Tirzepatide for managing overweight and obesity

The clinical-effectiveness evidence for tirzepatide comes from the SURMOUNT‑1 clinical trial. SURMOUNT‑1 was a randomised, double-blind trial that compared tirzepatide with placebo, both alongside diet and exercise support. It included adults with obesity (BMI of 30.0 kg/m² or more) with or without a comorbidity, or with overweight (BMI of 27.0 kg/m² to 29.9 kg/m²) with at least 1 of the following weight-related comorbidities: hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease. People with type 2 diabetes were excluded, but people with prediabetes were not. People with history of significant active, unstable major depressive disorder, or other severe psychiatric disorders within the last 2 years were also excluded. The trial was done in 9 countries but there were no study sites in the UK. The trial included 4 arms: 3 arms were given tirzepatide at either a 5 mg (n=630), 10 mg (n=636), or 15 mg (n=630) dose and 1 arm was given placebo (n=643). All arms were followed up for 72 weeks. The committee concluded that SURMOUNT‑1 was appropriate for decision making.

The company's target population included adults with a BMI of 30 kg/m² or more with at least 1 weight-related comorbidity. This was a subgroup of the full trial population in SURMOUNT‑1. The most common comorbidities in the company's target population at baseline in SURMOUNT‑1 were hypertension, dyslipidaemia and osteoarthritis. But, many other comorbidities were reported that meant people could be included in the target population. The committee noted that people with type 2 diabetes were not included in SURMOUNT‑1. It was aware that tirzepatide is recommended for some people with type 2 diabetes in NICE's technology appraisal on tirzepatide for treating type 2 diabetes. If recommended, more people with type 2 diabetes may be eligible for tirzepatide if they meet the criteria for tirzepatide treatment for weight management. At consultation, stakeholders raised concerns that SURMOUNT‑1 excluded people with type 2 diabetes and so there is no clinical-effectiveness data on tirzepatide for managing obesity for these people. During the third committee meeting a clinical expert explained that there may be greater health gains in people with type 2 diabetes than people without. This is because tirzepatide affects blood glucose levels as well as weight loss. They explained that although evidence suggests there is less weight loss for people with type 2 diabetes than for people without, tirzepatide's impact on blood glucose levels is greater. The EAG also highlighted evidence that suggested that natural history weight gain is slower in people with diabetes. So, it is possible that people with type 2 diabetes would have a slower rate of weight regain after stopping tirzepatide (see section 3.17). A patient expert explained that there is often an overlap of people living with obesity and living with type 2 diabetes. Separating access to tirzepatide for the 2 populations could create confusion and worsen existing stigma. SURMOUNT‑1 also excluded people with a history of significant active or unstable major depressive disorder or other severe psychiatric disorders within the last 2 years. NHS England commented that the generalisability of the trial should be considered with caution because there is no clinical evidence to show the effectiveness of tirzepatide in this group. The company highlighted that people were only excluded from SURMOUNT‑1 if their mental health condition was considered unstable and that 21.6% of people in SURMOUNT‑1 reported a pre-existing psychiatric disorder. This included but was not limited to depression, anxiety, insomnia and major depressive disorder. The committee noted that people with some types of severe psychiatric disorders (such as bipolar or schizoaffective disorder) who may be on antipsychotic medicine did not appear to have been included in SURMOUNT‑1. So, it was unclear what level of additional psychological support these adults might need alongside tirzepatide. A clinical expert noted that people with severe psychiatric disorders are already having psychiatric care and that the interventions needed to support the delivery of tirzepatide should be considered separately. The committee concluded that the population in SURMOUNT‑1 had a wide range of comorbidities, which made them eligible for inclusion in the target population analysis. It also concluded that because SURMOUNT‑1 did not include people with type 2 diabetes or with certain mental health disorders, it did not cover the whole licensed population. It also did not cover the whole population who would potentially have tirzepatide in the NHS. But, the committee noted that the health benefit gained with tirzepatide seen in SURMOUNT‑1 was likely to be generalisable to people with type 2 diabetes. This is because for people with type 2 diabetes, tirzepatide would be more likely to have other health benefits in addition to weight loss (for example, its greater effect on blood glucose levels). The committee also noted that natural history weight regain is likely to be slower after stopping tirzepatide. The committee concluded that there was some uncertainty about the generalisability of the clinical-effectiveness results in SURMOUNT‑1 to the population who would potentially be offered tirzepatide, but this was acceptable.

People in all arms of SURMOUNT‑1 were advised on diet and exercise. This included a diet with a 500‑calorie per day deficit and to increase their weekly physical activity by 150 minutes. People in the trial also saw a dietitian (or equivalently qualified delegate according to local standards) for diet and exercise management counselling at weeks 0, 4, 8, and 12 during dose escalation. They then saw them again at week 24 and then every 12 weeks throughout the trial. The EAG highlighted that the trial protocol specified that an individualised diet plan should be developed for each person by a dietitian or another appropriately trained person and reviewed. The company explained that the individualised diet plan was a recommendation in the trial protocol and that the lifestyle modification used in SURMOUNT‑1 changed according to which country the trial was being done in. It also explained that the diet and exercise support was intended to be a light-touch approach that in many cases was delivered virtually rather than face-to-face, and not always by a dietitian. Based on this, the company suggested that the diet and exercise support used in SURMOUNT‑1 could be replicated in primary and secondary care in the NHS. It explained that its target population only included people with a comorbidity. So it expected that diet and exercise support for these people could be incorporated into the ongoing care they have for these comorbidities. A clinical expert noted that there would be differences in how the diet and exercise support is delivered in different countries. But they explained that, overall, the trial is generalisable to clinical practice in the NHS. They also explained that they would anticipate that the weight loss seen in the trial may be similar without the diet and exercise support provided. This is because diet and exercise contributes less to weight loss in combination with a treatment like tirzepatide. But, they noted that diet and exercise was an important component of the overall intervention. The committee noted that the diet and exercise support in SURMOUNT‑1 was given for the full 72‑week trial duration. It recalled that diet and exercise support interventions are being delivered in some areas within primary care. But it noted that the level of long-term diet and exercise support delivered alongside tirzepatide in SURMOUNT‑1 is not consistently available. It also noted that obesity services in the NHS are changing, and it was uncertain exactly what changes to obesity management services would be implemented if tirzepatide was to be delivered in primary care (see section 3.3). It was uncertain if the diet and exercise support included in SURMOUNT‑1 was similar to the obesity weight management services that could be delivered in primary care. There was particular uncertainty regarding the length of availability, intensity and consistency across the country. So, the committee concluded that it would need to consider tirzepatide in the context of a range of weight management services.

The company presented analyses for each arm of SURMOUNT‑1, which included 5‑mg, 10‑mg or 15‑mg doses of tirzepatide. The clinical experts explained that the highest tolerated dose of tirzepatide would likely be used in clinical practice. The company also presented evidence from SURMOUNT‑4, a randomised controlled trial in adults with obesity or overweight with at least 1 weight-related comorbidity. It compared a maximum tolerated dose of tirzepatide (either 10 mg or 15 mg) and placebo. This showed that 92.5% of people in the trial were able to tolerate a maximum dose of 15 mg. SURMOUNT‑1 used dose escalation for all arms, with the dose titrated up from 2.5 mg every 4 weeks until people reached the allocated maintenance dose by week 20. There was one chance to de-escalate the dose in the trial if a person had intolerable gastrointestinal side effects. The committee was aware that the summary of product characteristics for tirzepatide specifies the starting dose of 2.5 mg and dose escalation of 2.5 mg every 4 weeks. The patient expert explained that, based on experience with other similar treatments, it is important to titrate the dose up at the appropriate rate to avoid side effects. The committee concluded that it was likely that the highest tolerated dose of tirzepatide would be used, and for most people this would be 15 mg. The committee also concluded that dose escalation and de-escalation would need appropriate monitoring. How this was done would need to be considered in the implementation of the wraparound obesity management services for delivering tirzepatide.

The company presented clinical-effectiveness evidence comparing tirzepatide alongside diet and exercise support with placebo alongside diet and exercise support from SURMOUNT‑1. It presented evidence from 72‑week follow up for the full trial population (n=2,539), its target population (n=1,705; see section 3.4), and subgroups including adults with a BMI of 35 kg/m² and at least 1 weight-related comorbidity. The primary outcomes were mean percentage change in body weight and percentage of people with 5% or more body weight reduction. Evidence showed that in the full trial population, tirzepatide 15 mg was associated with a statistically significantly greater reduction in body weight from baseline compared with placebo (mean percentage change difference -20.1%, 95% confidence interval [CI] -21.2 to -19.0). Evidence also showed that a statistically significantly larger proportion of people on tirzepatide 15 mg lost 5% or more body weight from baseline (96.3%) compared with placebo (27.9%). Similar findings were reported for secondary outcomes in the trial. Evidence on tirzepatide's treatment effect compared with placebo in the company's target population and the subgroup including adults with a BMI of 35 kg/m² and at least 1 weight-related comorbidity is considered confidential so cannot be reported here, but results are similar to the results for the full trial population. Evidence also showed that tirzepatide was more clinically effective when using the higher dose, across all subgroups presented. The committee noted there was no evidence on tirzepatide's treatment effect compared with placebo beyond 72 weeks. So, it is uncertain what long-term effect tirzepatide would have on morbidity and mortality rates. It concluded that tirzepatide is an effective treatment for overweight and obesity in the full trial population, as well as in the company's target population and presented subgroups at 72‑week follow up. But it is uncertain what the effectiveness of tirzepatide is beyond the 72‑week period observed in the trial.

No head-to-head trial evidence was identified comparing tirzepatide with semaglutide. So, the company also presented network meta-analyses for this comparison for its target population, adults with a BMI of 30 kg/m² or more with at least 1 weight-related comorbidity. It used data for this population from STEP‑1 and SURMOUNT‑1. STEP‑1 was a randomised controlled trial comparing semaglutide alongside diet and exercise support with placebo alongside diet and exercise support in adults with overweight and obesity. The results of the network meta-analyses suggested that tirzepatide 15 mg was statistically significantly more effective than semaglutide 2.4 mg for weight loss and improvement of high-density lipoprotein levels. They also suggested there was no statistically significant difference between tirzepatide 15 mg and semaglutide 2.4 mg for total cholesterol and systolic blood pressure improvement. The exact data is confidential and cannot be reported here. The committee concluded that the network meta-analysis indicated that tirzepatide 15 mg was at least as effective as semaglutide 2.4 mg across all outcomes reported, and more effective than semaglutide 2.4 mg for weight loss in the target population.

People entering the model in the company's base case had a BMI of 30 kg/m² or more with at least 1 weight-related comorbidity, in line with its target population. People entered the model in a normal glucose tolerance state or with prediabetes. But they did not have any of the other complications or comorbidities at baseline that were later included as possible events in the model. Risk equations were used to estimate the probability of the 10 clinical events in the model (see section 3.12), and death, occurring. The treatment effects on the predictors informing these risk equations were taken from the company's network meta-analyses and directly from clinical trial data. The EAG noted that not including any of the later modelled complications or comorbidities for people entering the model was not in line with the baseline data from SURMOUNT‑1. In SURMOUNT‑1, a proportion of people had baseline comorbidities such as previous myocardial infarction, obstructive sleep apnoea and non-alcoholic fatty liver disease. It explained that this was likely to bias the cost-effectiveness results in favour of tirzepatide. After the first committee meeting, the EAG updated its base case to include a proportion of people entering the model with previous myocardial infarction, obstructive sleep apnoea and non-alcoholic fatty liver disease. The EAG highlighted that no one enters the model with type 2 diabetes. The company explained that it was inappropriate to include a proportion of people entering the model with type 2 diabetes because no benefits from improved glycaemic control would be modelled for these people. But clinical trial evidence (from SURMOUNT‑2 and SURPASS) suggests that people with type 2 diabetes do show improved glycaemic control and therefore additional health benefits with tirzepatide (see section 3.12). Clinical experts agreed that there are likely to be additional health gains with tirzepatide for people with type 2 diabetes (see section 3.7) and that this is not reflected in the economic model. The EAG agreed that the economic model is not set up to model people with type 2 diabetes. This is because one of the key drivers of the model is the avoidance or delay of type 2 diabetes, which does not apply to people who already have it. It did not include a proportion of people with type 2 diabetes in the baseline model population. So people who have type 2 diabetes at baseline are not represented in the model. This introduces uncertainty into the model because the results are driven by the cost offsets and utility gains from avoiding type 2 diabetes. The committee noted that NICE's technology appraisal guidance on tirzepatide for treating type 2 diabetes recommends tirzepatide alongside diet and exercise support for some people with type 2 diabetes (see section 3.7). This indicates that tirzepatide is cost effective for some people with type 2 diabetes and so reduced the uncertainty associated with not including this population in the model at baseline. The committee concluded that it was appropriate to include people in the baseline population who have the modelled complications and comorbidities. It also concluded that there was some uncertainty associated with the model's baseline population not including people with type 2 diabetes. But if this population were included in the model the benefits of tirzepatide would likely be underestimated. It concluded that it was appropriate to include people with type 2 diabetes within any population for which tirzepatide was recommended for weight management.

The company estimated the BMI distribution of people included in the model from a gamma distribution fitted to the SURMOUNT‑1 target population. The EAG raised concerns that the gamma distribution does not include enough people at the lower end of the BMI range. A comparator company also commented that the baseline BMI in SURMOUNT‑1 (mean BMI of 38.0 kg/m²) was higher than the average BMI of people who would potentially be eligible for tirzepatide in primary care. In response to draft guidance consultation, the company provided detailed graduation of the BMI distribution of people with a BMI of 30 kg/m² and higher with at least 1 comorbidity in SURMOUNT‑1. Based on this, the EAG noted that a relatively high proportion of people in SURMOUNT‑1 had a BMI of 30 kg/m² to 31 kg/m². It explained that people with a lower BMI have relatively fewer quality-adjusted life year (QALY) gains from tirzepatide than people with a higher BMI. So, by not including enough people at the lower end of the BMI range, the cost-effectiveness estimates would be biased in favour of tirzepatide. The company presented data on BMI distribution from primary care adult weight management services. It suggested that this represented people who were incentivised to seek treatment and so would represent people who would be likely to use tirzepatide. The data showed that 34% of people with overweight or obesity accessing primary care adult weight management services between April 2021 and December 2022 had a BMI between 30 kg/m² and 34.9 kg/m². The company noted that the proportion of people with overweight or obesity with a BMI between 30 kg/m² and 34.9 kg/m² in the target population of SURMOUNT‑1 was similar (35.5%). The EAG used a log-normal distribution fitted to Health Survey for England data on BMI distribution collected in the general population in its base case. This showed that 66% of people with a BMI of at least 30 kg/m² have a BMI between 30 kg/m² and 34.9 kg/m². The EAG suggested that the general population better reflects the population who would be given tirzepatide, because it was plausible that anyone from the general population eligible for tirzepatide may start treatment. The patient expert explained that it was likely that many people with a BMI between 30 kg/m² and 34.9 kg/m² would want to take tirzepatide if it was available. So, if tirzepatide was available for this population it is likely that the proportion of people with a BMI between 30 kg/m² and 34.9 kg/m² accessing primary care adult weight management services would increase. In response to draft guidance consultation, the company suggested data could be considered from the IMPACT‑O study, which collected BMI data on people from UK primary care clinics between January 2018 and September 2022. The company suggested that the data lies between the Health Survey for England data and the community weight management service data. The committee noted that the BMI distribution in SURMOUNT‑1 was aligned with people who are in primary care adult weight management services. But, more people from the general population with obesity may access tirzepatide through primary care if it is recommended. The committee considered that the BMI distributions in SURMOUNT‑1, primary care adult weight management services and IMPACT‑O were likely to be different to the population who would access tirzepatide in clinical practice. So, it concluded that the EAG's base case using the log-normal distribution of the Health Survey for England data to model BMI distribution was most appropriate. But, the BMI distribution was uncertain, so the committee would also like to have seen scenarios using the BMI distribution from IMPACT‑O.

After the first committee meeting, the committee requested further information on the potential composition and costs of obesity management services needed to deliver tirzepatide. NHS England submitted estimates of the potential resource use needed for obesity management services, which reflected the protocol in the SURMOUNT‑1 trial. This included:

• appointments for initial assessment

• education on diet and exercise

• injection training for patients

• monitoring appointments during dose titration

• diet and exercise counselling every 12 weeks

• a medicines review

• an additional MDT patient review, and

• psychological support for a third of people.
  
  NHS England suggested that the proposed services should be available for as long as tirzepatide is being used, because these services were given for the entire duration tirzepatide was given in SURMOUNT‑1. It highlighted that the resource estimates had been developed with clinical expert input and reflected the wraparound support that had been provided in SURMOUNT‑1. It also suggested that it is not appropriate to include these costs in the diet and exercise arm in the model because the services needed are not yet available. The company suggested that NHS England had overestimated the time and regularity needed for each appointment. It also suggested that other healthcare professionals may be able to provide some of the services that NHS England suggested would be delivered by GPs or dietitians. The company explained that the diet and exercise support provided in SURMOUNT‑1 was not necessarily provided by dietitians and that nurses were qualified to manage dose titration. The company proposed that the diet and exercise arm of the model should also include appointments for diet and exercise counselling. It proposed that the obesity management services that were unique to tirzepatide and so should be accounted for only in the tirzepatide arm of the model were:

• starting treatment, including injection training, which could be nurse-led

• 5 dose-titration appointments, which could be nurse-led, and

• an annual MDT review, which could be done by a GP by reviewing notes.
  
  The company presented a range of scenarios that showed the impact on the incremental cost-effectiveness ratio (ICER) of including its or NHS England's obesity management service proposals. But it did not apply any of these to its base case. The resource used in the company's base case included 4 GP visits, 8 nurse visits and 1 blood test per year, in all arms for the full time horizon of the model. The EAG amended its base-case assumptions after the first committee meeting to include the resource use proposed by NHS England for obesity management services. It applied all the proposed resource to the tirzepatide arm for the duration of tirzepatide treatment and assumed no resource costs for the diet and exercise arm. The committee discussed that primary care obesity management services would likely need to adapt to deliver tirzepatide alongside the diet and exercise support also needed (see section 3.3). But it noted that it is not clear what these services will include. The EAG estimated the resource use for obesity management services according to NHS England's proposals. This reflected the interventions used in the trial for tirzepatide for as long as the person was on tirzepatide, and 2 years of service use for people having diet and exercise support alone. The committee noted that primary care weight management services are being delivered, although access and level of support varies across the country (see section 3.2). The committee discussed that of all the proposals it had seen, NHS England's were likely to represent the highest cost impact for obesity management services needed for delivering tirzepatide. It concluded that, given the uncertainty around the weight management support needed for the tirzepatide and diet and exercise arms, it would consider a range of obesity management service scenarios in its decision making. It noted that it is likely that scenarios using NHS England's proposals would result in the highest likely cost-effectiveness estimates.

The company's model assumed that for the period of time that clinical trial data was available (72 weeks based on SURMOUNT‑1 data), weight decreased for those having tirzepatide and those having diet and exercise support alone. This was in line with the weight loss seen in each arm in the trial. After this point, for people having diet and exercise support alone, weight increase was assumed. This was in line with natural progression due to age, based on data from Ara et al. (2012). For tirzepatide, the weight lost because of the treatment and its associated benefits was assumed to continue indefinitely until treatment was stopped. The EAG explained that this meant that the relative treatment effect between the tirzepatide treatment arms (which assumed a constant weight) and the diet and exercise arm (where weight increased steadily in line with natural history) increased over time. The EAG highlighted that there was no evidence that this assumption was correct in the long term because data from SURMOUNT‑1 was only available for 72 weeks. In response to the draft guidance consultation, stakeholders were concerned about the lack of long-term treatment effect data. The EAG highlighted evidence from the SCALE study in liraglutide that suggested weight is regained over time while still on treatment. It explained that a similar reduction in absolute treatment effect over time is plausible for tirzepatide. The EAG removed the increasing difference in treatment benefit between arms included in the company's model. It did this by applying the same natural progressive increase in weight by age to the tirzepatide arm after 72 weeks, in line with the end of trial follow up. The company highlighted that by 72 weeks, the treatment effect for tirzepatide was constant. It explained that there is no evidence to suggest that the absolute treatment benefit of tirzepatide is lost over time and there is no biological rationale to support that assumption. It explained that a trial for tirzepatide with follow up of 102 weeks, SURPASS‑4 (Heerspink et al. 2022; including a population with type 2 diabetes and measuring kidney outcomes), showed no treatment effect waning for people having tirzepatide over that period. In response to draft guidance consultation, the company suggested that the data from SCALE was likely to include people who had stopped treatment. So it was not useful data to indicate what the absolute treatment effect for people on tirzepatide might be over time. It also highlighted that liraglutide is less effective than tirzepatide and so the applicability of findings from SCALE to indicate the treatment effect for tirzepatide is limited. The company also presented extension phase data from the SELECT study in semaglutide showing that there was no loss of absolute treatment effect over 221 weeks. The company stated that this is more representative of tirzepatide, but there is no data beyond 221 weeks. The clinical experts supported the notion that weight seemed to stabilise on treatment with GLP‑1 analogs (including semaglutide and tirzepatide) until they are stopped, but there is no long-term data. They explained that it is unlikely weight would be regained while on tirzepatide because of its mechanism of action. But they also explained that there is no observed data to show that people having the diet and exercise intervention in SURMOUNT‑1 would have an increase in weight over time. The clinical experts explained that in the SCALE study, the weight gain seen in the liraglutide arm could be because of a reduction in lifestyle interventions in combination with liraglutide. They added that diet and exercise contributes less to the overall treatment effect when more effective pharmacological treatments are used. So, the same level of loss of effect from a reduction in lifestyle intervention would not be expected for tirzepatide. The EAG also explained that the natural history weight gain parameter the company used from Ara et al. (2012) only included people without type 2 diabetes. It suggested that it was appropriate to use a combined weight gain parameter that also included people with type 2 diabetes to reflect the population eligible for tirzepatide. The committee considered that the rate of weight gain while on tirzepatide and when this would start was uncertain without long-term clinical data. But it had not been presented with any evidence that showed that the relative treatment effect difference between the tirzepatide and diet and exercise arms increases over time. It agreed that without long-term evidence this was highly uncertain. So, it concluded that it would consider multiple scenarios that assumed a constant relative treatment effect between the tirzepatide and diet and exercise arms in decision making. These include:

• applying natural history weight gain from 72 weeks in both the tirzepatide and diet and exercise arms based on weight gain parameters for people with and people without diabetes from Ara et al. (2012)

• applying no natural history weight gain in either the tirzepatide or the diet and exercise arm.

In its submission, the company's model assumed that after stopping tirzepatide, the weight that had been lost was regained at a steady rate over 3 years. At 3 years after stopping treatment, weight was aligned with where it would have been had treatment not started (in line with the diet and exercise support arm endpoints). The EAG explained that the rate of weight regain seen after stopping semaglutide treatment in STEP‑1 (see section 3.11) suggested that the time it takes for the treatment effect to be lost is closer to 2 years. The clinical experts explained that STEP‑1 provided relevant data to estimate the time that treatment benefits would be lost after stopping tirzepatide. They explained that for semaglutide, around two thirds of the weight lost while on treatment is regained within the first year after stopping. Some other benefits gained, such as reduced blood pressure, are also lost by this time. But they noted that there is no long-term data for what happens to weight after stopping tirzepatide. After the first committee meeting, the EAG updated its model to assume that weight would be regained in 2 years after stopping tirzepatide. The EAG noted that assuming either 2 or 3 years for time-to-weight-regain did not have a meaningful impact on the ICER. In response to draft guidance consultation, the company also updated its model to assume that weight would be regained in 2 years after stopping tirzepatide. The committee concluded that it was uncertain how quickly the benefits associated with tirzepatide would be lost after stopping treatment. But it preferred to assume that weight would be regained in 2 years after stopping, in line with the evidence for semaglutide.

The EAG highlighted that in the diet and exercise arm in the model, people who had prediabetes (also known as non-diabetic hyperglycaemia) at baseline that was reversed as a result of weight loss, had it return at 2 years. It explained that this was different from how prediabetes reversal was modelled in the active treatment arms. It explained that for people on tirzepatide, prediabetes reversal was lost 3 years after stopping treatment, in line with when weight was regained in the company's original model. The company explained that this was because prediabetic status cannot be gradually reversed in the individual patient simulation model. The EAG explained that handling the loss of prediabetes reversal differently in the diet and exercise arm and the active treatment arms biases the cost-effectiveness results, favouring active treatment. The EAG explained that it could not directly amend the model so that the diet and exercise and active treatment arms were aligned in how prediabetes reversal was handled. But, it advised that analyses to mimic this suggested that this could have a large effect on the cost-effectiveness results. The company explained that it is not possible to stop diet and exercise because ongoing diet and exercise support should always be available for people managing obesity. So, it is not possible to exactly replicate the approach to loss of prediabetes reversal in the diet and exercise arm that was used in the tirzepatide arm. But, the company presented a scenario in which the time points at which prediabetes reversal is lost and average weight returns to baseline are aligned in the diet and exercise arm in the model. This aligned more with the approach in the tirzepatide arm where prediabetes reversal occurs 3 years after treatment is stopped and weight that was lost has been regained. The company noted that there is no data to support the glycaemic improvements modelled in the diet and exercise arm and so this scenario is likely to overstate the duration of prediabetes reversal in that arm. The clinical experts explained that prediabetes reversal loss is likely to be slower after stopping tirzepatide than in people who have lost weight through diet and exercise alone. But they also explained that the rate of prediabetes reversal loss is primarily driven by the person's weight rather than whether they have had tirzepatide. At the second committee meeting, the committee concluded that prediabetes reversal loss was likely to be driven by weight regain. So, it concluded that it was appropriate for prediabetes reversal loss in both the tirzepatide and diet and exercise arms to align with when weight was regained in those arms. In response to draft guidance consultation, the EAG and company both updated their base-case assumptions to reflect the committee's preferred assumption. The committee concluded that the changes to the model made by the EAG and the company meant that prediabetes reversal loss had been appropriately incorporated into the model.

After the first committee meeting, the EAG highlighted that the model did not account for non-reversible long-term impacts on health outcomes from previously having a higher BMI. This is because the model assumes that someone with a high baseline BMI that decreases during the model's time horizon has equal health risks as someone with a consistently lower BMI. The EAG suggested that this might not be appropriate. For example, someone with long-term insulin resistance caused by their obesity is unlikely to have similar long-term cardiovascular outcomes to someone who had never had insulin resistance. The patient expert explained that the long-term impact of a previous higher BMI does affect some domains of health, including a long-term psychological impact for some people. The clinical experts explained that there is a lot of variation in the ongoing long-term adverse effects of having had a higher BMI, but it will impact some people. The EAG presented evidence from Haase et al. (2021), a retrospective study of UK databases that estimated the effect of intentional weight loss on the risks of various weight-related complications. The EAG acknowledged that there were limitations to Haase et al., but that it indicated it may be unreasonable to assume there is no long-term impact from having previously had a higher BMI. It also highlighted that Haase et al. did not include a measure of the increased risk of mortality. So there was no direct evidence to indicate if previous higher BMI was associated with increased mortality risk. The EAG suggested that the model may overestimate the effect of weight loss on obesity-related complications and potentially mortality risk, although the latter was less clear. The EAG presented scenario analyses that suggested what impact the residual risk of previously having had a higher BMI could have, as indicated by the results in Haase et al. It acknowledged that the scenarios presented reflected an arbitrary reduction in loss of effect based on the evidence that there is residual risk for some outcomes. But, that the scenarios provided a way of exploring the impact on the ICER if the long-term impacts of obesity were taken into account. The company raised concerns around the implementation of these scenarios and explained that it is well understood that losing weight has an overall benefit on long-term outcomes. It raised further limitations with Haase et al., including that the weight loss from baseline in Haase et al. was lower than the weight loss seen with tirzepatide in SURMOUNT‑1. The company highlighted a study by Khunti et al. (2023). This was an extension of the Haase et al. study that looked at the change in the risk of complications associated with weight loss. This study showed that the weight loss benefit on obesity-related complications depended on the amount of weight loss. The company highlighted the data indicating residual impacts from previously having had a higher BMI. It suggested that this shows there are important benefits associated with treating obesity early, before BMI progresses to later disease stages. Analysis based on Haase et al. and Khunti et al. was only incorporated into scenarios to show decision risk and not included in either of the company's or EAG's base cases. The EAG provided a scenario reducing the effect of type 2 diabetes on the model outputs to match the data from Khunti et al., which increased the ICER. There were potential biases with the Haase et al. data. But the committee considered that this data, and Khunti et al., showed it is reasonable to assume some long-term impact on some outcomes from having previously had a higher BMI. This was supported by the clinical experts. The committee felt that if the residual impact of a previously higher BMI was not included in the model, the QALY gain was likely to be overestimated. It noted that this was the case with the company and EAG base cases. So it concluded that there was uncertainty introduced into the model because it did not account for the residual impact of a previously higher BMI. It concluded that if any reduction in effect from this was taken into account, the base-case ICERs presented were likely to be higher.

The summary of product characteristics for tirzepatide states that a decision should be made on whether to stop treatment if less than 5% of initial body weight is not lost 6 months after titrating to the highest tolerated dose (non-responders). The patient experts explained that having this decision point was important to help identify people whose condition does not respond to tirzepatide and for whom treatment should be stopped. This is because these people will not gain the benefits from treatment but will continue to have the risk of side effects. The clinical experts agreed that stopping treatment after 6 months without a response at the highest tolerated dose was appropriate. The company originally estimated the number of people having the 15 mg dose who would stop tirzepatide at 46 weeks in the model (6 months after titrating to the 15‑mg dose) from the proportion of non-responders after 72 weeks in the full trial population in SURMOUNT‑1. In response to draft guidance consultation, the company updated its approach to estimating the number of people stopping treatment 6 months after titrating to the highest dose. To do this, it used data from the target population in SURMOUNT‑1 at 48 weeks. The company assumed that 10% of people on semaglutide would stop treatment after 6 months because of non-response, based on clinical expert opinion. The clinical experts in the committee meeting suggested that they would expect a higher proportion of people to stop semaglutide because of a lack of response. After the first committee meeting, a comparator company submitted evidence to show the proportion of people who stopped semaglutide because of non-response at 6 months in a trial of semaglutide for weight loss. The committee concluded that to estimate the proportion of people stopping tirzepatide because of lack of response after 46 weeks, it was appropriate to use data from the target population in SURMOUNT‑1 at 48 weeks. This is because this was the closest available data on this outcome. It further concluded that it was appropriate to include the available trial data for semaglutide to estimate the response rate at 6 months.

The company did not include a long-term stopping rule for tirzepatide in any of its analyses. This was because it suggested that tirzepatide could be used either within or outside specialist weight management services and so was not restricted by its time limitations (see section 3.2). The patient expert explained that obesity is a chronic condition that needs long-term treatment. The EAG explained that SURMOUNT‑4 data suggests that after stopping tirzepatide, weight is regained over time. The clinical experts explained that this was also supported by longer-term evidence for semaglutide from STEP‑1. At the first committee meeting, the EAG provided 2 base cases including and not including a 2‑year stopping rule for tirzepatide. After the first committee meeting, it updated its base case to not include a 2‑year stopping rule for tirzepatide. Both the company and the EAG included a 2‑year stopping rule for semaglutide. This was because semaglutide is only available in specialist weight management services and they are only accessible for a maximum of 2 years. In response to draft guidance consultation, some stakeholders suggested that it was appropriate to not include a long-term stopping rule because obesity is a chronic condition that needs long-term management. Other stakeholders raised that NICE's technology appraisal guidance on semaglutide recommends it with a 2‑year stopping rule. They suggested that it may be appropriate to also include a long-term stopping rule for tirzepatide, in line with recommendations for semaglutide. In NICE's technology appraisal guidance on semaglutide, the company proposed that semaglutide was used for up to 2 years and submitted a model reflecting this. The committee concluded that it was not appropriate to include a long-term stopping rule for tirzepatide. It also concluded that for the comparison with semaglutide, it was appropriate to apply a 2‑year stopping rule for semaglutide.

The risk equations in the company's model estimate the risk of events occurring (such as development of type 2 diabetes) over multiple years, based on a person's risk factors. The EAG explained that the risk of an event occurring is annualised from this value and it is applied in the model in an annual cycle. The EAG noted that it is unlikely that the risk of an event occurring is constant over a given time. So annualising the event risk may lead to estimating that events occur too early in the model. This would lead to bias because people would be assumed to have events for too long. It also explained that the model re-estimates the risk of each event annually, based on the updated health outcomes of the person in the model. This leads to some people in the model having increased risk of an event every year over the same time in which the risk equation estimates an initial risk of an event. The EAG explained that this leads to overestimation in the incidence of events in all arms. But because of the improved outcomes for people in the active treatment arms, the bias would favour those arms. The EAG provided analysis that estimated the amount of overestimation of the risk of events for an average person in the model. It presented scenario analyses that included adjustments to the 10‑year risk functions to account for these overestimations. It noted that these scenarios were illustrative and given the model structure it was not possible to quantify the exact impact of the potential compounding of the risk of events over time. The company also presented scenarios to show the impact on its base case if the risk of developing type 2 diabetes was reduced by 25% and 50% in all arms. The committee considered both the company's and the EAG's scenario analyses, noting that the EAG's adjustments especially had a limited impact on the ICER. It concluded that the compounding of the risk of events remained an uncertainty in the model. But it was reassured by the EAG's scenario analysis that showed this uncertainty did not have a large impact on the cost-effectiveness estimates.

In its submission, the company sourced the cost of type 2 diabetes from NHS reference costs from 2021 to 2022, covering diabetes-related hospital attendance across 74,041 people. The EAG suggested that this was not representative of the around 4 million people in the UK with type 2 diabetes. The EAG preferred to use the UK Prospective Diabetes Study (UKPDS) data, which estimated the cost of consultations, visits, admissions and procedures associated with diabetes-related complications between 1997 and 2007. The UKPDS data did not take into account expensive items of care for end-stage renal disease, dialysis and transplant. But the EAG suggested that because people in the model have newly developed type 2 diabetes, they were less likely to experience these more expensive items of care in the near future. The EAG explained that the resulting non-inpatient costs represented a total cost per year for someone with type 2 diabetes without complications, and not the net cost compared with someone with obesity. So, it likely overestimates the costs associated specifically with type 2 diabetes in people who also have obesity. In calculating the costs for type 2 diabetes, the EAG therefore applied a net cost that removed the ongoing costs for obesity included in the model. The EAG also applied drug costs based on drug tariff prices. This estimate takes into account the sequential treatment options that would be offered to someone with newly diagnosed type 2 diabetes. This is in line with recommendations in NICE's guideline on type 2 diabetes in adults: management. The company considered the EAG's approach to be overly conservative. It stated that the EAG's approach:

• excludes inpatient costs not otherwise captured by the model

• underestimates drug costs, and

• does not account for people with advanced disease who need more intensive treatment.
  
  In response to draft guidance consultation, the company updated its base case to use the UKPDS costs. But it used the gross cost, which included obesity costs, rather than the net cost used by the EAG. It also included drug costs from Capehorn et al. (2021). The company also disagreed with the EAG's method of cost inflation, which used the NHS Cost Inflation Index. It preferred to use the Personal Social Services pay and prices index to inflate the costs of type 2 diabetes. The EAG questioned the appropriateness of using data from Capehorn et al. to estimate the costs associated with newly diagnosed type 2 diabetes. This was because the average duration since diagnosis of type 2 diabetes in Capehorn et al. was 7 years. It suggested that the costs associated with type 2 diabetes are likely to be greater for people who have had the disease for longer. No one enters the model with type 2 diabetes (see section 3.13). So the committee considered it reasonable to use a cost estimate that more closely reflected people with recently diagnosed type 2 diabetes. It was therefore appropriate to use the UKPDS non-inpatient costs that did not include more expensive items of care. This was because they are likely to be more often associated with more advanced type 2 diabetes. It also considered the EAG's drug costs to be most appropriate. This was because the estimates from Capehorn et al. used by the company were based on people who had been diagnosed with type 2 diabetes for an average of 7 years. The committee agreed that the EAG's approach using the net costs for type 2 diabetes were appropriate. This was because this more accurately represented the costs associated specifically with type 2 diabetes in people who also have obesity. It also agreed that the EAG's methods for inflation using the NHS Cost Inflation Index was standard practice in health technology assessment and the NICE technology assessment manual permits both methods. So, overall, the committee concluded that it preferred the EAG's approach for estimating the costs of type 2 diabetes.

NICE's manual on health technology evaluations notes that, above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. But it will also take into account other aspects including uncaptured health benefits. The committee noted the high level of uncertainty, specifically around:

• the long-term treatment effects of tirzepatide (see section 3.16), and

• the impact of a previously higher BMI on long-term outcomes (see section 3.19).
  
  The committee discussed that, as well as the high levels of parameter uncertainty, there is also high decision risk given the potential population size eligible for tirzepatide if it is recommended. The committee noted that the acceptable ICER was £20,000 per QALY gained in the appraisal of semaglutide and other similar previous appraisals. It was aware that this was because of the uncertainties in the modelling assumptions, including the long-term treatment benefits. The committee also acknowledged the added decision risk of a new setting of care for tirzepatide. Because of the uncertainties the committee agreed that an acceptable ICER would not be greater that £20,000 per QALY gained.

After the draft guidance consultation, the company's base-case model assumptions included:

• BMI distribution estimated using a gamma distribution fitted to the SURMOUNT‑1 target population (see section 3.14)

• background resource costs for GP and nurse visits and for blood tests for both arms (see section 3.15)

• no decrease in absolute tirzepatide treatment effect while on treatment, and therefore a relative increase in tirzepatide treatment effect compared with diet and exercise over time (see section 3.16)

• weight regained during the 2 years after stopping treatment (see section 3.17)

• prediabetes reversal benefit lost in the tirzepatide and diet and exercise arms aligned to when weight is regained in those arms (see section 3.18)

• tirzepatide stopping rates because of non-response at 6 months after titration to the highest dose based on the proportion of people remaining on treatment at 48 weeks in the SURMOUNT‑1 target population (see section 3.20)

• semaglutide stopping rates (10%) at 6 months after titration because of non-response based on clinical expert opinion (see section 3.20)

• no long-term stopping rule for tirzepatide (see section 3.21)

• event risks estimated by risk equations, estimating the annual rate of events from multi-year event risks (see section 3.22)

• gross costs for type 2 diabetes taken from UKPDS, inflated using the Personal Social Services pay and prices index and drug costs from Capehorn et al. 2021 (see section 3.23)

• a modelled cohort size of 1,000.
  
  The following differences from the company's model were included in the EAG's base case:

• BMI distribution estimated using a log-normal distribution fitted to Health Survey for England data (see section 3.14)

• applying the resource use proposed by NHS England for obesity management services to the tirzepatide arm for the duration of tirzepatide treatment (see section 3.15)

• applying NHS England's proposed costs minus titration appointments for the diet and exercise arm for 2 years (see section 3.15)

• removing the net increase in tirzepatide treatment effect by applying a natural progressive increase in weight by age to the tirzepatide arm after 72 weeks, based on a parameter for people without type 2 diabetes from Ara et al. 2012 (see section 3.17)

• using the net costs for type 2 diabetes from UKPDS, inflated using the NHS Cost Inflation Index and drug costs associated with newly diagnosed type 2 diabetes, based on NICE clinical guidelines and drug tariff prices (see section 3.23)

• removing mortality modifiers applied in the company's model for cardiovascular disease and non-alcoholic fatty liver disease because the increased death from these events is covered by the BMI mortality modifier

• a model cohort size of 20,000.
  
  The EAG also presented a second base case including the above assumptions but using the Ara et al. (2012) natural history weight gain parameter for people with and without type 2 diabetes (see section 3.17).

The committee's preferred assumptions mostly aligned with the assumptions in the EAG's base case (see section 3.25). It concluded that there were uncertainties remaining around the long-term treatment effect (see section 3.16) and the BMI distribution in the model (see section 3.14). So, the committee requested to see additional scenarios with its preferred assumptions exploring the following:

• constant relative long-term treatment effect in the tirzepatide arm and diet and exercise arm after 72 weeks, by:

  • applying natural history weight gain in both the tirzepatide and diet and exercise arms based on weight gain parameters for people with and without type 2 diabetes from Ara et al. (2012) from 72 weeks (included in the EAG's second base case; see section 3.16)

  • applying no natural history weight gain in either the tirzepatide or diet and exercise arm

• the BMI distribution from the IMPACT‑O trial data, sampled directly from the graduated BMI data

• both of these scenarios with a range of obesity management service interventions.

The committee was aware that people with mental health disorders, especially those having atypical antipsychotics, may have increased risk of developing obesity. But it acknowledged that access to specialist weight management services may be limited for these people. The committee discussed that it would consider tirzepatide in primary and secondary care settings. So, eligibility for tirzepatide will not be restricted by access to specialist weight management services. The committee was also aware that SURMOUNT‑1 did not include people with a history of significant active or unstable major depressive disorder or other severe psychiatric disorders within the last 2 years. So, there was no evidence for the treatment effect of tirzepatide in this population, or any evidence for how much additional psychological support might be needed. But, despite the increased uncertainty this introduced into the model, the committee agreed that populations excluded from SURMOUNT‑1 should not be excluded from the recommendations for tirzepatide. The committee was also aware that overweight and obesity disproportionately affects socioeconomically disadvantaged communities and that this is likely to contribute to health inequalities. It considered comments from stakeholders that there are health inequalities associated with the inequitable access to nutritional food in these communities. There were stakeholder concerns that recommendations for a restricted calorie diet did not take into account the nutritional value of people's diet. The committee noted that it was expected that tirzepatide would be used alongside a diet and exercise intervention, including healthcare professionals who could advise on a healthy diet. But, the implementation of this could not be covered by a technology appraisal. The committee understood that services for overweight and obesity are unequal across the country and can be very limited, and they are not necessarily available in the areas of the country with the greatest need (see section 3.3). There is uncertainty around the level of additional diet and exercise support that will need to be implemented alongside tirzepatide. So the cost effectiveness of tirzepatide has been assessed across a range of service designs. But, the NHS England clinical adviser explained that obesity services are changing rapidly. The committee concluded that it was not within its remit to make recommendations about obesity management services, but tirzepatide should be accompanied by diet and exercise support services. It noted that people from some ethnicities are at an equivalent risk of the consequences of obesity at a lower BMI than people from White ethnicities. NICE's guideline on overweight and obesity management recommends using lower BMI thresholds for people from South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean ethnic backgrounds as a practical measure of overweight and obesity. The committee agreed that a similar adjustment to the BMI thresholds is suitable for tirzepatide.

The committee considered that there are likely to be challenges with implementing tirzepatide in primary care. So a funding variation to allow a longer implementation period than usual to comply with the recommendation has been included in this guidance (see section 4). This is because a large number of people would potentially be eligible for tirzepatide and the resources needed for its delivery, such as diet and exercise support, are not available equitably across the country (see sections 3.2 and 3.3). It is not within the remit of the committee to make recommendations for the funding variation. But it discussed if there were any groups of people who could be prioritised for tirzepatide, to help inform priority cohorts set out in the interim commissioning policy as part of the funding variation (see section 4.11). The patient expert explained that the greatest unmet need was for people with a BMI of at least 35 kg/m² (see section 3.1) and for people who lose and gain weight regularly. The clinical experts explained that people who need to lose weight before they can have surgery, or who have multiple weight-related comorbidities, may particularly benefit from tirzepatide. The clinical expert also explained that stratifying the eligible population based on risk should not be done only using BMI. This is because the presence of comorbidities is often a better indicator for the risk associated with overweight and obesity. The clinical expert explained that evidence-based recommendations assessing clinical risk would be more useful to identify those with highest risk. They highlighted the joint position statement by the Society for Endocrinology and Obesity Management Collaborative UK (PDF only), which provided guidance for the phased introduction of new medical therapies for weight management. This includes 4 cohorts, grouped by the various risk factors that indicate the level of risk people have from living with overweight or obesity. The committee concluded that the groups highlighted by the joint position statement may be useful to inform prioritisation as part of the funding variation. But, it was outside its remit to make recommendations for this. The summary of product characteristics for tirzepatide states that it is not recommended during pregnancy and in women of childbearing potential not using contraception. It also advises using a non-oral or barrier method of contraception for 4 weeks after starting tirzepatide, and after each dose escalation. These issues cannot be addressed in a technology appraisal, but they may be considered as part of an implementation strategy for tirzepatide. The committee concluded that although it was aware of the potential implementation challenges, its remit is to evaluate the clinical and cost effectiveness of tirzepatide. So it could not consider implementation issues further in its decision making.

For the company's target population, the ICERs that include all of the committee's preferred assumptions and relevant scenarios for tirzepatide compared with diet and exercise and with semaglutide were above the acceptable ICER. The ICERs for tirzepatide in adults with a BMI of at least 35 kg/m² and at least 1 weight-related comorbidity may be below or around the acceptable ICER. So, tirzepatide is recommended as an option for managing overweight and obesity, alongside a reduced-calorie diet and increased physical activity, in adults, only if they have:

• an initial BMI of at least 35 kg/m² and

• at least 1 weight-related comorbidity.
  
  A lower BMI threshold (usually reduced by 2.5 kg/m²) should be used for people from South Asian, Chinese, other Asian, Middle Eastern, Black African or African-Caribbean ethnic backgrounds.