Tirzepatide for treating type 2 diabetes

3.1 Type 2 diabetes is a chronic metabolic condition caused by reduced tissue sensitivity to insulin (known as insulin resistance) and loss of endogenous insulin production. This leads to elevated blood glucose levels (hyperglycaemia). Type 2 diabetes is serious and sometimes progressive condition that can greatly affect the health and wellbeing of people with it. If not managed effectively, it can lead to devastating, life-changing complications. An estimated 90% of adults with type 2 diabetes are living with overweight or obesity at diagnosis. This is linked to difficulties in managing blood glucose levels and to an increased risk of complications. The clinical experts explained that there are 8 different classes of glucose lowering treatments available (in addition to lifestyle interventions; see section 3.2). But despite this, fewer than 2 in 3 people with type 2 diabetes have HbA1c levels below 53 mmol/mol (7%), highlighting the need for further treatment options. The committee noted the high unmet need for new treatment options in type 2 diabetes.

3.2 Treatment options in diabetes are tailored to the individual circumstances of people with type 2 diabetes, such as their HbA1c levels, cardiovascular risk and kidney function. Current first-line treatment options in NHS practice include:

3.3 The NICE scope defined the relevant patient population as the same as that in tirzepatide's marketing authorisation (see section 2.1). But, in its submission, the company positioned tirzepatide in a narrower population, that is, as an alternative to GLP‑1 RAs in adults with type 2 diabetes inadequately controlled with 3 or more antidiabetic drugs. It explained that this is because this is where it expects tirzepatide is to be used in NHS practice (with 2 oral antidiabetic agents). It also noted that this population has the highest unmet need. The clinical experts explained that, internationally, tirzepatide is used earlier in the treatment pathway. But they agreed that it would likely be used as an alternative to GLP‑1 RAs in NHS practice. They noted that all GLP‑1 RAs have broad licences, ranging from for people who have not had treatment for type 2 diabetes to people who have had insulin. But their use in the NHS is limited to third or fourth line. The clinical experts also explained that treatments administered by injection, such as tirzepatide and most GLP‑1 RAs are less easily adopted in primary care than oral tablets. They are also more expensive than most oral treatments, so they would be reserved for further lines of treatment in the NHS. The EAG noted that the criteria for using GLP‑1 RAs in NHS practice are not only defined by previous treatment (see section 3.2). The committee would have preferred to have assessed tirzepatide in the broader population aligned with the NICE scope. But it was not presented with any evidence to do so. It acknowledged that the company's positioning of tirzepatide as an alternative to GLP‑1 RAs was reasonable. But it noted that this would mean that it could only consider tirzepatide for people:

3.4 The company submission included the following GLP‑1 RAs as relevant comparators: dulaglutide, liraglutide and semaglutide (oral and injectable formulations). The company noted that the GLP‑1 RAs lixisenatide and exenatide (standard and modified-release) were excluded because of limited market share in the UK. The clinical experts confirmed that lixisenatide and exenatide are less commonly used in clinical practice. The committee agreed that GLP‑1 RAs are relevant comparators, considering the company's positioning of tirzepatide as an alternative to them. It agreed that the GLP‑1 RAs chosen by the company represented those that would be used in NHS practice.

3.5 The clinical-effectiveness evidence for tirzepatide came from 4 trials, SURPASS‑2 to -5. These were multinational multicentre randomised phase 3 studies. They assessed tirzepatide 5 mg, 10 mg and 15 mg against:

3.6 In its second meeting, the committee considered whether SURMOUNT‑2 and the SURMOUNT‑CN trials should have been included in the company's submission. The company noted that the SURMOUNT trials focused on a different indication (weight loss) and were not relevant to this appraisal. Only SURMOUNT‑2 included people with type 2 diabetes, but it would not have been included in the company's network meta-analysis (NMA) for the current appraisal. This was because the definition of background therapies allowed was not directly relevant to the current appraisal's decision problem. The EAG noted substantial differences between SURMOUNT‑2 and the SURPASS‑2, -3, -4 and -5 trials, and that direct comparison was not advisable. A key difference was that people in SURMOUNT‑2 were allowed to change concomitant antidiabetic treatment during the trial, which was not allowed in SURPASS ‑2, -3, -4 and -5. Also, people in SURMOUNT‑2 did not need to have inadequate glycaemic control while on metformin monotherapy (with or without other antidiabetic medication) when entering the study. In SURPASS‑2, -3 and -4, they did. The committee was content with the SURMOUNT trials being excluded from the company submission.

3.7 The committee noted that tirzepatide (all doses) showed statistically significant reductions in HbA1c levels and weight compared with comparators in all SURPASS trials. But weight reduction was more pronounced with higher doses of tirzepatide, while the effect on HbA1c seemed less dose-dependent. The company noted that the dose response curve may have appeared flat for HbA1c reduction from baseline. But the actual baseline HbA1c was not particularly high in the SURPASS trials. The company highlighted that, importantly, 81% to 97% people reached HbA1c levels of less than 53 mmol/mol (7%) across all trials, which was statistically significantly more than with any comparator. The clinical experts noted that fairly flat dose response curves for HbA1c mean that people can have good glucose control with lower doses of tirzepatide. They noted that people may still wish to increase their doses to have the additional benefit of further weight loss. The committee concluded that tirzepatide (all doses) showed statistically significant reductions in HbA1c and body weight compared with all comparators in SURPASS trials. It also concluded that higher tirzepatide doses give higher weight reductions.

3.8 Overall, tirzepatide was reasonably well tolerated in the SURPASS trials, with the most common adverse effects being nausea, dyspepsia and vomiting. The clinical experts explained that the adverse effects are consistent with those of GLP‑1 RAs. They explained that a way to minimise the risk of these adverse effects is to slowly up titrate the dose. This is currently done in the NHS with the GLP‑1 RAs. The clinical experts noted that titration of tirzepatide will be much slower than it is with GLP‑1 RAs, so more resource-intensive. The clinical experts further explained that, in clinical practice, if someone has any gastrointestinal problems, dose increases may be delayed, or they may remain on their current dose. In contrast, the option for slower titration is generally unavailable in clinical trials. The committee acknowledged that the adverse effects of tirzepatide are aligned with those of GLP‑1 RAs, and expected them to be manageable in clinical practice.

3.9 The committee noted that the marketing authorisation for tirzepatide states that it should be titrated as needed to recommended maintenance doses of 5 mg, 10 mg or 15 mg. In contrast, in the SURPASS trials, people were randomised to their maximum dose of tirzepatide. The company acknowledged there was a mismatch between dosing of tirzepatide in clinical practice and the clinical trials, but noted the same issue applies to all comparator trials. The clinical experts explained that, in NHS practice, the focus is on blood glucose levels, so if the target HbA1c is met, people would stay at the current dose of tirzepatide. The committee recalled that people may also stay at their current (lower than maximum) dose when they have adverse effects (see section 3.8). The committee concluded that the way in which tirzepatide was used in the clinical trials, and so the NMA, did not match how it would be used in clinical practice. But it acknowledged that this was the best evidence available.

3.10 Because of a lack of direct evidence from clinical trials, the company did an NMA to assess the relative efficacy and safety of tirzepatide compared with all GLP‑RAs available in NHS practice. The network was defined to align with SURPASS‑2 and -3, and included studies in people on 1 or 2 oral antidiabetic drugs. The EAG was concerned that these criteria did not match the company's target population (people on triple therapy; see section 3.3). The company explained that an NMA criteria of 1 or 2 oral antidiabetic drugs referred to a background treatment of up to 2 oral antidiabetic drugs. Once tirzepatide or GLP‑1 RAs were added, people would be having double or triple therapy. The EAG highlighted that previous and background treatments are 2 separate issues. In the NHS, people would have to have a triple therapy before becoming eligible for GLP1‑RAs, while the company's NMA excluded studies in people on triple therapy. One of the clinical experts explained that treatment effect is not expected to be affected very much by previous treatment. Treatment effect is mostly dependent on a person's initial glycaemic control level, with lower responses for people whose HbA1c levels are close to their targets. They noted that GLP‑1 RAs were shown to be equally effective across different lines of treatment. The company explained that it had done a subgroup analysis of SURPASS‑4, NMA meta-regression analyses and NMA sensitivity analyses to assess the effect of differences in background treatment on the clinical-effectiveness results. All results were consistent with the main results, supporting their generalisability regardless of baseline treatment. The EAG noted that:

3.11 The company described its PRIME type 2 diabetes model (PRIME T2D), which was developed in JAVA, as a discrete-time event, patient-level simulation model. It explained that the model type and structure was similar to the CORE Diabetes Model and the UK Prospective Diabetes Study (UKPDS) model. JAVA was used for its computational efficiency, which was needed to run complex patient simulations. These captured treatment algorithms and risk factor progression, and projected the cumulative incidence of micro- and macrovascular complications, and hypoglycaemic events. The company highlighted that pre-existing type 2 diabetes models used risk equations based on population with low-risk complications. In comparison, PRIME T2D used a model averaging approach, in which the risk predictions from 3 models are combined. This considered patient characteristics over time and was shown to better predict micro- and macrovascular complications (see section 3.12). Also, it used data exclusively from populations with type 2 diabetes, while older models used data from mixed type 1 and type 2 diabetes. The EAG noted that the company's model was very complex and done in a software that is not standard for health economic evaluation. So, it was very challenging for the EAG to scrutinise the model. After consultation, the company provided additional analyses to improve committee confidence in the economic model. These included:

3.12 No comparative data on micro- and macrovascular complications of diabetes, including cardiovascular outcomes, was available. Instead, these outcomes needed to be modelled. The company noted that current diabetes models were shown to poorly predict cardiovascular outcomes, as shown in the Ninth Mount Hood Diabetes Challenge. To better predict these outcomes, they need to be calibrated with hazard ratios from cardiovascular outcomes' trials, which can be challenging. PRIME T2D uses an alternative approach and estimated the rates of micro- and macrovascular complications using model averaging. This drew on 3 different risk models:

3.13 In line with the EAG's recommendations, the company's revised base-case model used UKPDS OM2 risk factor progressions for:

3.14 In PRIME T2D, people were assumed to intensify treatment, that is, stop initial treatment and switch to basal insulin therapy, when their HbA1c levels rose above 59 mmol/mol (7.5%). In the model, there were no other causes for stopping treatment. The clinical experts explained that, in clinical practice, when HbA1c levels rise above agreed targets, people usually have insulin added on to an existing GLP‑1 RA, rather than the GLP‑1 RA being stopped. The committee noted that NICE's guideline on managing type 2 diabetes in adults states that GLP‑1 RAs should only be continued if the person with type 2 diabetes has had a beneficial metabolic response (that is, a reduction of at least 11 mmol/mol [1.0%] in HbA1c and weight loss of at least 3% of initial body weight in 6 months). But it acknowledged clinical advice that use in clinical practice may deviate from this recommendation. After consultation, the company provided a scenario analysis that assumed treatment is intensified by adding insulin to tirzepatide and GLP‑1 RAs when people's HbA1c targets are not met. The results showed limited impact on the cost-effectiveness estimates. The committee accepted the company's modelling of treatment intensification.

3.15 The company's revised base-case model only included nausea rates for tirzepatide and comparators. Severe and non-severe hypoglycaemic rates were only included for basal insulin therapy. The EAG preferred to include both nausea and vomiting. The clinical experts highlighted that vomiting is less common than nausea, and in clinical practice you can avoid it by a very gradual up titration (see section 3.8). They noted that vomiting is the potential outcome of nausea, so there is a risk of double-counting if both are included. After consultation, the company provided a scenario analysis incorporating diarrhoea as an adverse event. The EAG noted that this had only a minor impact on the cost-effectiveness estimates. The committee concluded that the company's inclusion of this adverse event was acceptable.

3.16 The company's revised base-case model adjusted utility values for aging, in line with the EAG's suggestion. But the EAG noted that the company's baseline utility value for people with type 2 diabetes (0.815) was still higher than the utility score for the general population at the same age (0.804). It noted that a recent meta-analysis of 19 studies reported an average utility of 0.772 for people with type 2 diabetes (Redenz et al. 2023). The company emphasised that it used a baseline value from NICE's guideline on managing type 2 diabetes in adults to align with it as closely as possible. It also noted that the study by Redenz et al. was published after its submission. After consultation, the company provided 2 scenario analyses using lower baseline utilities for people with type 2 diabetes: 0.785 from Clarke et al. (2002) and 0.772 from Redenz et al. The EAG noted that both scenario analyses resulted in cost-effectiveness estimates slightly lower than the company's base-case results. The committee concluded that it preferred to use the lower baseline utility value identified by the EAG. But it acknowledged that changing the value had limited impact on the cost-effectiveness estimates.

3.17 The company's revised base-case model applied disutility for complications, adverse events and overweight to the baseline utility value for type 2 diabetes using an additive approach. It highlighted that source publications reported all disutilities as additive values. Also, previous NICE technology appraisals guidance adopted an additive approach to combine disutilities. The company emphasised that using the multiplicative approach may underestimate the effect of diabetes-related complications on people's health-related quality of life (HRQoL). After consultation, the company highlighted evidence from Gough et al. (2009). This concluded that HRQoL decrements associated with type 2 diabetes and obesity showed no significant interaction, so could be assumed to be additive. Also, studies by Sullivan et al. (2011) and Hayes et al. (2016) considered it reasonable to treat comorbidities for diabetes as independent and add utility decrements. The company also provided a scenario analysis using a multiplicative approach for combining disutilities. The EAG noted cost-effectiveness estimates increased with the multiplicative approach compared with the company's base-case results. But the incremental cost-effectiveness ratios (ICERs) remained below £20,000 per quality-adjusted life year (QALY) gained. The committee noted that NICE health technology evaluations: the manual states that the multiplicative method is a preferred approach for combining disutilities. But it acknowledged that the evidence provided by the company supported using an additive approach. The committee concluded that an additive approach for combining disutilities was acceptable for this appraisal.

3.18 The company explained that the probabilistic sensitivity analysis in PRIME T2D aimed to capture uncertainty around all aspects of simulation, not only uncertainty around model parameters. It also stated that it followed the methods used in the CORE Diabetes Model. The EAG explained the company's approach was not standard, and that the estimated mean results might have been correct but distribution around results was likely distorted and uncertainty underestimated. The committee concluded that the company's probabilistic sensitivity analysis may have underestimated the uncertainty around the ICERs. But it thought that the mean results were likely to be appropriately estimated.

3.19 The company's revised base-case ICERs were less than £20,000 per QALY gained for tirzepatide (all doses) against all comparators. Additional analyses provided by the company after consultation improved confidence in the clinical-effectiveness results (see section 3.10) and the economic model (see section 3.11). Scenario analyses included:

3.20 The committee noted that people of Black Caribbean, Black African and South Asian family background are at a higher risk of being diagnosed with type 2 diabetes, and at a younger age. It acknowledged that there is a higher prevalence of the condition among people in more deprived areas and they have poorer care, leading to poorer outcomes. It noted that a high proportion of people with type 2 diabetes have excess weight. It also noted that people who experience weight stigma are less likely to have good care and to seek help from a healthcare professional to support weight loss. The committee noted these concerns, but concluded that they had no effect on its recommendations.

3.21 The committee noted that tirzepatide is a first in class dual GLP‑1 and GIP RA. But it did not identify additional benefits of tirzepatide not captured in the economic modelling. So, the committee concluded that all the additional benefits of tirzepatide had already been considered.

3.22 The committee concluded that all ICERs for tirzepatide (all doses) against all comparators were within what NICE considers a cost-effective use of NHS resources. Because of tirzepatide's positioning as an alternative to GLP‑1 RAs, it is recommended in a narrower population than its marketing authorisation.