REVIEWS. Management of diabetes mellitus: is the pump mightier than the pen? John C. Pickup

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1 Management of diabetes mellitus: is the pump mightier than the pen? John C. Pickup Abstract Continuous subcutaneous insulin infusion (CSII, or insulin pump therapy) reduces levels and hypoglycaemia in patients with type 1 diabetes mellitus (T1DM) compared with multiple daily insulin injections (MDI). The greatest reduction in levels with CSII occurs in patients with the worst glycaemic control; therefore, the most appropriate and cost-effective use of CSII in adults with T1DM is in those who have continued, elevated levels or disabling hypoglycaemic episodes with MDI (including the use of longacting insulin analogues and structured patient education). The disadvantages of CSII include higher costs than MDI and the risk of ketosis in the event of pump failure. In children with T1DM, CSII may be used when MDI is considered impractical or inappropriate. Pumps are not generally recommended for patients with type 2 diabetes mellitus but may improve control in some subgroups. A new generation of smaller insulin infusion pumps with an integrated cannula, called patch pumps, could improve uptake of CSII in general. The important clinical question is not whether CSII is more efficacious than MDI in general adult T1DM, but whether CSII further improves glycaemic control when this control continues to be poor with MDI, and evidence exists that in most cases it does. Pickup, J. C. Nat. Rev. Endocrinol. 8, (2012); published online 28 February 2012; doi: /nrendo Introduction Over the past 30 years, two main intensified insulin regimens have been used to achieve strict glycaemic control in patients with type 1 diabetes mellitus (T1DM). Both were introduced in the late 1970s 1,2 and aim to achieve the best control by mimicking nondiabetic insulin secretion patterns: a slow, basal delivery throughout the 24 h and boosts (boluses) at meal times. Continuous subcutaneous insulin infusion (CSII), also known as insulin pump therapy, uses a small, portable electromechanical pump to infuse short-acting insulin via a subcutaneously implanted cannula to provide basal delivery, with patient-activated prandial boluses. 3 Multiple daily insulin injections (MDI), also known as basal bolus therapy, is a regimen that employs longacting insulin formulations (originally isophane or lente types but nowadays usually the insulin analogues glargine or detemir) to supply the basal component, with short-acting insulin injected at or before meals. 4 Insulin pens were introduced in 1981 as convenient injection devices in which the insulin is contained in a cartridge inside a pen-like implement, which incorporates a fine replaceable needle. 5 The convenience, ease of use and less painful injection associated with insulin pens has increased patient acceptance of multiple injections, and pens are now commonly used as a part of MDI regimens in many countries. Competing interests The author declares associations with the following companies: Animas, Cellnovo, Medtronic, Roche. See the article online for full details of the relationships. Neither insulin pumps nor MDI (whether insulin is delivered via a pen or a syringe and needle) should be considered in isolation. Both are part of a package of measures for intensive insulin therapy that also includes frequent self-monitoring of blood glucose (SMBG), regular exercise, structured diabetes education with advice on insulin dosage adjustment for the size and composition of the meal ( carbohydrate counting ), dietary advice and frequent contact with health-care professionals. Understandably, the question of whether insulin pump therapy is better than MDI requires debate, because CSII is more expensive and complex than MDI. Organizational problems could arise in setting up an insulin pump service with the necessary specialist team of at least one physician with an interest in pumps and a diabetes specialist nurse and dietitian trained in CSII procedures. 6 Moreover, considerable advances in MDI have occurred over the past few decades, with the introduction of long-acting insulin analogues with more predictable subcutaneous absorption and flatter blood insulin profiles than traditional long-acting insulin formulations 7 and a renewed interest in structured diabetes education. 8 Together, these advances have resulted in excellent levels of glycaemic control in many individuals with T1DM. In the UK, the National Institute for Health and Clinical Excellence (NICE) has recommended CSII as a costeffective treatment option in adults with T1DM when attempts to achieve target levels with MDI have resulted in disabling hypoglycaemia or when levels have remained high ( 8.5%) despite best efforts (Box 1). 6 In children with T1DM, MDI is often considered Diabetes Research Group, King s College London School of Medicine, Guy s Hospital, London SE1 1UL, UK. john.pickup@kcl.ac.uk NATURE REVIEWS ENDOCRINOLOGY VOLUME 8 JULY

2 Key points Continuous subcutaneous insulin infusion (CSII) can reduce levels and hypoglycaemia in many patients with type 1 diabetes mellitus (T1DM), compared with multiple daily insulin injections (MDI) However, an MDI regimen that includes frequent self-monitoring of blood glucose levels and structured diabetes education can achieve good glycaemic control in many individuals with T1DM A trial of CSII is indicated in patients who do not achieve acceptable glycaemic control with MDI because of continued, elevated levels or disabling hypoglycaemic episodes The greatest reduction in levels with CSII occurs in patients with T1DM who have the worst glycaemic control with MDI Blood glucose variability, quality of life and treatment satisfaction are also usually improved with CSII versus MDI Sensor-augmented insulin pump therapy further improves glycaemic control, with the best effect in patients with the highest levels and in those who use the sensor most often Box 1 Summary of NICE guidance on the indications for CSII Adults and children 12 years with T1DM CSII is recommended as a treatment option when attempts to achieve target levels with MDI have resulted in disabling hypoglycaemia or when levels have remained high ( 8.5%) despite a high level of care Children <12 years with T1DM CSII is recommended as a treatment option when MDI is considered impractical or inappropriate, and with the expectation that children would normally undergo a trial of MDI between the ages of 12 and 18 years Other important points CSII should be discontinued (in adults and children 12 years who have been started on CSII because of elevated or disabling hypoglycaemia) if no sustained improvement in or rate of hypoglycaemic episodes occurs CSII should be initiated by a specialist team consisting of at least a diabetes physician with a special interest in pump therapy, and a diabetes specialist nurse and dietitian trained in CSII CSII should be considered in pregnancy or preconceptually in women with T1DM when the target (normally 6.1%) in the first trimester or preconceptually cannot be achieved without disabling hypoglycaemia CSII is not generally recommended in type 2 diabetes mellitus, although some subgroups may benefit Abbreviations: CSII, continuous subcutaneous insulin infusion; MDI, multiple daily insulin injections; NICE, National Institute for Health and Clinical Excellence; T1DM, type 1 diabetes mellitus. impractical or inappropriate to deliver at school because children might be unwilling or unable to inject or need a parent to come to school to give a lunchtime injection, or they might be restricted from school trips and various activities because of the need to inject. 6,9 Under these circumstances, CSII has been recommended by NICE for children, without them first having to have failed to achieve adequate glycaemic control with MDI. Other countries have adopted similar guidelines for CSII use. 8,10 A treatment pathway for the management of T1DM by intensive insulin therapy can, therefore, be proposed (Figure 1). In adults, MDI is usually the first-line intensive insulin regimen, and many (probably most) patients can achieve target levels with this strategy. For the ~20% of patients who have continued disabling hypoglycaemia and/or elevated levels with MDI, a trial of CSII is indicated. In most cases, CSII achieves a clinically significant improvement in glycaemic control in this group; however, in the minority who still have poor glycaemic control, other measures, such as combining pump therapy with continuous glucose monitoring (CGM), might be indicated (see below). The important clinical issue is, therefore, not whether insulin pumps are more efficacious than MDI in the general adult population with T1DM, but whether pumps improve glycaemic control when it continues to be poor with MDI. Unfortunately, many of the trials that have compared CSII and MDI have been carried out in unselected patients with T1DM, making judgments about the merit and appropriate use of either therapy sometimes difficult. Known benefits of CSII versus MDI Hypoglycaemia reduction A meta-analysis has shown that in patients with a clinically significant problem with severe hypoglycaemia (namely, episodes requiring third-party assistance), the frequency of such hypoglycaemia is reduced by a mean of ~75% during treatment with CSII compared with MDI (rate ratio 4.19, 95% CI ). 11 In this meta-analysis, care was taken only to select trials of adequate duration that involved the use of modern pumps and monomeric insulins in the pump. In this analysis, there were relatively few randomized controlled trials (RCTs) that compared the rate of severe hypoglycaemia with MDI and CSII, compared with the larger number of observational studies. Patients who experience the highest frequency of severe hypoglycaemic episodes with MDI at baseline show the greatest reduction with CSII, and the rate ratio (hypoglycaemia on MDI:CSII) can reach in those with very frequent severe hypoglycaemia on MDI (Figure 2). 11 The meta-analysis also shows that both adults and children have reduced hypoglycaemia with CSII; however, the reduction is somewhat smaller in children than adults (for example, a mean rate ratio of about 3 in a 10-year old child) because children generally have a shorter duration of T1DM than adults and, therefore, less frequent hypoglycaemia the frequency of hypoglycaemia increases as duration of T1DM increases. 15 Some reported meta-analyses have indicated no significant reduction in severe hypoglycaemia with CSII versus MDI, 16,17 but these studies have included short-term trials in which rates of severe hypoglycaemic episodes cannot be accurately assessed (<6 months) and trials with very low rates of hypoglycaemia at baseline and the studies are, therefore, misleading. Mild-to-moderate hypo glycaemia, recorded as SMBG-measured tests <3.5 mmol/l, is also reduced by about 75% with CSII versus MDI. 18 Reduced levels In several meta-analyses comparing glycaemic control during CSII and MDI, the mean difference between the two therapies has been reported to be about %, favouring CSII. 11,19,20 A Cochrane review 21 has reported a somewhat lower mean difference of 0.3%; however, this review included studies of very short duration and early trials from the 1980s when pumps were less reliable and less technically sophisticated (for example, in the flexibility of the infusion rate adjustments that were possible). 426 JULY 2012 VOLUME 8

3 Both meta-regression of mean levels from conducted trials 11 and data from individual patients show that the greatest reduction in levels with CSII occurs in those with the highest level on MDI at baseline (Figure 3). Thus, although the mean difference between the two therapies is a rather modest % for the whole population with T1DM and unlikely to be cost-effective, in the substantial number of patients with an elevated level on MDI, a marked reduction can occur for example, ~ % when the baseline value is 10%. Because of the curvilinear relationship between level and microvascular risk, 25 reductions in level from this high starting point produce a more marked reduction in the risk of diabetic complications and better cost-effectiveness than that achievable for unselected patients with a lower mean level. NICE in the UK judged that, when quality of life improvements are taken into account along with reductions in level, CSII is cost-effective when levels on MDI are 8.5% and, therefore, used this cut-off value in their guidance (Box 1). Blood glucose variability Glycaemic variability, particularly when unpredictable, is a major frustration for patients with T1DM that prevents logical alteration of insulin regimens in order to improve glycaemic control. High glycaemic variability correlates with an increased frequency of hypoglycaemia, 26 and individuals with the most variability maintain the highest level on MDI, 22 probably to avoid increasing the frequency of hypoglycaemia as attempts are made to tighten control. CSII reduces both the within-day and day-to-day variability, as determined by a reduction in the mean amplitude of glycaemic excursions 27 and the standard deviation or interquartile range of either daily or successive fasting blood glucose levels. 22 This improvement is probably because the large variation in subcutaneous absorption associated with large injected volumes of long-acting insulin (±50% for isophane) is reduced to about ±3% with CSII (probably because there is a subcuta neous insulin depot of only about 1 unit at any time during basal rate infusion). 28 CSII versus MDI with long-acting analogues Most of the RCTs comparing glycaemic control with CSII or MDI involve traditional isophane-based long-acting insulin as the basal component of the MDI regimen, rather than one of the more recently introduced longacting insulin analogues, glargine or detemir. These two insulin analogues are now commonly used in MDI regimens. Many physicians consider it best practice either to use glargine or detemir insulins as a first-line choice for the basal insulin of MDI, or to switch patients to glargine or detemir if they are not achieving target levels of gly caemic control with isophane-based MDI. Although many patients achieve excellent control with these insulin analogues, others do not, and as recommended by NICE in the UK, these patients should be offered a trial of CSII. 6 A group of 16 patients with T1DM who had poor glyca emic control with isophane-based MDI and who MDI: Basal/bolus insulin injections Structured education: including insulin dosage adjustment at meals, dietary advice Frequent SMBG Frequent contact with health-care professionals Satisfactory glycaemic control ~80% Much improved glycaemic control ~70 80% remained poorly controlled on glargine MDI benefited from a fall in level from 8.7 ± 1.2% (mean ± SD) on MDI to 7.2 ± 1.0% when they were transferred to CSII. 29 Comparatively few RCTs have compared MDI using long-acting analogues versus CSII. Doyle et al. 30 randomly allocated adolescent patients with T1DM to receive either CSII with aspart insulin or to MDI with glargine and aspart, with a follow-up of 16 weeks. Whilst Continued disabling hypoglycaemia and/or elevated level ~20% Trial of CSII considered Continued poor control ~20 30% CGM and other measures Figure 1 A proposed treatment pathway for adults with type 1 diabetes mellitus. MDI is the mainstay regimen for achieving strict glycaemic control; patients who have a continuously elevated level or frequent and disabling hypoglycaemia with MDI (approximately 20%), should then be offered a trial of CSII. Most patients have improved glycaemic control on insulin pump therapy but those who do not (for example, because they have continued disabling hypoglycaemia) might benefit from further measures such as sensor-augmented pump therapy (CSII with CGM). Abbreviations: CGM, continuous glucose monitoring; CSII, continuous subcutaneous insulin infusion; MDI, multiple daily insulin injections; SMBG, self-monitoring of blood glucose. Mean hypoglycaemia rate ratio ,000 Mean hypoglycaemia rate on MDI (episodes per 100 patient-years) Figure 2 Meta-regression of severe hypoglycaemia rate ratio (MDI:CSII) with hypoglycaemia rate with MDI as a covariate. Data were obtained from trials reported in a metaanalysis. 11 The greatest effect of CSII at reducing severe hypoglycaemia is in patients with type 1 diabetes mellitus with the highest frequency of hypoglycaemia at baseline. Abbreviations: CSII, continuous subcutaneous insulin infusion; MDI, multiple daily insulin injections. Permission to adapt obtained from John Wiley and Sons Pickup, J. C. & Sutton, A. J. Diabet. Med. 25, (2008). 11 NATURE REVIEWS ENDOCRINOLOGY VOLUME 8 JULY

4 Mean difference (%) Mean MDI (%) Figure 3 Meta-regression of the mean difference in level (CSII versus MDI) with on MDI as a covariate. Data were obtained from trials reported in a metaanalysis. 11 The greatest reduction in level achieved by CSII is in patients with type 1 diabetes mellitus with the highest level at baseline. Abbreviations: CSII, continuous subcutaneous insulin infusion; MDI, multiple daily insulin injections. Permission to adapt obtained from John Wiley and Sons Pickup, J. C. & Sutton, A. J. Diabet. Med. 25, (2008). 11 the level in adolescents treated by MDI did not change over the study period (8.2% at baseline, 8.1% at completion), the level in those on CSII fell from 8.1% to 7.2% at completion (P <0.05 versus MDI). In a shortterm study, Hirsch et al. 31 randomly allocated 100 patients with T1DM to either CSII or MDI based on glargine for 5 weeks. The researchers reported significantly lower serum levels of fructosamine (indicating lower average blood glucose levels) and area under the curve of glycaemia measured by CGM for CSII than MDI. By contrast, Bolli et al. 32 reported a similar decline in level when isophane-treated individuals with T1DM were randomly allocated to either CSII or MDI with glargine ( 0.7% for CSII and 0.6% for MDI). However, the baseline level of the participants of this study was not excessively elevated (7.7% for CSII and 7.8% for MDI); therefore, no significant treatment difference in terms of reduction in level would be expected (Figure 3). The advantage of insulin pump therapy over MDI has probably diminished somewhat since the advent of long-acting insulin analogues, 33 in the sense that fewer patients fail on MDI because of mild to moderate nocturnal hypoglycaemia or glycaemic variability, which are often improved with glargine or detemir. However, little or no evidence exists that levels or the frequency of severe hypoglycaemia are lower if MDI is based on long-acting analogues rather than isophane. 34,35 Thus, the number of patients who have continued episodes of severe hypoglycaemia and/or elevated with MDI and are, therefore, suitable for a trial of CSII is probably largely unchanged after the introduction of glargine-based or detemir-based regimens. Quality of life and psychosocial factors The discontinuation rate for CSII (those who revert to MDI by choice or because their health-care professionals judge them to be receiving little or no value from pump therapy) is low at most centres, at about 5%. This rate of satisfaction is surprisingly high considering the com plexity and demands of pump treatment. Formal compari sons of quality of life using validated measures have given mixed results in some studies; for example, Tsui et al. 36 showed no benefit of CSII versus MDI although in this study, the baseline level was again relatively low at 7.7% for CSII and 8.2% for MDI, and no difference in glycaemic control between treatments was found. By contrast, many studies, both RCTs and observational studies, have reported a significant improvement of quality of life with CSII compared with MDI Patients on pump therapy in ordinary clinical practice often report improvements in thinking, mood and wellbeing when they are transferred from MDI, and these and other psychosocial factors are being increasingly reported more formally in research studies of CSII. Knight et al. 42 showed that the improvement in level upon switching to CSII in children with T1DM was accompanied by improvements in a number of measures of cognition, such as perceptive reasoning, selective attention and working memory. Parents reported fewer mood-related symptoms and fewer behavioural problems in the children. Interestingly, quality of life improvements extend to the parents as well as the children who are treated by CSII, with lower parental stress, hypoglycaemia worry and overall diabetes burden. 41 Good and not-so-good control on CSII Large international surveys of CSII indicate that most patients have good glycaemic control with CSII; for example, in nearly 15,000 pump patients in North America and Europe the mean level was 7.0%. 43 How ever, notable proportions of patients on CSII continue to have suboptimal glycaemic control, although con trol is usually much better than with MDI. In an audit of 104 people with T1DM on CSII, 27% had an level of 8.5%. 44 The reasons why glycaemic control cannot be further improved in some individuals needs further study, and a number of possible reasons are being explored. Fear of hypoglycaemia is common in T1DM, including patients on CSII, 44 and, logically, some patients might resist tightening glycaemic control because they are concerned about hypoglycaemia; however, one study has shown no correlation between the achieved on CSII and fear of hypoglycaemia. 44 Other psychological factors probably play a more impor tant role in patients with suboptimal glycaemic con trol with CSII than fear of hypoglycaemia. Aberle et al. 45 found that a high level on CSII correlated with a high external locus of control, in which individuals believe that disease and life events are dependent on external factors and beyond their control and that no action needs to be taken. Generally, the best predictor of how well patients will do on CSII is their level with MDI: those who are poorly controlled on MDI tend to be amongst the most poorly controlled on CSII, 44 although they have the highest change in from baseline, as mentioned above. Thus, a patient with an level of 10.5% with MDI might expect to benefit from about a 1.7% reduction in after switching to 428 JULY 2012 VOLUME 8

5 CSII (Figure 3), but the outcome level of 8.8% will still be suboptimal. Studies of patients with T1DM who have been treated by CSII for several years show that the mean level for the group is best after about 6 12 months and then deteriorates slightly, although good glycaemic control is maintained. 46,47 However, within the group, clinical experi ence shows that some individuals initially do well with CSII, whereas their glycaemic control deteriorates quite markedly after a year or so. Nevertheless, the proportion of deteriorators and extent or worsening have not been well-documented. One could speculate that factors such as reduced enthusiasm or contact between patient and/or health-care professionals or the development of intercurrent illness or other issues could be important in worsening of glycaemic control over time, but no formal studies have been reported. Pump features not enjoyed by MDI Bolus profiles The meal-time insulin bolus with CSII is probably best delivered for most meals as quickly as possible. 48 However, most pumps have the facility for selecting alternative bolus profiles either an extended or square wave delivered typically over some hours, or a dual-wave or combination-wave in which a proportion of insulin is given immediately and the rest as an extended wave. Experimental studies show that the square wave option better controls blood glucose levels after a fatty meal, when gastric empty ing is slowed and insulin resistance can occur for some hours. 49 Extended-wave boluses might also be useful in some cases of gastroparesis, in which gastric emptying is also delayed. Heinemann 50 has, however, pointed out that rigorous examination of many of the studies comparing postprandial glycaemic control after standard versus extended or dual-wave boluses have problems of experimental design, such as different premeal glucose or insulin levels on the test days, and are, therefore, difficult to interpret. Overall, the evidence base for the value of extended meal insulin profiles is suggestive but relatively weak at the moment. Bolus calculators On-board bolus calculators or wizards were introduced into insulin pumps in 2002 and serve to recommend to the patient an appropriate meal insulin bolus based on premeal blood glucose concentration, intended carbo hydrate to be eaten, target blood glucose levels, insulin:carbohydrate ratio, insulin sensitivity and insulin onboard (that remaining after the previous meal). Trial evi dence, although limited, suggests that the mean postprandial blood glucose concentration is reduced in patients using bolus calculators versus manual estimation of meal insulin. For example, Sashaj et al. 51 found that the mean peak postprandial glucose level in indivi duals randomly allocated to an insulin pump with use of bolus calculator was 9.2 mmol/l compared with 10.5 mmol/l during CSII without the calculator. Similar bolus calculators are now being introduced for MDI users; however, they are yet not in common use. Computer downloads The data from most modern pumps can be downloaded to a computer or to the web, and a wealth of information is available to the patient and health-care professional, such as number and magnitude of basal rate changes and temporary rates; timing, size and type of meal boluses; correction doses; pump alarms; carbohydrate given; entered meter blood glucose values or CGM data, if in use. This data is useful for uncovering pump problems such as nonadherence or misunderstanding of pump procedures and often helps to optimise control. Interpretation of data can be time consuming. On a cross-sectional basis, patients who use the download capability of pumps have lower values than those who do not, 52 but that might be because they are generally more motivated and en thusiastic in their diabetes care. CGM connectivity CGM can be used with CSII; this combination is sometimes known as sensor-augmented pump therapy. CGM can also be used with MDI; 53 however, for some insulin pump models, CGM data can be wirelessly transferred from the implanted glucose sensor to the pump itself, giving a display of glucose values and trends that enable the patient to optimise control. Meta-analysis of RCTs of real-time CGM or SMBG used with either CSII or MDI shows that CGM is associated with a significant lowering of mean level of ~0.3%. 54 However, best-fit models created using individual patient data from RCTs of realtime CGM versus SMBG indicate that the best effect on levels in patients using CGM occurs in those who use the sensor most frequently and/or who have the highest baseline level. 54 For example, a patient who uses CGM 7 days per week and has a baseline level of 10% might expect a reduction in of about 0.9% when using CGM compared with SMBG. 54 The most appropriate and cost-effective use of CGM in pump users is, therefore, likely to be in those who have not achieved target levels after an extended trial of CSII, and in those who use CGM almost daily. Why some patients use the sensor less than others is not completely clear. Low use might be associated with patients who are less engaged with their diabetes care in general, perceive little benefit from CGM, have body image issues connected with wearing the device or, most probably, react negatively to the complexity, demands and burden of current CGM use, such as sensor insertion, calibration and responding to alarms. Hypoglycaemia changes during CGM versus SMBG when used with either CSII or MDI have been less wellstudied than changes. Evidence exists for a significant reduction in sensor-measured mild-to-moderate hypoglycaemia with CGM versus SMBG. 54,55 How ever, even though CGM was originally developed for the clinical problem of frequent severe hypoglycaemia, the approach has not been evaluated in an RCT specifically in patients with this clinical problem. Uncertainty, therefore, exists about the impact of this technology when used in patients who have continued disabling hypo glycaemia on CSII. NATURE REVIEWS ENDOCRINOLOGY VOLUME 8 JULY

6 Hypoglycaemia, however, could be reduced by another CGM-linked technology: low-glucose insulin-suspend (LGS) pumps. One commercially available pump now has an LGS facility whereby CGM values that fall below a preset hypoglycaemic threshold automatically activate a suspend of the basal insulin infusion rate for up to 2 h, which enables glucose levels to re-enter the target range. In a short-term trial, the duration of nocturnal hypoglycaemia during CSII when the LGS was activated was reduced by 96% in those with the highest quartile of hypoglycaemia at baseline. 56 This technology is an example of the control-to-range strategy, 57 whereby glucose levels are allowed to fluctuate between quite wide upper and lower limits. Control to range can be considered as a first step towards fully closed-loop insulin delivery and the artificial pancreas. Future insulin pumps of this type are expected to have a trigger for the suspension of insulin that is activated by the rate of fall and thus the predicted rather than absolute glucose level. Subsequent versions may also have activation of an insulin boost when the CGM trace exceeds a preset high blood glucose level threshold. CSII versus MDI in diabetic pregnancy CSII has potential advantages that would be especially useful in pregnant women with T1DM, including improved level, and reduced frequency of hypoglycaemia and glycaemic fluctuations. But potential dis advantages include the risk of ketoacidosis if pump delivery is interrupted and the sometimes long learning curve for patients to become pump-educated. 58 CSII is safe and effective in pregnancy, but no convincing evidence exists from either observational studies or the relatively few RCTs conducted that glycaemic control or pregnancy outcomes differ between CSII or MDI Maternal hypoglycaemia, ketoacidosis, retinopathy progression, pre-eclampsia, spontaneous miscarriage, congenital abnormalities, birth weight, neonatal hypoglycaemia and stillbirths have all been found to be similar during CSII or MDI in pregnant women with T1DM. In clinical practice, many health-care professionals reserve CSII in pregnant women with T1DM for the subset who have not achieved strict glycaemic control with MDI. This subset often show an improvement when they are switched to CSII. 59 However, an RCT is needed to compare glycaemic control with CSII versus MDI in this group. Patch pumps and technology developments The term patch pump refers to a new generation of insulin infusion pumps that are smaller than existing pumps; they are usually attached to the body by an adhesive patch and have an integrated cannula and are, therefore, sometimes called tubeless pumps. 63 Many patch pumps are simpler to operate than conventional pumps, and some are controlled by a hand-held remote, perhaps with a touch screen. This new technology has at least two major implications. Firstly, the small size and relative simplicity makes the pumps more suitable than conventional pumps for use in type 2 diabetes mellitus (T2DM). Patients with T2DM, who are often elderly, frequently cannot tolerate the relatively large size of conventional pumps. In addition, this type of pump can be managed by relatively simple infusion regimens, such as one basal rate throughout the day. Some manufacturers are, therefore, targeting their patch pumps specifically at patients with T2DM. Secondly, the improved ease-of-use and less obtrusive size promises that patient acceptance will be good, which might increase uptake of insulin pump therapy in general. Potential disadvantages of CSII Cost Insulin pump therapy is more expensive than MDI, with a typical pump costing about 2,500 or more in the UK, with a 4 6 year warranty, and additional consumable costs related to infusion sets, reservoirs and batteries. The annualised cost of CSII was estimated to be about 1,600 greater than that of MDI in 2009, 3 but without including the costs of extra staff training and medical, nursing and dietitian time needed to run the service. Several cost-effectiveness studies comparing CSII and MDI have been published, 6,64 67 including one in the UK NICE guidelines on CSII. 6 The cost-effectiveness models used incorporate the expected reduction in levels with CSII, and, therefore, the reduced risk of microvascular disease and associated health-care costs. Hypoglycaemia reduction has less effect on costs but improves quality of life and can be factored into the cost-effectiveness analysis. 6 CSII is generally considered to be cost-effective in these models, with an incremental cost-effectiveness ratio varying from about 17,000 to 35,000 per qualityadjusted life year compared with MDI, depending on the baseline level with MDI. NICE has an informal willingness-to-pay threshold of about 20,000 30,000 per quality-adjusted life year gained, and considers that CSII is a cost-effective use of National Health Service resources in the UK for the two clinical indications of continued disabling hypoglycaemia and level 8.5% during MDI. Pump complications The frequency of diabetic ketoacidosis is not significantly different during modern CSII versus MDI; 6,16,68 however, the potential risk of ketoacidosis is greater with CSII in the event of pump malfunction with interrupted insulin delivery, or with the increased insulin requirements of illness, because of the smaller subcutaneous insulin depot with CSII. For this reason, regular SMBG and a prompt response to hyperglycaemia is a crucial part of pump management. 3 Skin infections at the site of infusion are rare and minimized by the standard practice of changing the cannula and site every 2 3 days and a notouch technique for insertion. 68 Modern insulin pumps are very reliable and robust compared with the original models of the 1970s and 1980s, but a variety of technical pump and cannula problems still occur, and the system is undoubtedly more complex and liable to malfunction than the pens, syringes and needles of MDI. 430 JULY 2012 VOLUME 8

7 CSII in type 2 diabetes mellitus Insulin pump therapy is not generally recommended for use in T2DM, 6 a view that is based on the lack of RCT evidence for any difference in glycaemic control between CSII and MDI in T2DM Nevertheless, in several observational studies in which patients with T2DM have been switched from MDI to CSII, the fall is significant and clinically meaningful, with a weighted mean change of about 0.95% As with T1DM, individuals who had the highest level at baseline on MDI in these studies had the greatest improvement when transferred to CSII. Often these patients were obese or insulin resistant, had an elevated level and coexistent diseases which made glycaemic control difficult with MDI. The fall in level is often associated with improved quality of life and treatment satisfaction. 80 Retrospective surveys of patients with T2DM transferred from MDI to CSII show that the fall in level is maintained over a follow-up period of up to 6 years. 81 The use of U500 insulin (insulin at a strength of 500 units/ml) in patients with T2DM treated by CSII is also being increasingly explored in subsets of patients with poor glycaemic control. Lane et al., 82 for exam ple, studied 20 insulin-resistant patients with T2DM (mean insulin dose 1.7 U/kg) who were uncontrolled on U100 (100 units/ml) insulin via CSII or MDI. When switched to CSII with U500 insulin, the level fell from a mean of 8.60% to 7.37% over 12 months. Possibly, the effectiveness of U500 CSII was connected with the smaller volumes infused and the improved sub cutaneous ab sorption, or with improved adherence. The cost-effectiveness of CSII in T2DM has yet to be fully explored, but it might be cost-effective in certain groups. Wolff-McDonagh et al. 83 reported a retrospective analysis of 15 patients with T2DM with an elevated level on MDI who were switched to CSII with a follow-up of 1 year. The mean level fell from 9.3% to 8.3%, with an accompanying reduction in basal insulin dose. The cost-effectiveness was estimated on the basis of pump or injection supplies and insulin over a 4 year period (the lifetime of a pump), but the cost-effectiveness resulting from level changes was not considered. CSII was found to be more expensive than MDI when the insulin dose was <150 units per day but less expensive by about US$12,000 when the dose was >150 units per day. The best use of pumps in T2DM will probably correspond to them being targeted at subgroups of patients with continued poor control on MDI, as with T1DM. RCTs are now needed to test this hypothesis. Conclusions Comparisons of glycaemic control and other outcomes during CSII versus MDI need to be interpreted with caution. For example, cross-sectional studies that compare clinic patients who have chosen or been allocated to CSII or MDI by their health-care professional sometimes demonstrate equivalent control, 84 but the pump patients might have been previously poorly controlled with MDI and then switched to CSII with good effect. By contrast, patients who chose CSII in reported studies sometimes have better outcomes than those who chose MDI, 85 but that might be because they are the more motivated, adherent and enthusiastic members of the clinic. The difficulty of demonstrating differences between CSII and MDI when the baseline level in the study is relatively good is mentioned above. Furthermore, whilst many studies take care to incorporate structured patient education with carbohydrate counting and enthusiastic health-care attention and support into both treatment regimens, some apparently do not. Undoubtedly, in everyday clinical practice, if not in trials, the glycaemic control in some patients on MDI could be brought close to that achievable on CSII by closer attention to education and other support from health-care professionals. Equally, outcomes with insulin pump therapy could sometimes be improved further by appropriate education of staff and patients and by the use of the measures outlined above, such as bolus calculators, optimal bolus timing and types, and computer d ownloads of pump data. The answer to the question of whether the pump is mightier than the pen is that for many with T1DM it is not, and such patients can achieve good glycaemic control using MDI. However, for the considerable number of patients who cannot achieve target levels without disabling hypoglycaemia, good evidence exists that insulin pump therapy can improve glycaemic control in a large proportion, and they should be given the op portunity to undergo a trial of CSII. Finally, the equitable use of insulin pump therapy in T1DM deserves comment. The uptake of CSII in different countries is variable, 3 ranging from <5% of patients with T1DM in some countries such as the UK to >35% in the USA. Furthermore, within some countries, patients in certain areas have little or no access to pumps. On the basis of the frequency of elevated levels and severe and disabling hypoglycaemia in patients with T1DM using MDI, and allowing for individuals who might be judged unsuitable or choose not to use CSII, the percentage of adults with T1DM who would benefit from insulin pump therapy on clinical grounds alone can be estimated at about 15 20%. 86 A strong argument, therefore, exists that insulin pumps should be used more often and more consistently in adult T1DM than presently occurs in many countries. CSII is safe and effective in children, even when used as a first-line therapy from diagnosis. 87,88 Given the difficulties of instituting MDI in children, 9 CSII also needs to be used more often in this patient group. Review criteria This narrative review is based on data from individual studies and meta-analyses known to the author. Additional relevant studies were identified by searching Ovid Medline, EMBASE and Google Scholar for articles up to July 2011 with the search terms insulin pump therapy, continuous subcutaneous insulin infusion, CSII, continuous glucose monitoring and diabetes mellitus, as well as cited literature in retrieved articles. NATURE REVIEWS ENDOCRINOLOGY VOLUME 8 JULY

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