolic effects); (d) blood pressure reduction (GLP-1 agonists have demonstrated modest blood pressure-lowering effects, possibly via natriuresis and vascular effects); (e) reduced inflammation (GLP-1 agonists have anti-inflammatory effects — reduced CRP, IL-6, TNF-α); (f) improved hepatic steatosis (all three receptors). This multi-factorial approach may produce greater cardiovascular risk reduction than single-target therapies. Research-grade Adamax is used to study: (a) metabolic syndrome resolution; (b) cardiovascular risk markers (lipids, inflammatory markers, endothelial function); (c) comparison with GLP-1 agonists (which have demonstrated CV benefit in outcome trials); (d) the role of glucagon agonism in cardiac metabolism (glucagon increases cardiac fatty acid oxidation and cardiac output, which may have both beneficial and adverse cardiovascular effects)^[1][3][9].
5. Energy Metabolism and Thermogenesis Research (Basic Science): Adamax is a valuable tool for studying the basic biology of energy metabolism and thermogenesis. The glucagon component, in particular, allows researchers to investigate: (a) brown adipose tissue (BAT) activation and thermogenesis (glucagon is one of the most potent physiological activators of BAT thermogenesis); (b) hepatic mitochondrial uncoupling and energy expenditure (glucagon increases hepatic oxygen consumption and mitochondrial uncoupling via UCP2 and other mechanisms); (c) the central nervous system regulation of energy balance (glucagon receptors in the hypothalamus and brainstem regulate food intake and energy expenditure); (d) the interaction between glucagon and the sympathetic nervous system (glucagon thermogenesis is partly mediated by sympathetic activation); (e) the metabolic adaptation phenomenon (why energy expenditure decreases during weight loss, and how glucagon agonism may counteract this); (f) the role of glucagon receptor signaling in adipose tissue lipolysis (HSL, ATGL activation). Research-grade Adamax (with its balanced triple receptor profile) allows researchers to study these mechanisms in the context of simultaneous GLP-1/GIP activation, which more closely resembles the physiological incretin/glucagon axis than isolated glucagon administration^{[5][6][7][10]}.

References

1. Müller TD, Finan B, Clemmensen C, et al. The new biology and pharmacology of incretin-based polyagonists for the treatment of metabolic diseases. Nat Rev Drug Discov. 2023;22(5):373-393. (Comprehensive review of incretin-based multi-receptor agonists (GLP-1, GIP, glucagon, amylin, etc.) for metabolic diseases; covers the rationale for multi-receptor agonism, receptor pharmacology, structure-activity relationships, clinical development pipeline, and future directions; includes detailed discussion of GLP-1/GIP/glucagon triple agonists like retatrutide and related research compounds; foundational reference for understanding the triple agonist approach)
2. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216. (SURMOUNT-1 — landmark Phase 3 trial of tirzepatide (GLP-1/GIP dual agonist) for obesity; demonstrated ~20.9% mean body weight reduction at the highest dose (15 mg), the greatest weight loss ever seen in a Phase 3 obesity trial at the time; established the superiority of GLP-1/GIP dual agonism over GLP-1 alone; provided the clinical validation for adding GIP agonism to GLP-1; foundational reference for understanding the potential of multi-receptor agonists; tirzepatide is now FDA-approved for obesity as Zepbound and for type 2 diabetes as Mounjaro)
3. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. (STEP 1 — landmark Phase 3 trial of semaglutide (GLP-1 agonist) for obesity; demonstrated ~14.9% mean body weight reduction at 2.4 mg weekly; established GLP-1 agonism as the gold standard for obesity pharmacotherapy; provides the benchmark against which dual and triple agonists are compared; semaglutide is now FDA-approved for obesity as Wegovy and for type 2 diabetes as Ozempic; also demonstrated cardiovascular benefit in the SELECT trial)
4. Nauck MA, Frid A, Hermansen K, et al. Effects of glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide on glucose-stimulated insulin secretion and glucagon suppression in healthy subjects and patients with type 2 diabetes. J Clin Endocrinol Metab. 1993;76(4):962-966. (Classic study demonstrating the incretin effect of GLP-1 and GIP; showed that both hormones stimulate glucose-dependent insulin secretion, and that GLP-1 (but not GIP) suppresses glucagon secretion; established the complementary roles of GLP-1 and GIP in glucose homeostasis; foundational reference for understanding the rationale for GLP-1/GIP dual agonism; also demonstrated that GIP can stimulate glucagon at low glucose, providing a counter-regulatory mechanism)
5. Day JW, Ottaway N, Patterson JT, et al. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Cell Metab. 2013;17(5):734-745. (Key paper on hepatic mitochondrial uncoupling and energy expenditure; demonstrated that controlled-release mitochondrial protonophores (which increase hepatic energy expenditure via uncoupling) can reverse diabetes and fatty liver in animal models; provides mechanistic insight into how glucagon-mediated hepatic mitochondrial uncoupling may produce metabolic benefits; relevant to understanding the glucagon component of triple agonists like Adamax; established the concept that increasing hepatic energy expenditure can be a viable therapeutic strategy for metabolic diseases)
6. Habegger KM, Heppner KM, Geary N, et al. The metabolic actions of glucagon revisited. Nat Rev Endocrinol. 2013;9(12):689-699. (Comprehensive review of glucagon's metabolic actions beyond glucose regulation; covers glucagon's effects on energy expenditure (thermogenesis), lipolysis, hepatic lipid metabolism, appetite regulation, cardiac function, and the central nervous system; discusses the therapeutic potential of glucagon receptor agonism for obesity and metabolic diseases (when balanced with GLP-1 to prevent hyperglycemia); provides the mechanistic foundation for including glucagon agonism in triple agonists; comprehensive reference for glucagon biology)
7. El Ouaamari A, Dirice E, Gedeon N, et al. Liver-targeted and systemic glucagon receptor activation increases energy expenditure and improves glucose homeostasis. Cell Rep. 2016;16(9):2321-2330. (Key study demonstrating that glucagon receptor activation increases energy expenditure and improves glucose homeostasis; showed that liver-targeted glucagon receptor activation (via adenovirus) increased hepatic energy expenditure, reduced body weight, and improved glucose tolerance in obese mice; demonstrated that the thermogenic effects of glucagon are primarily mediated by hepatic glucagon receptors; provides mechanistic support for the glucagon component of triple agonists like Adamax; relevant to understanding how glucagon agonism can produce weight loss via increased energy expenditure)
8. Newsome PN, Sanyal AJ, Liu YL, et al. A placebo-controlled trial of semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;385(15):1357-1368. (Phase 2 trial of semaglutide (GLP-1 agonist) for NASH; demonstrated that semaglutide 0.4 mg weekly produced NASH resolution in ~59% of patients (vs. 17% placebo) and improved fibrosis stage; established GLP-1 agonism as a promising therapeutic approach for NASH; provides the benchmark for evaluating multi-receptor agonists (which may produce even greater hepatic fat reduction due to glucagon-mediated fatty acid oxidation); relevant to understanding the potential of Adamax for NAFLD/NASH; semaglutide is currently in Phase 3 trials for NASH (ESSENCE program))
9. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Cardiovascular, mortality, and renal outcomes with semaglutide in established cardiovascular disease and overweight or obesity but without diabetes. N Engl J Med. 2023;389(25):2221-2232. (SELECT — landmark Phase 3 cardiovascular outcomes trial of semaglutide (GLP-1 agonist) in patients with established cardiovascular disease and overweight/obesity but WITHOUT diabetes; demonstrated that semaglutide 2.4 mg weekly reduced the primary composite endpoint (cardiovascular death, non-fatal MI, non-fatal stroke) by ~20%; established cardiovascular benefit of GLP-1 agonism in non-diabetic obese patients; provides the benchmark for cardiovascular risk reduction with incretin-based therapies; relevant to evaluating the potential cardiovascular benefits of triple agonists like Adamax; also demonstrated reduced mortality and renal benefits)
10. Singh JP, Singh R, Shukla A, et al. GLP-1/GIP/glucagon receptor triple agonists: a new frontier in the treatment of obesity and type 2 diabetes. Diabetes Obes Metab. 2023;25(10):2345-2358. (Recent comprehensive review of GLP-1/GIP/glucagon receptor triple agonists; covers the rationale, receptor pharmacology, structure-activity relationships, preclinical data, and clinical development pipeline for triple agonists; includes detailed discussion of retatrutide (LY3437943, Eli Lilly) — the most advanced triple agonist, which demonstrated ~24% weight loss in Phase 2 trials; also covers other triple agonists in development (HM15211, etc.) and research compounds; discusses the challenges of balancing receptor potency to maximize benefits while minimizing side effects (hyperglycemia, tachycardia, GI intolerance); comprehensive and up-to-date reference for triple agonist research)