Background
Type 1 diabetes mellitus and its treatment
People with type 1 diabetes mellitus (T1DM), around 250,000 individuals in the UK, have lost the ability to make insulin because of autoimmune destruction of the insulin-secreting β cells within the islets of the pancreas. Insulin is essential in the short term to prevent the onset of ketoacidosis, a potentially fatal condition. In the long term, the aim of insulin therapy is to keep blood glucose close to normal and so prevent the development of microvascular complications, such as retinopathy, neuropathy and diabetic kidney disease. Insulin is generally administered by intermittent subcutaneous injection, with the dose adjusted according to eating and other activities, such as exercise. Traditionally, insulin was given twice a day, often as premixed insulin, but such an approach imposes a rigid lifestyle and makes it difficult to maintain a glucose level close to normal. The need for intensification of therapy and its integration into flexible lifestyles is promoted in DAFNE (Dose Adjustment for Normal Eating) and other structured education courses. It involves giving quick-acting insulin just before eating and administering longer-acting background insulin, preferably twice daily, to maintain blood glucose levels in between meals.1,2 This multiple daily injection (MDI) regimen involves a total of five or six injections a day. Blood glucose levels are monitored from finger-prick samples using a portable meter, and insulin dose calculations are based on self-assessed carbohydrate estimations on a meal-by-meal basis.
Insulin given subcutaneously cannot reproduce the physiological insulin profiles of non-diabetic individuals because of the limitations of insulin formulations and the site of delivery. The relatively slow rate of insulin absorption leads initially to postprandial hyperglycaemia, followed, 1 or 2 hours later, by an increased risk of postabsorptive hypoglycaemia, particularly during the night. Thus, keeping blood glucose close to normal can delay or prevent complications, but brings with it frequent periods of hypoglycaemia. These are categorised as mild, moderate or severe episodes, ranging from mild symptoms, self-managed by ingesting rapid-acting carbohydrate, through to greater disruption in daily routine due to cerebral dysfunction, through to major episodes of coma and seizure requiring third-party assistance. The inability of intermittent injection therapy to control blood glucose tightly without an attendant risk of hypoglycaemia results in many individuals keeping their blood glucose at higher than desirable levels. This leads to an increased risk of serious diabetic complications, which can affect the eyes, feet and kidneys. These complications, plus the associated high risk of cardiovascular disease, reduce both the length and quality of the individuals’ lives.
Insulin analogues
Short- and long-acting insulin analogues have slightly more physiological profiles than insulins of human or animal structure, but cannot reproduce those observed in people without diabetes.2 Systematic reviews of clinical trials of insulin analogues involving people with T1DM have reported only minor advantages compared with human insulin, with a reduced risk of symptomatic hypoglycaemia, particularly at night.3,4 This may be, in part, because those people who are at the greatest risk of hypoglycaemia are frequently excluded from clinical trials. Interestingly, in a recent crossover trial comparing MDI of human insulin with analogue insulin, the investigators specifically recruited individuals who had experienced problems with hypoglycaemia, and found that those using analogue insulin had significantly lower risks of severe hypoglycaemia, particularly at night.5
Insulin pumps
There is clearly an urgent need for better methods of insulin delivery. Insulin pumps were first used clinically in the early 1980s, but randomised controlled trials (RCTs) conducted in the UK failed to show any clinical benefit. At the time, the technology was poorly developed, but has advanced considerably, particularly in the last few years. Insulin pumps are now the size of a small mobile phone and deliver insulin continuously under the skin via a small plastic tube and cannula [continuous subcutaneous insulin infusion (CSII)].6,7 These devices are filled with reservoirs of quick-acting insulin only (usually an insulin analogue), which provides insulin replacement by delivering both the mealtime and background insulin. When infused continuously at low rates they ‘mimic’ basal insulin secretion, and this is generally delivered more consistently and accurately than is achievable by the longer-acting insulins, particularly at night. The insulin boluses used to cover meals and correct high blood glucose levels are delivered much more rapidly. All of the insulin doses can be controlled by the patient, based on calculations similar to those required for insulin dosing with a MDI regimen.
The purchase and use of pumps is more expensive than MDI, with pumps at current prices costing around £2500 each, plus £1500 per year extra for running costs.8 The marginal cost per annum over MDI is about £1800.9 The potential advantages are more stable blood glucose levels, a reduced risk of hypoglycaemia and a more flexible lifestyle. Pump treatment may deliver insulin more effectively than MDI but does not provide a technological ‘cure’. The same competencies needed for successful insulin self-management, previously described for MDI, are required for pumps, but with additional skills required to operate the pump device itself. Thus, pumps are probably more useful to those individuals who are actively and effectively self-managing their diabetes rather than those who expect the pump to ‘manage’ their diabetes for them.
Pumps are currently used by around 40% of people with T1DM in the USA and > 15% in Europe.10 In contrast, the proportion in the UK was around 6% in adults in 2012.11,12 Proponents of pump treatment have proposed that far more patients should be offered treatment in the UK and that current policies are depriving many of the opportunity to improve glycaemic control, reduce hypoglycaemia and improve quality of life (QoL).12 The UK’s National Institute for Health and Care Excellence (NICE) has recently extended recommendations for the use of pumps for adults with T1DM. The guidance suggests that pump treatment be considered for individuals who are experiencing problems with hypoglycaemia, particularly when this limits the ability to improve glycaemic control. NICE has noted the paucity of evidence for efficacy from RCTs.13
Problems with evidence in National Institute for Health and Care Excellence appraisals
There have been two appraisals9,14 of pumps by NICE, both supported by technology assessment reports undertaken by some of the present authors, which reviewed the evidence on clinical effectiveness and cost-effectiveness. The first report14 noted that there were no trials of pumps against ‘best MDI’ with long- and short-acting analogue insulins; some trials had unequal amounts of education in the arms (with more in the pump arms); and the trials had focused on easily measurable outcomes such as glycated haemoglobin (HbA1c), rather than on benefits in terms of flexibility of lifestyle and QoL. The report recommended trials of pumps against analogue-based MDI.
The second report9 found that few such trials had been done: one in children, not relevant to this work, and three in adults. Furthermore, the three adult studies15–17 presented data for a small number of participants who were followed over a short period only. The first of these studies was a 24-week pilot study15 in adults with altered hypoglycaemia awareness and debilitating hypoglycaemia. The three study arms consisted of seven patients each and compared (1) analogue MDI, (2) pump and (3) education and relaxation of glycaemic targets. All of the subjects were naive to analogue insulin use and some had never tried MDI, and so were not representative of the type of patients for whom NICE recommends pumps.
The second trial16 recruited 39 adults with T1DM, who had already been on pump therapy for at least 6 months, and who were randomised to stay on pump or switch to glargine (Lantus, Sanofi-Aventis, Guildford, UK)-based MDI for 4 months. The primary end point was glucose variability, which was 5–12% less with the pump. Despite this, there was no significant difference in the frequency of hypoglycaemic episodes or HbA1c.
The third study17 studied 50 patients with T1DM from Italy, UK (Newcastle, Bournemouth) and France, who were naive to pumps and glargine, to which they were switched for the trial, having been previously managed on neutral protamine Hagedorn (NPH)-based regimens. Follow-up was for 24 weeks. Patients were randomised to pump or analogue MDI in an equivalence study. The difference in HbA1c at the study end was only 0.1% (approximately 1 mmol/mol) and the costs with the pump were three times higher.
Thus, the evidence base from trials for comparing pumps and ‘best MDI’ remains weak in terms of numbers, with a total of only 103 patients and short-term follow-up. Furthermore, the patients in the trials were dissimilar to those considered suitable for a pump by NICE, which expects patients to have tried analogue-based MDI before using the pump.
Given the paucity of RCTs, the assessment group also looked at observational studies of adults in which a pump was clinically indicated, mostly because of the limitations of intermittent injections. This comparison has the advantage of measuring change in glycaemic control and hypoglycaemia in those who have most to gain, and these studies showed improved HbA1c of the order of around 0.5% (5.5 mmol/mol). Interpretation of data from observational studies face limitations from bias, and, furthermore, of the 48 observational studies, only nine reported QoL. Study numbers were small and duration was usually short. The longest study noted that initial benefits from pumps might not be sustained.
Therefore, again, NICE was faced with an evidence base with considerable shortcomings, too few trials, durations too short, numbers too small and a need to use observational studies. A recent meta-analysis by Monami et al.18 concluded that ‘available data justify the use of CSII for basal-bolus insulin therapy in type 1 diabetic patients unsatisfactorily controlled with MDI’. However, most of the RCTs in their analysis were NPH-based and the Bolli et al.17 trial, with its negative result, was missed.
A systematic review of the cost-effectiveness of insulin pump therapy in adults with T1DM was conducted by Roze et al.19 They identified four cost-effectiveness studies in the UK setting, three of which presented an incremental cost-effectiveness ratio (ICER).9,14,20,21 The ICERs in these studies were £11,461 per quality-adjusted life-year (QALY) gained, £25,648 per QALY gained and £37,712 per QALY gained. Two out of the three studies had ICERs that lie within, or below, the £20,000 to £30,000-per-QALY-gained range that NICE usually uses to determine if a health technology is cost-effective.22 These two studies did receive commercial sponsorship, whereas the study with an ICER of £37,712 was commissioned on behalf of NICE.
Rationale for the trial
We hypothesised that much of the benefit of pumps may come from the retraining and education in intensive insulin management, which allows patients to use pumps safely.23 In many DAFNE centres, reimbursement for pump use is conditional on patients having attended a DAFNE education course and so some patients undertake DAFNE training with the intention of moving to pump treatment thereafter. It has been our clinical experience that many individuals decide not to switch to the pump after attending a DAFNE course, as they then realise that what they required was training in insulin self-adjustment rather than a different technical way of delivering insulin. Ray et al.24 found that 69% of those being considered for insulin pump therapy stay on MDI after completing DAFNE. Importantly, trials and observational studies of high-quality training alone (with standard insulin injections) show benefits in blood glucose control, hypoglycaemia and QoL, which are as good, if not better, than those reported after pump therapy.2,25,26
To our knowledge, no trials in adults, comparing pump treatment with modern MDI, used the same structured training in insulin adjustment, resulting in the added benefit of the pump technology remaining unclear.23 There was an urgent need to establish this, and identify patients who benefit the most. A RCT was needed to establish these outcomes without bias.
The DAFNE course is a 1-week structured education course, teaching adults with T1DM the skills in insulin self-adjustment and carbohydrate counting.2 DAFNE courses are currently delivered in more than 70 centres across the UK, with over 37,000 individuals (DAFNE graduates) now trained. We therefore set out to conduct a novel study in which adults waiting for a DAFNE course were randomly allocated to undertake either the standard MDI course or DAFNE incorporating use of pump therapy.
The investigators involved in this work have been undertaking research into other aspects of DAFNE for many years. During recent work funded by a National Institute for Health Research (NIHR) programme grant [Programme Grants for Applied Research (PGfAR)] we measured cost-effectiveness and identified which components of the course are crucial, as well as identifying the factors determining which DAFNE patients managed their diabetes more effectively.27 This work included funding to pilot a combined DAFNE and pump course, which enabled us to develop a pump curriculum and associated pump-specific resources, ensure that the outcome measures that we wanted to use were feasible and estimate the likely recruitment and retention rates.
We then assembled a study group with expertise in structured T1DM education, pump therapy (having trained in total over 700 pump patients) and health economic assessment of diabetes interventions.
Decision problem: aim of the REPOSE Trial
The aim of our trial was to establish for patients, professionals and those funding the service, the added benefit of using a pump during intensive insulin therapy. We conducted a RCT comparing optimised MDI therapy (using rapid and twice-daily, long-acting insulin analogues) with pump therapy in adults with T1DM, for which both were provided with high-quality structured education (DAFNE).
