The GLP-1 Pipeline: Triple Agonists, Older Adults, and the Cautious Move Toward Type 1

The starting point is familiar. Liraglutide, the first GLP-1 receptor agonist approved for weight management, produced roughly 6–8% weight loss. Once-weekly semaglutide pushed that to around 12–15%. Tirzepatide, which engages both the GIP and GLP-1 receptors, has reported about 20% in adults with obesity but without diabetes. Each step has been a genuine clinical advance, and each has reset expectations for what an injectable metabolic drug can do. A 2025 review in Expert Opinion on Investigational Drugs lays out the trajectory in plain terms and surveys what is moving through phase 2 and phase 3 development.

What that pipeline shows is a field branching in several directions at once. There are multi-receptor agonists, including GLP-1/glucagon co-agonists and the triple agonist retatrutide, which targets GIP, GLP-1, and glucagon receptors simultaneously. There are combinations, such as semaglutide paired with the long-acting amylin analogue cagrilintide, now in phase III. And there are oral formulations — both peptide-based oral semaglutide and a generation of small-molecule, non-peptide GLP-1 agonists designed to be swallowed rather than injected.

Retatrutide is the molecule attracting the most attention, and for understandable reasons. By adding glucagon-receptor activity to the GIP/GLP-1 mechanism of tirzepatide, it appears to lean harder on energy expenditure as well as appetite. Reported phase 2 weight-loss figures sit above the tirzepatide benchmark, with the 2025 review describing weight reductions in the region of 20%-plus across the multi-agonist class and noting parallel benefits on steatotic liver disease.

The appropriate posture here is measured optimism. Phase 2 data are encouraging, not definitive; larger phase 3 trials are still needed to confirm durability, cardiovascular safety, and how the drug behaves outside tightly controlled study populations. The class as a whole also shares a familiar adverse-event profile — nausea, vomiting, constipation, diarrhoea — generally manageable with slow dose titration, but real enough that a meaningful number of patients discontinue.

One of the quieter but more clinically useful findings of 2025 comes from a post-hoc analysis of the SURPASS programme, published in Diabetes Therapy. The researchers pooled participants from SURPASS-1 through -5 and looked specifically at adults aged 65 and over with type 2 diabetes and a body mass index below 30 — a group often under-represented in obesity-focused trials. In that subgroup, tirzepatide produced HbA1c reductions of roughly 1.97% to 2.10% regardless of the maintenance dose assigned.

Weight loss in this leaner, older group was, as one might expect, more modest in absolute terms than in the overall trial population, and dose-proportional. The safety picture was broadly reassuring: overall adverse-event incidence was low, and hypoglycaemia rates were consistent with the broader cohort. The notable caveat is that older participants without obesity were somewhat more likely to discontinue because of adverse events — a reminder that tolerability, not just efficacy, drives real-world outcomes.

The practical takeaway is narrower than the data: when the priority is glycaemic control rather than weight reduction, tirzepatide appears to retain meaningful efficacy in older adults who are not obese. That is a conversation worth having with a clinician, not a prescription delivered by a magazine.

Perhaps the most genuinely new territory is the use of second-generation incretin analogues in autoimmune forms of diabetes. A 2025 review in the Journal of Clinical Medicine examines the emerging — and explicitly off-label — evidence for semaglutide and tirzepatide in type 1 diabetes and latent autoimmune diabetes in adults (LADA). Neither drug is currently approved for these conditions.

The rationale is that the type 1 population has changed. Overweight and obesity are increasingly common alongside T1D, and clinicians now talk about "double diabetes" — patients with T1D who also carry features of insulin resistance, metabolic syndrome, or a family history of T2D. The review summarises a growing body of work suggesting that, as add-ons to insulin, semaglutide and tirzepatide may improve glucose control, support weight loss, and potentially help preserve residual beta-cell function in selected patients.

The language matters here. "May," "growing body of evidence," and "add-on" are doing real work in that sentence. The evidence base is still early, the populations studied are heterogeneous, and the risks specific to type 1 diabetes — including the potential for diabetic ketoacidosis when insulin needs shift — make this firmly a decision to be made with an endocrinologist, not by analogy from a friend's experience with weight loss.

Even within the established uses of GLP-1 medicines, important questions remain open. The most pressing, flagged squarely by the 2025 pipeline review, is maintenance of weight loss. The current expectation is that pharmacological treatment may need to be long-term, possibly indefinite, to preserve the benefit. That has implications for cost, adherence, side-effect tolerance over years rather than months, and the still-young evidence base on very long-term safety.

The gastrointestinal side effects that dominate the early weeks for most patients can usually be reduced by slow up-titration, but they are not trivial, and they are a common reason for stopping. And while the cardiovascular and hepatic signals so far are encouraging, particularly in steatotic liver disease, they need to be confirmed across the newer multi-agonists.