24th December 2021, Dr Chee L Khoo
Obesity is often the core underlying pathology leading to many degenerative and inflammatory diseases. Unfortunately, there is no easy fix to treat obesity. Over the last 12 months we have explored a number of novel molecules which have proven efficacious in reducing fat mass in patients with obesity with or without diabetes. We last looked at the up and coming tirzepatide. Cagrilintide just released its clinical trial results as a standalone agent as well as in combination with semaglutide. Cagrilintide is a new class of anti-obesity drug which will hit our shores sooner than you think.
Amylin is a peptide hormone which is co-secreted with insulin from the pancreatic beta-cell. Individuals with type 1 diabetes, (T1D) and some individuals with type 2 diabetes (T2D) are characterised by amylin deficiency. It reduces hyperglycaemia by inhibiting postprandial glucagon secretion but without increase in hypoglycaemia. It also delays gastric emptying, increase satiety, increase energy expenditure and reduce adiposity. Funny, that’s exactly what GLP-RAs do.
Mechanism of action of amylin
The transmembrane calcitonin G protein–coupled receptor (CTR) interacts with receptor activity-modifying proteins (RAMPs) to form amylin receptors (AMYRs). There are three different subtypes of RAMPS and this gives rise to three different AMYRs phenotypes. AMYRs have high affinity and potency in response to amylin. Binding of human calcitonin (hCT) invoke a weak response but salmon CT (sCT) is a nonselective agonist and has high affinity and potency for both CTR and AMYRs and sCT have demonstrated efficacy in controlling appetite and body weight. However, this is not seen with the selective CTR agonist hCT (1-3). These observations have led to the hypothesis that the anorectic actions of these peptides are mediated by one or more of the AMYR subtypes.
This has led to an increased interest in the development of AMYR agonists for the treatment of obesity, as they could provide a novel mechanism of action relative to other proposed anorectic agents, including those acting at the GLP-1 receptor.
Human amylin is predisposed to aggregate and form amyloid fibres, which makes it unsuitable for pharmacological use. A stable analogue, pramlintide, with actions and pharmacokinetic and pharmacodynamic properties similar to the native peptide was developed and approved by the FDA for treatment in patients with diabetes in 2005.
Despite great expectations on the role pramlintide could play in patients with T1D and in some patients with T2D, pramlintide improved HbA1c levels only by 0.2% to 0.4% compared with placebo in both type 1 and type 2 diabetes populations. In patients with T1D managed with intensive insulin treatment, there was no significant difference between groups. None of the trials, however, evaluated long-term health outcomes and adverse events to determine whether benefits outweigh risks, and few data are published on patient-reported outcomes.
Although weight loss was greater with pramlintide than placebo, the amount lost was relatively small. The largest improvements in HbA1c levels and weight occurred during the initial 6 months of treatment and then deteriorated with time. Pramlintide’s greatest effect on HbA1c levels and weight were observed in obese and overweight patients with type 2 diabetes at 26 weeks of follow-up. Pramlintide is significantly better than placebo at reducing fasting plasma glucose, postprandial glucose, or total daily insulin dose but the effects were small.
So, the effects from pramlintide were modest. In any case, in patients who are on insulin, a reduction of insulin dose is not a game changer but weight loss is. So, the hunt went out for longer acting and more efficacious amylin agonists.
Cagrilintide is a long-acting, amylin agonist with high homology to natural amylin that reduces food intake and bodyweight in a dose-dependent manner. It was developed by Novo Nordisk as a long-acting (once-weekly administration) and is a nonselective AMY and CT receptor agonist. It has recently completed a phase 2 clinical trial as monotherapy for obesity and a phase 1 combination trial with the GLP-1 receptor agonist semaglutide for obesity.
Phase 2 Once-weekly monotherapy Cagrilintide trial (4)
706 participants were randomised to various doses of cagrilintide (0.3-4.5mg), 99 were randomised to daily liraglutide 3.0mg (i.e. Saxenda) and 101 to placebo. Eligible participants were adults aged at least 18 years without diabetes, with a body-mass index of at least 30 kg/m² or at least 27 kg/m² with hypertension or dyslipidaemia. Compared with placebo, weight loss were greater with weekly cagrilintide at all doses (6.4-11.5 kg) over the study period of 26 weeks. Weight reductions were also greater with cagrilintide 4·5 mg versus liraglutide 3·0 mg (11·5 kg vs 9·6 kg).
The most frequent adverse events were gastrointestinal disorders (eg, nausea, constipation, and diarrhoea) and administration-site reactions. More participants receiving cagrilintide 0·3–4·5 mg had gastrointestinal adverse events compared with placebo (41%–63% vs 32%), primarily nausea (20%–47% vs 18%).
Phase 1b Once-weekly Cagrilintide with 2.4mg semaglutide trial (5)
Individuals aged 18–55 years with a body-mass index 27·0−39·9 kg/m2 and who were otherwise healthy were recruited from a single centre in the USA. 71 participants were randomised to receive various weekly doses of cagrilintide (0.16-2.4 mg) in combination with weekly semaglutide 2.4mg. 23 were randomised to received placebo with semaglutide. At 20 weeks, participants on cagrilintide and semaglutide lost between 8.0 to 15.9 kg of body weight depending on the dose of cagrilintide with those on 1.2 and 2.4mg cagrilintide losing the most weight. Participants on placebo and semaglutide lost on average 7.8 kg over the same period.
Overall, no unexpected safety concerns were identified in the trial and no apparent difference was seen in the number of adverse events across treatment groups. Most adverse events were mild or moderate in severity. The occurrence of gastrointestinal disorders was expected because of the known effect of semaglutide and cagrilintide on gastrointestinal motility
The effects of semaglutide on bodyweight are thought to be mediated by a reduction in appetite and energy intake, pri[1]marily through its action on GLP-1 receptors in the hypothalamus (6) but also other regions of the brain (area postrema, nucleus of the solitary tract, and parabrachial nuclei) (7). Cagrilintide induces satiety and satiation, and is thought to affect food choices by targeting both homoeostatic and hedonic regions of the brain (8).
Although both semaglutide and cagrilintide induce satiety, they operate in different regions of the brain, which might result in an additive effect on appetite regulation. Moreover, the potential for cagrilintide to affect food choices might contribute to the modification of eating behaviours, further improving treatment efficacy. Thus, combining treatments with different but complementary mechanisms of action has the potential to increase efficacy.
The combination of cagrilintide with semaglutide 2·4 mg has the potential to further close the gap between the available pharmacological options for weight management and bariatric surgery with clinically significant weight reductions in just 20 weeks.
References:
- Lutz TA, Tschudy S, Rushing PA, Scharrer E. (2000) Amylin receptors mediate the anorectic action of salmon calcitonin (sCT). Peptides 21:233–238
- Chelikani PK, Haver AC, Reidelberger RD. (2007) Effects of intermittent intraperitoneal infusion of salmon calcitonin on food intake and adiposity in obese rats. Am J Physiol Regul Integr Comp Physiol 293:R1798–R1808
- Feigh M, Henriksen K, Andreassen KV, et al. A novel oral form of salmon calcitonin improves glucose homeostasis and reduces body weight in diet-induced obese rats. Diabetes Obes Metab 13:911–920.
- Lau DCW, Erichsen L, Francisco AM, et al. 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. Lancet. 2021 Dec 11;398(10317):2160-2172. doi: 10.1016/S0140-6736(21)01751-7. Epub 2021 Nov 16. PMID: 34798060.
- Enebo LB, Berthelsen KK, Kankam M, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet. 2021 May 8;397(10286):1736-1748. doi: 10.1016/S0140-6736(21)00845-X.
- Blundell J, Finlayson G, Axelsen M, et al. Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes Obes Metab 2017; 19: 1242–51.
- Gabery S, Salinas CG, Paulsen SJ, et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight 2020; 5: e133429.
- Boyle CN, Lutz TA, Le Foll C. Amylin—its role in the homeostatic and hedonic control of eating and recent developments of amylin analogs to treat obesity. Mol Metab 2018; 8: 203–10.