While lifestyle changes such as dietary modification and increased physical activity can be very effective in improving glycemic control, over the long-term most individuals with T2DM will require medications to achieve and maintain glycemic control. The purpose of this chapter is to provide the healthcare practitioner with an overview of the existing oral and injectable (non-insulin) pharmacological options available for the treatment of patients with T2DM. Currently, there are ten classes of orally available pharmacological agents to treat T2DM: 1) sulfonylureas, 2) meglitinides, 3) metformin (a biguanide), 4) thiazolidinediones (TZDs), 5) alpha glucosidase inhibitors, 6) dipeptidyl peptidase IV (DPP-4) inhibitors, 7) bile acid sequestrants, 8) dopamine agonists, 9) sodium-glucose transport protein 2 (SGLT2) inhibitors and 10) oral glucagon like peptide 1 (GLP-1) receptor agonists . In addition, glucagon like peptide 1 (GLP-1) receptor agonists and amylin can be administered by injection. Medications from these distinct classes of pharmaceutical agents may be used as treatment by themselves (monotherapy) or in a combination of 2 or more drugs from multiple classes with different mechanisms of action. A variety of fixed combination of 2 agents are available in the US and in many other countries. In this chapter we discuss the administration, mechanism of action, effect on glycemic control, other benefits, side effects, and the contraindications of the use of these glucose lowering drugs. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

Automated Insulin Delivery (AID) systems represent the most effective and safe treatment for the management of type 1 diabetes (T1D). Antidiabetic agents used for the treatment of type 2 diabetes, such as the Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists (RAs), the dual Glucose-dependent Insulinotropic Polypeptide and GLP-1 RA and the Sodium-Glucose co-Transporter 2 inhibitors are associated with clinically significant weight loss and cardioprotective effect. Given the increased prevalence of overweight, obesity, and cardiovascular risk in patients with T1D, the addition of these medications to AID treatment is of considerable clinical interest. In this review limited data from randomized controlled and observational trials show that in overweight and obese patients with T1D treated with AID, the addition of weekly semaglutide, or tirzepatide is associated with significant weight loss, reduction in total daily insulin dose and increase in Time In target Range (TIR) without increased risk for hypoglycemia and Diabetic Ketoacidosis (DKA). Similarly, adjunctive treatment with empagliflozin resulted in increased TIR without increase in hypoglycemia, reduction in insulin requirements, and increase in the mean plasma ketone value, although DKA remained rare. However, studies of longer duration with more participants are required to establish the long-term safety and efficacy of these interventions in patients with T1D treated with AID.

Pramlintide has a high molecular weight, so it is unlikely to pass into breastmilk in clinically important amounts. It also has a short half-life and it is a peptide that is likely digested in the infant's gastrointestinal tract, so it is unlikely to reach the clinically important levels in infant serum. However, because no information is available on the use of pramlintide during breastfeeding an alternate drug may be preferred, especially while nursing a newborn or preterm infant. Monitor breastfed infants for signs of hypoglycemia such as jitteriness, excessive sleepiness, poor feeding, seizures cyanosis, apnea, or hypothermia. If there is concern, monitoring of the breastfed infant's blood glucose is advisable during maternal therapy with pramlintide.[1]

Escalating resistance among bacterial and fungal pathogens calls for new therapeutic strategies that go beyond classical small-molecule antibiotics. Antimicrobial peptides (AMPs) are attractive candidates because they can act through multiple mechanisms and often evade conventional resistance pathways. Biologically essential metal ions such as Zn(II) and Cu(II) further expand this chemical space: metal binding can modulate peptide structure, morphology, local charge and transport, thereby generating metallo-AMPs with distinct modes of action. In this review, we discuss selected Zn(II)- and Cu(II)-binding AMPs and peptidic zincophores in which the link between coordination chemistry and biological activity has been analysed in detail. Rather than simply listing examples, we use these systems to show how a coherent research programme in bioinorganic AMP chemistry can be built around one guiding idea: connecting metal coordination to function across different peptide families. Pramlintide and shepherins illustrate Zn(II)-driven conformational change and fibril formation associated with antifungal activity. Semenogelins and calcitermin highlight how histidine-rich motifs and local charge tuning can activate peptides without relying on nutritional immunity. Clavanins reveal a "chemical butterfly effect", where subtle differences in pre-organization translate into changes in complex lability and antimicrobial outcome. Histatin systems show that metal-dependent effects can be strongly pH-gated. Finally, thermodynamic and structural studies of fungal zincophores and bacterial periplasmic transporters provide a basis for targeted peptide designs that exploit Zn(II) uptake pathways. Together, these case studies outline mechanism-based design principles for future metal-peptide therapeutics.

The first therapeutically useful amylin receptor (AMYR) agonist, pramlintide was based upon the structure of non-aggregating rat amylin and found limited application as an adjunct to insulin therapy. It acts centrally to induce satiety, promote weight loss, suppress prandial glucagon release and reduce prandial hyperglycaemia. Recent understanding of the heterodimeric structure of amylin-calcitonin receptor complexes and of amylin structure-function properties has assisted the design of a second generation of non-aggregating, long-acting amylin analogues. These are now advancing in clinical development and promise to provide an effective additional resource for the management of obesity and type 2 diabetes. Amongst these agents is the dual AMYR/ calcitonin-receptor (CTR) agonist, cagrilintide that has also been co-formulated into a once weekly subcutaneous injection with the long-acting glucagon-like peptide-1receptor (GLP-1R) agonist, semaglutide (CagriSema). In clinical trials, CagriSema has achieved greater effects than either component alone. A unimolecular AMYR/CTR/GLP-1R multi-agonist peptide, amycretin has been developed for weekly injection and as a once-daily tablet. Several recently developed long-acting amylin analogues have shown strong efficacy as monotherapy in clinical trials: these include eloralintide, petrelintide, Met-233 and AZD6234. Other analogues with marked efficacy in preclinical studies, including non-peptide AMYR agonists are under development. Gastrointestinal side effects, especially nausea, similar to those reported for GLP-1R agonists are commonplace during initiation and up-titration of amylin analogues but mostly resolve during continued use. Evidence is emerging that long-acting AMYR agonists may show potential therapeutic benefits in treatment of patients with fatty liver disease, diabetes-associated kidney complications and resistant hypertension.

Amylin is a glucoregulatory peptide hormone discovered in 1986. Almost 20 years later, pramlintide, a human amylin analogue, emerged as the first amylin-based drug, approved as an adjunct treatment to insulin for type 1 diabetes (T1D) and type 2 diabetes (T2D). Despite its effects on multiple organ systems, the therapeutic potential of amylin has remained relatively underexplored until recently, when growing interest in amylin has prompted advancement of several amylin-based therapies towards clinical use. This Review contextualizes the evolving therapeutic potential of amylin, focusing on recent preclinical and clinical data, amylin receptor pharmacology and its broader biological effects. We discuss the potential and challenges of developing amylin-based treatments for cardiometabolic disease, including milestones in drug development of amylin, and its combination with additional molecules as part of the future landscape of therapies for patients with diabetes or obesity.

Peptide hormone-based weight-loss therapeutics have gained increasing attention, driven amongst other reasons, by the clinical and commercial success of semaglutide. Their increasing accessibility raises concerns about their potential misuse in sports, especially in disciplines where weight management is decisive for athletic performance. Semaglutide has been included in the World Anti-Doping Agency's monitoring program since 2024. Given that amylin signalling is a key therapeutic target for next-generation weight-loss drugs, amylin receptor agonists such as pramlintide, cagrilintide and KBP-066 also warrant consideration as to metabolism and detection strategies in sports drug testing programs. This study aimed to characterize the metabolic profiles of pramlintide, cagrilintide and KBP-066, identify analytically suitable metabolites and develop and validate a LC-MS/MS-based detection approach. Comprehensive in vitro models, including human skin S9 fraction, kidney S9 fraction and biological fluids, were used to investigate metabolic pathways. HRMS/MS was employed to characterize metabolites and evaluate their suitability as analytical targets. For comparison, authentic post-administration rat samples were analysed for cagrilintide and respective biotransformation products. All three peptides underwent N-terminal and C-terminal degradation, yielding multiple stable metabolic products suitable as detection targets. Cagrilintide metabolites predicted from in vitro experiments were observed in authentic post administration rat plasma samples, confirming in vivo relevance. Finally, suitable preparation and detection methods were established and validated. This study provides the first systematic metabolic characterization of pramlintide, cagrilintide and KBP-066. The identified metabolites and LC-MS/MS detection approach offer a foundation for future monitoring of emerging weight-loss peptide hormone analogues in anti-doping contexts.

Amylin is a pancreatic peptide hormone that regulates blood glucose levels and appetite. This review outlines the physiological role of amylin and highlights recent clinical studies exploring its therapeutic potential in diabetes and obesity. Amylin lowers postprandial glucose levels by delaying gastric emptying and suppressing glucagon secretion, while promoting satiety via central nervous system pathways. Preclinical research has driven the development of long-acting amylin analogs with enhanced pharmacokinetics and reduced aggregation, resulting in significant weight loss and metabolic benefits in animal models. Clinically, the synthetic analog pramlintide has been shown to modestly improve glycemic control and induce weight loss in patients with diabetes. More recently, cagrilintide, a long-acting analog, has produced substantial weight reduction in individuals with obesity. Combination therapy with glucagon like peptide-1 receptor agonists has achieved synergistic effects, with weight loss exceeding 15%, positioning amylin analogs as a promising approach for treatment of diabesity-the co-existence of diabetes and obesity. This review summarizes recent advancements and discusses their implications for future therapeutic applications in diabesity management.

Obesity is a chronic, relapsing metabolic disorder driven by complex genetic and environmental factors, leading to an imbalance in energy regulation. Despite the presence of GLP-1 receptor agonists with induced mild weight loss, there are significant unmet clinical needs with poor efficacy and tolerability problems. Amylin, a neuroendocrine hormone co-released with insulin, controls hunger, gastric motility, glucagon secretion, and energy metabolism via divergent amylin receptor (AMYR) subtypes (1-3), namely the calcitonin receptor (CTR) and the receptor activity-modifying proteins (RAMPs). Novel insight into the molecular make-up of AMYRs and central signaling reinforces its key function in modulating homeostatic and hedonic feeding mechanisms. The article is a review of the emerging preclinical and clinical data regarding the application of peptide-based amylin receptor agonists (AMYRAs), including pramlintide and cagrilintide, KBP-series DACRAs, and investigational drugs, including ZP8396 and amycretin. The agents show enhanced pharmacokinetics, synergy with GLP-1 receptor agonist, and favorable impact on weight regulation and metabolic plasticity. Genetic CALCR and RAMP mutations, new delivery approaches, and dual therapy by digital health technologies and bariatric surgery are also discussed in this review. Of particular interest, amylin-derived medications can have advantages over weight loss but definite disease-modifying action remains to be determined. Taken together, AMYRAs represent a potential category of therapeutics with promising disease-modifying effects that goes beyond weight loss, providing fresh perspectives for precision obesity management by 2030.

We hypothesise that amylin receptor agonists (eg, pramlintide) and dual amylin and calcitonin-receptor agonists (eg, cagrilintide), which are emerging treatments for obesity and type 2 diabetes, can activate the renin-angiotensin system (RAS) and potentially undermine the cardiorenal benefits of these therapies. Paradoxically, new-generation amylin-based therapies, such as CagriSema, showed substantial blood pressure reductions in phase 3 trials. Beyond amylin's weight loss-mediated effects, we hypothesise that concurrent use of RAS inhibitors (angiotensin-converting enzyme [ACE] inhibitors or angiotensin-receptor blockers) redirects amylin-induced RAS activation towards the protective alternative RAS pathway, which is characterised by vasodilatory, anti-inflammatory, and antiproliferative effects via Mas receptors, potentially explaining part of their therapeutic benefit and cardioprotective and renoprotective potential. To test this, we propose: (1) preclinical studies investigating amylin-RAS interactions with or without RAS blockade; (2) post-hoc analyses of phase 2/3 trials stratified by RAS inhibitor use; (3) biomarker studies monitoring renin, aldosterone, angiotensin-(1-7), and ACE2; and (4) mechanistic human studies prospectively assessing cardiovascular-kidney metabolic effects by RAS inhibitor status. These suggestions aim to determine whether RAS inhibition enhances the overall efficacy of amylin-based therapies, and whether RAS blockers should be strongly recommended in patients receiving them.

Amylin is a feeding-suppressive hormone which acts centrally in the control of energy balance. Some evidence suggests it reduces motivation for food rewards. Pramlintide is a synthetic amylin analog that is used clinically in the treatment of diabetes, and it also reduces feeding and weight gain. However, the mechanisms behind these pramlintide-induced reductions in feeding are unclear. Here we tested the hypothesis that pramlintide would decrease motivation for a palatable food, sucrose pellets. Results show that peripheral (IP) pramlintide had no effect on progressive ratio responding for sucrose pellets. In contrast, intracerebroventricular (ICV) pramlintide reduced active lever pressing, reinforcers earned, and breakpoint for sucrose, even at lower doses subthreshold for effects on 24 h chow intake and body weight change. However, lever pressing behavior was completely abolished for many rats, raising concern for unexpected motor effects. To test whether central pramlintide impacted locomotor activity, we conducted an open field study and found that ICV pramlintide significantly reduced distance traveled at several timepoints, suggesting suppressed locomotor activity. Overall, our results suggest that peripheral pramlintide does not affect motivation for sucrose, and that although central pramlintide does reduce outcomes assessing motivation, this may be confounded by a concurrent reduction in locomotor activity.