Disease-specific reference case extension: Management of overweight and obesity in adults

Cameron Lilley |

03/12/2025

Key takeaways – PMG 10019 [1]

Obesity is an area where modelling is inherently complex, highly assumption-sensitive, and evolving rapidly as new therapies emerge. Although there is nothing enormously controversial included in the proposal (the majority of the recommendations simply pull through Committee preferred assumptions or approaches from prior technology appraisals – TA664 [2], TA875 [3], TA1026 [4]) we feel there are some elements that NICE should consider to ensure the reference case becomes a sustainable and genuinely useful tool to aid decision-making.

Governance and sustainability

There have been previous attempts to streamline decision-making through the provision of greater levels of specificity in evidence requirements, under NICE’s ‘Proportionate Approach’, including through the ‘pre-specified assumptions’ initiative. The PATT evaluation report published in April 2023 [5] found that there was insufficient consistent precedent to support pre-specification and that maintaining assumptions would be resource-intensive with limited efficiencies. Without a clear governance framework, regular review cycles, and a process for incorporating learning from completed TAs there is a risk that the reference case becomes outdated as new evidence, service models and therapeutic classes evolve. We would welcome more explicit commitment to:

Time-bound reviews with details on how NICE will ensure the reference models are kept up to date considering the rapidly evolving therapeutic landscape.
Clarification on how feedback from completed TAs will influence revisions to the reference case extension.
Explaining how learnings from previous pilots have been brought forward to help design an approach that can be adopted routinely to a broader number of disease areas.

Resource use assumptions

The draft reference case leans heavily on interim commissioning guidance for tirzepatide to inform assumptions around monitoring and multidisciplinary support. In reality, hypothetical or early service models often diverge significantly from intended designs, and implementation varies widely across regions. These assumptions should be treated as a potential input, not the default base case. Encouraging triangulation with real-world data and exploration of plausible high/low intensity scenarios would help prevent systematic misspecification of resource use that may bias against technologies that require different service configurations.

Required vs recommended

Distinguishing between required and recommended elements is a sensible way to balance consistency with flexibility. But more detail on how each category was determined and what non-compliance with a “recommended” element actually means in practice would be valuable. Clearer guidance, or even an ‘evidence-conditional’ category may help manufacturers prioritise effort and avoid unnecessary complexity. Further clarity on implementation may also be warranted. Will the company be expected to explain within their submission how they have adhered to the reference case? Will a new Appendix be created for this? Will EAGs structure their reports around adherence to the reference case?

Research recommendations

There is also a call for research recommendation that would support further development of the reference case extension. There are several methodological gaps that merit focused research:

Weight-regain trajectories

Weight regain may be non-linear and depend on the duration of obesity, time on treatment and magnitude of weight loss. More long-term, treatment-specific data are needed, alongside clearer expectations for scenario analyses [6,7].

Residual risk after weight loss

Event risk for obesity related complications may not fully reset after weight loss and standard risk equations don’t capture this especially well. More research exploring the shape, magnitude, and duration of residual cardiometabolic risk following pharmacologically induced weight loss, accounting for prior-obesity duration would allow more dynamic modelling of long-term outcomes [8].

Non-BMI-mediated cardiovascular benefits

There is some evidence to suggest that treatment with GLP-1 receptor agonists is associated with cardiovascular risk reduction that is not fully explained by BMI, blood pressure, HbA1c, or lipid changes alone. Without a way to model broader pleiotropic pathways, there is a risk of systematically undervaluing treatments with broader cardiometabolic effects. A structured programme of research is needed to quantify and integrate these effects into future modelling guidance [9].

[1]	Consultation \| Disease-specific reference case extension: Management of overweight and obesity in adults \| Guidance \| NICE.
[2]	Overview \| Liraglutide for managing overweight and obesity \| Guidance \| NICE.
[3]	Overview \| Semaglutide for managing overweight and obesity \| Guidance \| NICE.
[4]	Overview \| Tirzepatide for managing overweight and obesity \| Guidance \| NICE.
[5]	Proportionate Approach to Technology Appraisals: Final report 2022/23.
[6]	Kolli RT, Aoutla S, Jyothi N, Mohamed Kalifa MRH, Raju A, Cheenikkal Muralidharan K. Rebound or Retention: A Meta-Analysis of Weight Regain After the Discontinuation of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists and Other Anti-obesity Drugs. Cureus. 2025 Oct 19;17(10):e94926. doi: 10.7759/cureus.94926. PMID: 41116804; PMCID: PMC12535773.
[7]	Pennington B, Cummins E, Chandler A, Fotheringham J. Challenges in Modelling the Cost Effectiveness of Pharmacotherapies for Obesity. Pharmacoeconomics. 2025 Oct;43(10):1171-1178. doi: 10.1007/s40273-025-01520-0. Epub 2025 Jul 28. PMID: 40717166; PMCID: PMC12450117.
[8]	Haase, C.L., Lopes, S., Olsen, A.H. et al. Weight loss and risk reduction of obesity-related outcomes in 0.5 million people: evidence from a UK primary care database. Int J Obes 45, 1249–1258 (2021).
[9]	Deanfield, J., Verma, S., Scirica, B.M., Kahn, S.E., Emerson, S.S., Ryan, D., Lingvay, I., Colhoun, H.M., Plutzky, J., Kosiborod, M.N. and Hovingh, G.K., 2024. Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial. The Lancet, 404(10454), pp.773-786.