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By way of background, for much cost-effectiveness modelling in type 2 diabetes the results of the UKPDS have been used. Until recently the main UKPDS publication relevant to cost-effectiveness modelling was the UKPDS68.193_{This outlines a number of equations for estimating the progression of the risk factors of}

HbA1c, SBP, TC/HDL and smoking status through time. Given the evolution of these risk factors, the

UKPDS68193_{also specifies a number of equations that calculate the annual risk of experiencing first}

‘events’, these events being the macrovascular complications of diabetes, such as stroke, and the microvascular complications of diabetes, such as blindness. The UKPDS68193_{also permits the calculation}

of annual probabilities of death. The UKPDS68193_{was used by Oxford University to develop an electronic}

cost-effectiveness model, the UKPDS Outcomes Model v1 (OM1). There are 10 equations:

l equation 1: ischaemic heart disease (IHD)

l equation 2: MI

l equation 3: CHF

l equation 4: stroke

l equation 5: amputation

l equation 6: blindness

l equation 7: renal failure l equation 8: event mortality

l equation 9: diabetes-related mortality l equation 10: other mortality.

The UKPDS68193_{has recently been partially updated by the UKPDS82,}194_{the latter incorporating longer}

follow-up data of the UKPDS. This provides an alternative set of equations to estimate the probability of events and deaths, and also permits the estimation of the probability of some second events: MI, stroke and amputation. Oxford University has developed an updated electronic model, the UKPDS Outcomes Model v2 (OM2). As far as the AG is aware, this currently relies upon the UKPDS68193_{for the evolution of}

the risk factors and the UKPDS82 for the probabilities of events and deaths. The AG has not had access to the OM2 during the course of the assessment.

The UKPDS82194_{provides the following table (Table 15) to outline the differences in the predicted number}

Ischaemic heart disease includes angina and consequences of procedures to relieve it, such as angioplasty and coronary artery bypass grafting.

The OM1 predicts roughly double the number of MIs over 10 years, and the rates of IHD are also noticeably higher. Possibly mainly as a consequence of the higher rate of MI predicted by the OM1, the 10-year death rate predicted by the OM1 is also noticeably higher. The OM1 will tend to over-predict event rates compared with the OM2. The OM1 is now likely to overstate the benefits and cost savings arising from any avoidance of the complications of diabetes that are associated with the more

effective treatment.

It is anticipated that the longer follow-up data of the UKPDS associated with the UKPDS82194_{will result in}

additional publications, one of which will update the evolution of the risk factors. The costs associated with events have already been updated, the UKPDS84195_{being an update of the UKPDS65.}196_{The QoL}

estimates have also been updated in Alvaet al.197_{But the format of the analysis of Alvaet al.}197_{is less}

closely aligned with the events of the UKPDS84195_{when compared with the alignment of the QoL}

estimates of the UKPDS62198_{with the events of the UKPDS68.}193 Company submissions

There are three company submissions: l Boehringer Ingelheim for empagliflozin l AstraZeneca for dapagliflozin

l Janssen for canagliflozin.

An overarching summary of the companies’and the AG’s modelling assumptions, inputs and results is presented at the end of the economics section, permitting an easy read across. Readers may wish to work through this overarching summary first, before turning to the more detailed summaries presented below for more clarity around specific points of the individual modelling exercises.

TABLE 15 Table 2 of UKPDS82:194

10-year event rates (%): OM1 vs. OM2

Event

50_–54 years 60_–64 years 70_–74 years All ages

OM1 OM2 OM1 OM2 OM1 OM2 OM1 OM2

First MI 14.9 7.5 22.5 10.3 29.6 13.3 21 9.9

Second MI n/a 0.9 n/a 1.0 n/a 1.1 n/a 1.0

Ulcer n/a 1.5 n/a 1.9 n/a 2.2 n/a 1.8

Blindness 2.2 2.2 3.5 3.1 4.9 4.0 3.3 2.9

IHD 8.6 6.9 10.3 8.3 10.5 9.0 9.5 7.8

First stroke 3.3 3.3 7.9 6.4 14.2 10.7 7.6 6.2

Second stroke n/a 0.3 n/a 0.7 n/a 1.5 n/a 0.7

Renal failure 0.9 0.3 1.4 0.6 1.6 0.8 1.3 0.5

First amputation 1.7 1.3 2.0 1.6 1.7 1.8 1.8 1.5

Second amputation n/a 0.4 n/a 0.6 n/a 0.4 n/a 0.4

Heart failure 3.0 2.5 5.9 4.3 9.9 6.4 5.7 4.0

Death 14.5 11.1 32.1 22.3 58.8 43.3 31.6 22.5

All of the submissions contain modelling exercises with long-term time horizons of around 40 years, which for the majority of patients will be a lifetime horizon. They all undertake a cost–utility analysis using the appropriate perspectives of the NHS and Personal Social Services (PSS) for costs and the patient for benefits, and discount costs and benefits at 3.5%.

Boehringer Ingelheim designed a front end to the UKPDS OM1 model. The Boehringer Ingelheim submission has a great deal in common with the modelling of recent NICE CGs for type 2 diabetes, and the AG modelling for the current assessment, both of which design a front end to the UKPDS OM1. AstraZeneca uses the Cardiff Diabetes Model (CDM), which uses many of the UKPDS68193_{equations and}

so has much in common with the UKPDS OM1 model, but updates the calculation of the probabilities of having an event to use the UKPDS82,194_{which is the basis of the OM2.}

Janssen differs from AstraZeneca and Boehringer Ingelheim in using the ECHO-T2DM model. Its base case has assumptions that differ quite noticeably from those of the other two submissions. There is also relatively little detail in the Janssen submission, with most of the detail being contained in the appendices to the submission and the submitted electronic copy of the model.

In light of the above, the review of the company submissions below provides a reasonably in depth review of the Janssen modelling. This is followed by shorter reviews of the Boehringer Ingelheim and the

AstraZeneca modellings, which are more in line with the AG modelling.