NATURE REVIEWS | ENDOCRINOLOGY VOLUME 10 | NOVEMBER 2014

NEWS & VIEWSDIABETES

Insulin pump therapy for type 2 diabetes mellitusJohn C. Pickup

The evidence base for the efficacy of insulin pump therapy in type 2 diabetes mellitus (T2DM) has been inconsistent to date. However, a recent large-scale randomized controlled trial comparing pump treatment with multiple daily insulin injections in patients with poorly controlled T2DM has shown substantial improvement in glycaemic control with pump therapy.Pickup, J. C. Nat. Rev. Endocrinol. 10, 647–649 (2014); published online 12 August 2014; doi:10.1038/nrendo.2014.142

Continuous subcutaneous insulin infusion (CSII, also known as insulin pump therapy) has become an established treatment for type 1 diabetes mellitus (T1DM), mainly in those patients who fail to achieve adequate glycaemic control by intensified insulin injections, either because of elevated levels of blood glucose and HbA1c or because of frequent disabling hypoglycaemia.1 How­ever, contemporary clinical recommenda­tions on CSII, such as the influential NICE guidelines in the UK,2 do not recom mend insulin pump therapy in type 2 dia betes mellitus (T2DM). This advice is mainly due to a lack of consistent and convincing evidence regarding the efficacy of insulin pumps in this type of diabetes in the few small­scale randomized controlled trials (RCTs) performed to date in which CSII was compared to multiple daily insulin (MDI) injections for T2DM.3,4 Now, the results of a large­scale, multicentre RCT reported by Reznik and colleagues5 have shown that patients with poorly controlled T2DM who received CSII over 6 months achieved significantly greater reductions in HbA1c levels than those patients treated with MDI injections (mean difference between groups 0.7%, 8 mmol/mol). The reduction in HbA1c levels observed in the CSII group was asso­ciated with a 20% decrease in the total daily insulin dosage compared with total daily insulin dosage in the MDI injection group, and was not accompanied by an increase in hypoglycaemia or weight gain.

CSII has been investigated as a possible therapy for T2DM for nearly 35 years, almost since the introduction of insulin

pump therapy for T1DM. CSII has been tested in various patient groups, includ­ing those with newly diagnosed T2DM, those with poor control on diet and exer­cise, and those receiving maximal doses of oral agents for glycaemic management. However, the question that has been the major focus of interest in this area is whether or not insulin pump therapy has a role in T2DM management when poor glycaemic control has persisted, despite intensive treatment with MDI injec­tions. At least one quarter of patients with T2DM who receive insulin injections have very poor glycaemic control (HbA1c ≥9%; 75 mmol/mol).6

Notwithstanding the inconsistent evi­dence from RCTs, CSII has been suggested to be of possible use in T2DM in certain patients, notably in those receiving MDI injections who have elevated HbA1c levels and/or high insulin requirements. Several observational studies7,8 have demon­strated a decrease in HbA1c levels of ≈1% (11 mmol/mol) when patients with T2DM treated with MDI injections who have an HbA1c level of ≈9% (75 mmol/mol) are switched to CSII therapy. The mean baseline HbA1c level in the RCTs con­ducted before 2014 was much lower (7.8%; 62 mmol/mol). Reznik and co­workers5 tested the effects of CSII in the target group that was most likely to benefit from this treatment strategy (and in whom the therapy was likely to be most cost­ effective)—those with per­sistently poor glycaemic control or insulin resistance despite receiving MDI injections.

After a run­in period to optimize glycaemic control with MDI injections, 331 patients with T2DM who still had an HbA1c level of 8–12% (64–108 mmol/mol) and who received insulin dosages of 0.7–1.8 U/kg were randomized to receive either insulin pump therapy or to continue MDI injec­tions for 6 months. Although the mean difference in HbA1c levels between treat­ment arms was substantial and clinically significant for a mean baseline HbA1c level of 9% (75 mmol/mol), for those in the highest tertile of HbA1c level at baseline (9.3–11.5%) the between­group treatment difference was 1.1% (12 mmol/mol).

Why might CSII work better than MDI injections in T2DM? Firstly, the large­volume bolus of injected, delayed­action insulin that has to be used in insulin­ resistant patients receiving MDI injections is absorbed more poorly and inconsistently than the small­volume basal rate adminis­tered by CSII. In another study,9 the same dose of insulin delivered by either CSII at the basal rate or an injection of long­acting insulin glargine achieved better glycae­mic control and higher circulating insulin levels that fluctuate less with CSII than with insulin glargine therapy. Secondly, from previous RCTs,3 we know that treat­ment satisfaction in patients with T2DM is higher with CSII than with MDI injec­tions, suggesting that adherence to treat­ment might be increased in those receiving pump therapy.

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NEWS & VIEWS

There might, however, be some prob­lems with using CSII to treat T2DM in routine practice, even when this approach is restricted to patients with very poorly controlled diabetes. These patients are often more elderly than those with T1DM treated by insulin pumps and might have multiple pathologies, such as decreased dextrous abilities, impaired eyesight and cognitive impairment, which are problems compounded in some cases by the lack of a partner to assist them. Interestingly, Reznik and colleagues5 found that a surprisingly large percentage (38%) of partici pants in their trial had mild cognitive impairment, indicating that this problem is unlikely to be a barrier to the successful use of insulin pumps in patients with T2DM. Some patients, however, might be unable or unwilling to cope with the relative com­plexity of traditional CSII and the large number of potential patients with T2DM presents organizational and affordability problems to the wide implementation of this approach.

Many patients with uncontrolled T2DM and a poor quality of life who are treated with MDI injections would benefit from current­technology insulin pump therapy. Nonetheless, what future developments will help to optimise the use of insulin pump therapy in T2DM? Smaller and less sophisticated pumps that use simpler CSII procedures than those neces sary for T1DM management might be more appro­priate for T2DM; a number of so­called ‘patch pumps’ that have an integrated cannula and are attached to the body via an adhesive patch are under development by various manufacturers. Evidence exists that simpler pump insulin regimens are effective and more suitable for T2DM: in most cases a fixed basal rate administered throughout the entire day is adequate,7,10 rather than a preset basal rate that changes

during the day and night as is often used in T1DM. A limited number of fixed basal rate options would probably suffice for most patients with T2DM. Reznik and colleagues5 also found that the meal­time insulin bolus calculator function on their pump, which was intended for T1DM manage ment, was used only sporadically (≈60% of patients used it for only 25% of the time) and its use was not related to reductions in HbA1c levels; a c onclusion reached by others studying CSII in T2DM.8 There is thus a case for developing insu­lin pumps for T2DM that employ less s ophisticated meal­time insulin delivery.

The next crucial step will be to demon­strate cost­effectiveness of CSII in T2DM. Targeting pump therapy at patients with T2DM who have persistently high baseline HbA1c levels when treated with MDI injec­tions when all other measures have been exhausted (including renewed structured diabetes education) is probably the most cost­effective strategy, as the reduction in HbA1c levels is the largest in this group5 and is accompanied by a cost­saving reduction in insulin dose. Additionally, the reduc­tion in the risk of microvascular complica­tions for a given decrease in HbA1c level is much greater at high HbA1c levels than at low baseline HbA1c levels. Cheaper pumps would help cost­effectiveness but simpler pumps also have a role in affordability, as less staff time would be needed for train­ing and starting patients on CSII. Further investigation of insulin pump therapy in T2DM in a wider clinical setting is eagerly awaited.

Diabetes Research Group, King’s College London School of Medicine, Hodgkin Building, Guy’s Hospital, London SE1 1UL, UK. john.pickup@kcl.ac.uk

Competing interestsJ.C.P. has received speaker and/or consultancy fees from manufacturers of insulin pumps, including Cellnovo, Cequr, Medtronic and Roche.

1. Pickup, J. C. Insulin-pump therapy for type 1 diabetes mellitus. N. Engl. J. Med. 366, 1616–1624 (2012).

2. National Institute for Health and Care Excellence. Continuous subcutaneous insulin infusion for the treatment of diabetes mellitus. NICE Technology Appraisals [TA151] [online], http:// www.nice.org.uk/guidance/TA151 (2008).

3. Raskin, P. et al. Continuous subcutaneous insulin infusion and multiple daily injection therapy are equally effective in type 2 diabetes: a randomized, parallel-group, 24-week study. Diabetes Care 26, 2598–2603 (2003).

4. Berthe, E. et al. Effectiveness of intensive insulin therapy by multiple daily injections and continuous subcutaneous insulin infusion: a comparison study in type 2 diabetes with conventional insulin regimen failure. Horm. Metab. Res. 39, 224–229 (2007).

5. Reznik, Y. et al. Insulin pump treatment compared with multiple daily insulin injections for the treatment of type 2 diabetes (OpT2mise): a randomised open-label controlled trial. Lancet http://dx.doi.org/10.1016/S0140–6736(14)61037–0.

6. Dodd, A. H. et al. Treatment approach and HbA1c control among US adults with type 2 diabetes: NHANES 1999–2004. Curr. Med. Res. Opin. 25, 1605–1613 (2009).

7. Edelman, S. et al. Insulin pump therapy in patients with type 2 diabetes. Safely improved glycemic control using a simple insulin dosing regimen. Diabet. Technol. Therapeut. 12, 627–633 (2010).

8. Leinung, M. et al. Use of insulin pump therapy in patients with type 2 diabetes after failure of multiple daily injections. Endocr. Pract. 19, 9–13 (2013).

9. Parkner, T. et al. Insulin and glucose profiles during continuous subcutaneous insulin infusion compared with injection of a long-acting insulin in type 2 diabetes. Diabet. Med. 25, 585–591 (2008).

10. King, A. B., Clark, D. & Wolfe, G. S. The number of basal rates required to achieve near-normal basal glucose control in pump-treated type 2 diabetes. Diabet. Technol. Therapeut. 14, 900–903 (2012).

‘‘…simpler pump insulin regimens are effective and more suitable for T2DM…’’

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