Type 2 diabetes remission: 2 year within-trial and lifetime-horizon cost-effectiveness of the Diabetes Remission Clinical Trial (DiRECT)/Counterweight-Plus weight management programme

Ethics approval was granted in January 2014 by the West of Scotland Research Ethics Committee 3, with approvals by the NHS health board areas in Scotland and by clinical commissioning groups in Tyneside, UK.

DiRECT intervention costs over the 2 year trial period included costs for initial training of practitioners (dietitians or nurse practitioners, who each received a total of 16 h face-to-face training from Counterweight-Plus instructors), sachets of low-energy formula diet, practitioner monitoring appointments and the tailored Counterweight-Plus workbooks issued to each participant (Table 1). Costs of the sessions included practitioners’ attendance time and standard Counterweight-Plus materials. The number of sachets issued to each participant and the number and duration of practitioner appointments were collected prospectively throughout the study. Full costs for participant Counterweight-Plus workbooks were applied irrespective of participants’ persistence with the programme, the details of which are described elsewhere [8, 10, 12].

Details of all primary and secondary care visits for each of the participants were obtained directly from the participating general practitioner (GP) practice records. The costs of these were calculated using the recorded duration of contact for each appointment. Medication use was costed based on dose, frequency and start and end dates of individual participants’ medication records in each participating GP practice. Hospitalisation costs were estimated by matching reason for admission and recorded length of stay in DiRECT to the appropriate NHS reference cost (excluding excess bed-days, where length of stay recorded in DiRECT exceeded the national average). Unit costs were obtained from published national sources (Personal Social Service Research Unit [13], NHS reference costs [14], or Information Services Division Scotland [15], and British National Formulary [16]) and have been reported previously [17].

Statistical analysis was conducted based on the intention-to-treat principle. Missing data were minimal, as all resource use data were obtained directly from participating GP practices. Five intervention (3%) and three control (2%) participants relocated with loss to follow-up during the study. Their medication use was assumed to continue as at their last available records, and other healthcare resource use was assumed to be zero after relocation. Twenty intervention (13.4%) and six control (4%) participants had no data available for the 2 year remission outcome. In line with the primary outcome analysis, these participants were assumed not to have achieved remission.

Mean costs were calculated for each group, with clustering-adjusted SEs for each cost item. Incremental cost per remission at 2 years was reported as the difference in the groups’ total 2 year costs, divided by the difference in diabetes remission rates. All analyses were undertaken in Stata/MP, version 14.2 (StataCorp LP, USA), with 95% CIs based on 1000 non-parametric bootstrap iterations.

Long-term outcomes were projected for each treatment arm in DiRECT. A three-state model (remission, diabetes, death) was constructed. Individuals enter the model with existing diabetes. After 1 year a proportion achieve remission but are subject to relapse in future years. The proportion remaining in remission over time was estimated based on the rate of relapse observed in year 2; however, all participants were assumed to relapse after a given number of years (a maximum period of 10 years of remission in the base case). Life expectancy was calculated for each potential year of remission by applying rates of mortality for people free of diabetes up to the year of relapse and with diabetes thereafter. Along with life expectancy, quality-adjusted life expectancy and healthcare costs were estimated conditional on each potential year of relapse.

Life expectancy was calculated based on rates of mortality in people free of diabetes (N = 2.75 million) and with diabetes (N = 272,597), based on a recent UK study [18] which reported mortality rates by sex and 5 year age bands during the period 2012–2014 in Scotland. Reported life expectancy for men aged 55–59 years was 23.0 and 26.0 years with diabetes and free of diabetes, respectively, and 24.4 and 28.7 for women.

QALYs were calculated by applying standard UK age-dependent health state utility population norms [19]. These were assigned directly to people in remission from diabetes. For people not in remission, including those who had relapsed, these age-dependent health state utilities were reduced using a constant multiplier of 0.925 to reflect a decrement due to diabetes. This was estimated based on the mean population score (0.828) and the regression coefficient for diabetes (−0.0621) in the US Medical Expenditure Panel Survey catalogue of UK EuroQol EQ-5D scores [20]. This estimate was employed rather than being based on data from DiRECT, for reasons discussed below.

The lifetime healthcare costs associated with diabetes were compiled first from the measured costs for the first 2 years of DiRECT, to which were added further costs for ongoing weight management for participants remaining in remission and long-term healthcare costs associated with diabetes. Long-term diabetes-related healthcare costs were assumed to increase linearly with duration of diabetes (i.e. time since relapse), over 15 years, from £1250 in the year of diagnosis to £3117 after 15 years, based on a UK cost of diabetes study [2, 21]. No further increase in long-term healthcare costs beyond 15 years was applied. Long-term healthcare costs due to diabetes were applied to the proportion of people projected to be in the diabetes state each year after year 2.

We compared the incremental cost and QALYs for the intervention and control arms over the 2 year follow-up of DiRECT and over a lifetime horizon. Sensitivity analysis was undertaken for the long-term analysis, including exploring the impact of alternative relapse rates and maximum assumed durations of diabetes remission. Probabilistic sensitivity analysis was performed using 1000 bootstrap iterations of the DiRECT data (remission and 2 year costs), and Monte Carlo simulations for other variables (e.g. long-term mortality rates). Model input data are summarised in Table 2; all costs and outcomes beyond year 1 were discounted at the standard UK annual rate of 3.5%.

During the first year of the DiRECT intervention, a mean of approximately 500 sachets of low-energy formula diet were issued to each participant, over 80% of the total 2 years’ consumption being consumed during the initial total diet replacement phase (Fig. 1). Each participant received a mean of 23 practitioner visits, the majority of these also during year 1. The cost of formula diet and practice visits together was £1364 (95% CI £1260, £1464) per participant entered over 2 years, and total intervention costs, including amortised clinic set-up costs, amounted to £1411 (95% CI £1308, £1511).

The focus and resource need of the Counterweight-Plus programme shifts from weight loss using total diet replacement in the initial 12–20 weeks to long-term weight maintenance, with data currently available for 2 years (Table 1, Fig. 1). Use of formula diet sachets in year 2 was limited to regular maintenance, for those who elected to use them, and for relapse management purposes (when participants regained over 2 kg body weight). Their total use amounted to less than 20% of the year 1 consumption, when they were used for total diet replacement, and decreased over the food reintroduction phase. Similarly, planned practitioner appointments in year 2, for maintenance and relapse management, were approximately 50% fewer than in year 1.

Participants in the intervention group had substantially fewer days on oral glucose-lowering and antihypertensive drugs. Over the 2 years, participants in the intervention group had a mean of 290 days on oral glucose-lowering medications, compared with 910 for those in the control group (difference 620 days; 95% CI 501, 738), and a mean of 381 days on antihypertensive medications, compared with 782 for those in the control group (difference 410 days; 95% CI 258, 537) (Table 3). The intervention group had fewer GP visits related to diabetes (difference 0.6 visits; 95% CI 0.2, 1.0). Other items of resource use were mostly lower in the intervention arm, including fewer hospital days. Lower use of glucose-lowering and antihypertensive medications, combined with fewer healthcare contacts, provided total savings in the intervention arm over 2 years of £796 (95% CI £150, £1465). This cost saving in routine (non-trial) resource use offset 56% of the 2 year intervention costs, leaving a 2 year incremental cost for the intervention of £616 (95% CI –£45, £1269) per participant entered. Given remission rates of 35.6% and 3.4% in the intervention and control arms, respectively, at 2 years, the resulting incremental cost per remission at 2 years was £1907 (lower 95% CI: intervention dominates, i.e. is cost-saving and more effective; upper 95% CI: £4212). Medication cost savings were principally due to lower use of glucose-lowering medicines (approximately 90% of total medication savings) and were divided equally between years 1 and 2. The difference in the total other non-intervention resource use (i.e. healthcare contacts and hospitalisations) in year 1 was negligible [17] and over the 2 years did not reach statistical significance; however, these cost savings were significant in year 2 (£521; 95% CI £12, £1085).

Across both arms of the trial, 79 participants achieved remission during the 2 year period, including five who did so during year 2. Of 74 participants in remission at year 1, 21 had relapsed by the end of year 2. At this observed annual relapse rate in DiRECT (28%), mean time to relapse would be approximately 3.5 years, with 13% of participants expected to remain in remission beyond 5 years. The resulting mean gain in life expectancy for a person in remission at 1 year is 0.30, and, for all participants entered in DiRECT, 0.13. Discounted QALYs were modelled to be increased by 0.06. Total costs relating to diabetes (other than ongoing intervention costs) were modelled, based on current treatment costs, ranging from approximately £15,000 for people remaining in remission until year 10 to £30,000 for those not in remission after 1 year. After accounting in the model for intervention costs and time to relapse, the intervention generated a £1337 cost saving (95% CI £674, £2081) per participant entered into the programme (Table 4). The intervention therefore dominated standard care and had the probability of being both cost-saving and cost-effective at a threshold of £20,000 per QALY of 1.00.

Follow-up of participants in DiRECT is continuing. As this analysis relies on 2 year data we estimated time to total cost equivalence (or break-even) and explored sensitivity to shorter times to relapse. The model predicted the intervention would become cost-saving overall after a period of 5–6 years under base case assumptions for relapse (Fig. 2). Assuming all people who achieved remission relapsed after a maximum of 3 years, the intervention remained cost-saving due to deferred diabetes (Table 5). Increasing the rate of relapse without modifying the maximum period of remission had a lesser impact on cost savings. The intervention also remained cost-saving when a reduced rate of remission after 1 year was assumed, and with a shorter time horizon for analysis. In these cases, although QALY gains were also reduced, the intervention remained dominant.

Relapses were more frequent among women than among men in year 2. When the analysis was performed using sex-specific relapse rates, the overall QALY gain and cost were little different, although health gains and cost savings were more concentrated in men.

Assuming no detrimental impact of diabetes on QoL resulted in an increased QALY gain, the result of life expectancy being valued more highly. The model assumed that type 2 diabetes, with a diagnosis at about 55 years of age, and without intervention, would reduce life expectancy by 3.2 years in men and by 5.2 years in women. Reducing mortality rates for people with diabetes by 10% reduces the QALY gains from intervention to approximately 0.05. The intervention remained cost-saving both when excluding other healthcare cost savings in the early period and when substantially lower long-term costs due to diabetes were assumed.