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��Papers Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials John Pickup, Martin Mattock, Sally Kerry Department of infused subcutaneously from a portable pump at one Abstract Chemical or more basal rates, with boosts in the dose activated by Pathology, Objective To compare glycaemic control and insulin the patient at mealtimes. Overall control, as measured Metabolic Unit, dosage in people with type 1 diabetes treated by Guy s, King s, and by mean blood glucose concentrations and percentage St Thomas s continuous subcutaneous insulin infusion (insulin of glycated haemoglobin, is considerably improved Hospitals School of infusion pump therapy) or optimised insulin during treatment with insulin infusion pumps com- Medicine, Guy s injections. Hospital, London pared with the non-optimised insulin injection therapy SE1 9RT Design Meta-analysis of 12 randomised controlled that was prevalent in management of diabetes until John Pickup trials. relatively recently.2 3 However, with the emergence of professor of diabetes Participants 301 people with type 1 diabetes and metabolism new treatment strategies such as insulin pens, which allocated to insulin infusion and 299 allocated to encourage multiple injection regimens, and the publi- South West Thames insulin injections for between 2.5 and 24 months. cation of the diabetes control and complications trial4 Institute for Renal Research, St Helier Main outcome measures Glycaemic control the importance and utility of intensive insulin injection Hospital, measured by mean blood glucose concentration and regimens in achieving near normoglycaemia and slow- Carshalton, Surrey percentage of glycated haemoglobin. Total daily SM5 1AA ing the development of microvascular complications Martin Mattock insulin dose. has become increasingly apparent. senior research fellow Results Mean blood glucose concentration was lower Though there have been several randomised Department of in people receiving continuous subcutaneous insulin controlled trials of insulin pumps compared with opti- General Practice infusion compared with those receiving insulin and Primary Care, mised insulin injection regimens, many had relatively injections (standardised mean difference 0.56, 95% St George s small numbers of participants.5 8 Some of these studies Hospital Medical confidence interval 0.35 to 0.77), equivalent to a showed better control with pumps,5 6 and others School, London difference of 1.0 mmol/l. The percentage of glycated SW17 0RE showed broadly similar control.7 8 haemoglobin was also lower in people receiving Sally Kerry We reviewed the literature on pump therapy and lecturer in medical insulin infusion (0.44, 0.20 to 0.69), equivalent to a carried out a meta-analysis of glycaemic control and statistics difference of 0.51%. Blood glucose concentrations insulin dosage in randomised controlled trials that Correspondence to: were less variable during insulin infusion. This compared continuous subcutaneous insulin infusion J Pickup improved control during insulin infusion was john.pickup@ and optimised insulin injection therapy. kcl.ac.uk achieved with an average reduction of 14% in insulin dose (difference in total daily insulin dose 0.58, 0.34 to BMJ 2002;324:1 6 0.83), equivalent to 7.58 units/day. Methods Conclusions Glycaemic control is better during Identification and selection of trials continuous subcutaneous insulin infusion compared To identify published trials that met the inclusion crite- with optimised injection therapy, and less insulin is ria we searched Medline (1975 to 2000) and Embase needed to achieve this level of strict control. The (1980-2000) for literature on insulin infusion systems/ difference in control between the two methods is insulin infusion and the Cochrane database of small but should reduce the risk of microvascular randomised controlled trials. We also searched a complications. personal (JP) collection of peer reviewed articles and reviews about infusion systems and lists of papers on pump therapy supplied by two manufacturers of insu- Introduction lin infusion pumps (MiniMed and Disetronic). We Continuous subcutaneous insulin infusion, often called reviewed cited literature in retrieved articles and infor- insulin pump therapy, was introduced in the 1970s as a mation and references supplied by INPUT, a support way of achieving and maintaining strict control of group for pump patients. blood glucose concentrations in people with type 1 We selected only those studies that were ran- (insulin dependent) diabetes.1 Short acting insulin is domised controlled trials of pump therapy compared BMJ VOLUME 324 23 MARCH 2002 bmj.com 1 Papers with optimised insulin injection therapy. We consid- include HbA1c, HbA1 and glycated haemoglobin meas- ered optimised injection therapy as part of the trial urements made by different methods). We also noted design if multiple insulin injections were used, there total daily insulin dose on the two regimens. We was adjustment of insulin dosages or timing, or both, recorded the type of pump, the type of insulin, and the according to hospital and home monitored blood glu- insulin injection regimen. cose concentrations, or the authors described the regi- men as intensive or optimised. We did not included Statistical analysis trials of alternative infusion and injection systems, such We used a random effects model (StataCorp, College as the pen infuser and jet injectors, which are not Station, TX, USA) for the meta-analysis. We calculated based on electromechanical pumps or regular the weighted mean difference of the standardised blood subcutaneous needle injection. We also excluded short glucose concentration, percentage of glycated haemo- term studies (two weeks duration on either therapy), globin, and insulin dosage on pump and injection those in people with newly diagnosed type 1 diabetes, therapy (that is, the number of SDs of the value) to com- those in pregnant women with diabetes, controlled pensate for different scales (for example, because of dif- trials that were not randomised, those that used ferent methods of measuring glycated haemoglobin). non-optimised ( conventional ) insulin injection We calculated the estimated treatment effects in absolute therapy, and those when it was unclear whether units by multiplying the combined treatment effects by injection therapy was optimised. When several the average pooled SDs in all studies. publications reported different aspects of the same We assessed potential publication bias by a funnel study for example, effect on glycaemic control in one plot and Egger s test.9 Sensitivity to the estimate of paper and subsequently effects on various microvascu- publication bias was assessed by the trim and fill lar complications in another paper we chose only one method.10 We assessed heterogeneity between trials by 2 paper to represent the trial data on glycaemic control. the test. Sources of heterogeneity were assessed with We extracted data from text, tables, and graphs. a random effects regression analysis with age, duration Data were examined independently by two reviewers of diabetes and treatment, and year of study as (JP and MM). Differences over inclusion of studies and independent variables. We tested the robustness of the interpretation of data were resolved by consensus analyses in sensitivity analyses by comparing the sum- reached after discussion. mary results of random effects meta-analysis with meta-analysis using a fixed effect model and analysis Outcome measures with data in absolute rather than standardised units. We assessed glycaemic control with each method as We tested the hypothesis that variability in blood mean (SD) blood glucose concentration (to include glucose concentration was less during continuous whole blood, plasma, and serum glucose concentra- insulin infusion than during injection therapy by tion) and percentage of glycated haemoglobin (to calculating the ratio of the minimum variance Characteristics of trials included in meta-analysis of continuous subcutaneous insulin infusion versus intensive insulin injections Mean (SD or Mean (SD or range) Duration of No of range) age duration of diabetes treatment Author participants (years) (years) (months) Type of pump Type of insulin Injection regimen Schiffrin, 19828 16 24.9 (8.8) 10.4 (5.1) 6 Mill Hill Connaught/Lilly regular Regular thrice daily; isophane insulin at bedtime Home, 19826 10 40.4 (7.3) 23.5 (8.3) 2.5 Mill Hill, Auto-Syringe Pork Actrapid Regular thrice daily; ultralente pm Nathan, 19825 5 31 (5.7) 7.4 (1.8) 2-3 Auto-Syringe NA Regular thrice daily; regular isophane insulin twice daily; ultralente before breakfast Schiffrin, 198411 24 13-20 9 4 Mill Hill Connaught/Lilly regular Regular thrice daily; isophane insulin pm/bedtime Dahl-J�rgensen, 15 26 (19-42) 12.8 24 Nordisk Pork Velosulin Regular twice daily; isophane 19867 insulin am/bedtime 15 26 (18-32)! 12.8! Auto-Syringe Helve, 198712 65 31.1 (1) 12 (1) 6 Nordisk Auto-Syringe Velosulin Actrapid Multiple Marshall, 198713 12 36 (21-50) 18 (10-29) 6 Nordisk Velosulin Regular twice daily; isophane insulin twice daily/bedtime Bak, 198714 20 24 (2) 5.8 (3.8) 6 Graseby Actrapid Regular thrice daily; isophane insulin at bedtime Saurbrey, 198816 21 32 (2.1) 14.5 (1.4) 2.5 Auto-Syringe, Medix NA Regular thrice or four times daily; lente bedtime Schmitz, 198917 10 36.5 (7.9) 23.7 (2.9) 6 Nordisk Velosulin Regular thrice daily; isophane insulin at bedtime D�sseldorf, 199018 47 32 (18-54) 18 (3-44) 24 Nordisk, Promedos NA Regular twice, thrice, or four times daily 49! Betatron, Auto-Syringe NA Twice daily isophane insulin (or before breakfast injection/bedtime) Hannaire-Broutin, 41 43.5 (10.3) 20.0 (11.3) 4 MiniMed, Disetronic Lispro Thrice daily monomeric; twice 200019 daily isophane insulin (or before breakfast injection/bedtime) NA=data not available. *Regular=regular soluble or short acting insulin. Participants on injections. ! Participants on pump therapy. 2 BMJ VOLUME 324 23 MARCH 2002 bmj.com Papers weighted geometric means of the SDs of blood glucose Study Difference (95% CI) concentrations on the two regimens. 8 Schiffrin et al 1982 0.09 (-0.61 to 0.78) 6 Home et al 1982 0.92 (-0.01 to 1.85) Results 5 Nathan et al 1982 0.92 (-0.40 to 2.23) 11 We identified 13 randomised controlled trials that Schiffrin et al 1984 0.39 (-0.18 to 0.96) 7 compared glycaemic control on continuous subcutan- Dahl-J�rgensen et al 1986 0.92 (0.16 to 1.67) 12 eous insulin infusion compared with optimised insulin Helve et al 1987 0.25 (-0.10 to 0.59) 13 injections.5 8 11 19 In one report the error terms were Marshall et al 1987 0.85 (0.01 to 1.69) 14 Bak et al 1987 0.29 (-0.34 to 0.91) ambiguous. As we could not reach consensus about 16 Saurbrey et al 1988 0.77 (0.14 to 1.40) reliable extraction of data we omitted this trial from the 17 Schmitz et al 1989 1.08 (0.13 to 2.02) analysis.15 The table shows the characteristics of the 18 D�sseldorf study 1990 1.00 (0.57 to 1.42) analysed trials. Eleven trials were of crossover 19 Hannaire-Broutin et al 2000 0.30 (-0.13 to 0.74) design.5 6 8 11 14 16 19 Nine different infusion pumps were used. In total 301 participants were randomised to Overall (95% CI) 0.56 (0.35 to 0.77) infusion pumps and 299 to optimised injections for -2 0 2 between 2.5 and 24 months. This represented 2522 Favours injection Favours pump patient months of pump treatment. therapy therapy Fig 1 Standardised mean differences (95% confidence interval) in blood glucose concentration Blood glucose control achieved during insulin pump compared with optimised insulin injection therapy Figure 1 shows that glycaemic control was better during pump treatment. The standardised mean The estimate from the fixed effect model was similar to difference in blood glucose concentrations between that of the random effects model (0.53, 0.36 to 0.71). insulin pump and optimised insulin injection therapy Analysis of insulin dose showed some evidence of was 0.56 (95% confidence interval 0.35 to 0.77). The heterogeneity (P=0.07). The funnel plot showed some estimate from the fixed effects model was similar (0.53, bias, though the result of Egger s test was not significant 0.36 to 0.70). The treatment effect in terms of absolute (P=0.17). The effect size corrected for bias was 0.42 units was 1.06 mmol/l (0.88, 0.52 to 1.24 mmol/l with (0.25 to 0.58). In regression analysis the duration of unstandardised data). 2 treatment was negatively related to effect size The results of the tests showed no significant (regression coefficient=-0.41( - 0.66 to - 0.15)). The heterogeneity among trials (P=0.17). There was no model estimated the effect size to be 0.66 (0.33 to 0.10) clear publication bias in a funnel plot, and the result of at six months and 0.05 ( - 0.59 to 0.70) at two years of Egger s test was not significant (P=0.168). The trim and treatment. fill method gave an estimated corrected effect size of 0.39 (0.15 to 0.63). Only duration of treatment was Variability in blood glucose concentration related to effect size in a regression analysis (regression Using SD of blood glucose concentration as a measure coefficient=0.32 (0.06 to 0.58)). This model estimated of glycaemic variability, we found the variability was the effect size as 0.46 (0.14 to 0.77) at six months of significantly higher with insulin injections than with treatment and 0.93 (0.30 to 1.57) at two years. pump therapy (weighted geometric mean of the SD ratios 1.27, 1.11 to 1.47). Glycated haemoglobin Figure 2 shows that the percentage of glycated haemo- Discussion globin was lower during pump therapy, the standard- ised mean difference being 0.44 (0.20 to 0.63). This is Meta-analysis of 12 randomised controlled trials shows equivalent to an effect size of 0.51% in original units, that use of insulin pumps results in better glycaemic consistent with that seen in a meta-analysis with unstandardised data (0.45%, 0.20% to 0.71%). The Study Difference (95% CI) fixed effect model gave a similar standardised mean 8 difference to the random model (0.41, 0.23 to 0.58). Schiffrin et al 1982 0.40 (-0.30 to 1.10) 2 6 There was some evidence of heterogeneity ( P=0.07), Home et al 1982 0.83 (-0.09 to 1.74) 5 Nathan et al 1982 2.47 (0.74 to 4.20) and a funnel plot and Egger s test (P=0.02) revealed 11 Schiffrin et al 1984 0.94 (0.34 to 1.54) some possible publication bias. The trim and fill 7 Dahl-J�rgensen et al 1986 0.29 (-0.43 to 1.01) method gave an estimated effect size corrected for bias 12 Helve et al 1987 0.14 (-0.21 to 0.48) of 0.31 (0.15 to 0.48). None of the measured variables 13 Marshall et al 1987 -0.13 (-0.93 to 0.67) was significantly related to effect size in regression 16 Saurbrey et al 1988 0.00 (-0.60 to 0.60) analysis. 17 Schmitz et al 1989 0.70 (-0.21 to 1.61) 18 D�sseldorf study 1990 0.68 (0.27 to 1.09) 19 Insulin dose Hannaire-Broutin et al 2000 0.37 (-0.06 to 0.81) Figure 3 shows that the improved control during insu- lin pump therapy was achieved at a reduced total daily Overall (95% CI) 0.44 (0.20 to 0.69) insulin dosage. The standardised mean difference in -2 -1 0 1 2 3 insulin dose was 0.58 (0.34 to 0.83). This represents a Favours injection Favours pump mean dosage reduction of 14% during pump therapy. therapy therapy The effect size was 7.58 units/day in original units, Fig 2 Standardised mean differences (95% confidence interval) in percentage of glycated which was similar to that seen in a meta-analysis with haemoglobin during insulin pump compared with optimised insulin injection therapy unstandardised data (7.33, 4.07 to 10.59 units/day). BMJ VOLUME 324 23 MARCH 2002 bmj.com 3 Papers eity was a tendency for trials with a longer duration to Study Difference (95% CI) be associated with a larger difference in control of gly- caemia between pump and injection therapy and a 8 Schiffrin et al 1982 0.29 (-0.41 to 0.98) smaller difference in insulin dosage. This finding is 6 Home et al 1982 1.27 (0.30 to 2.24) 5 consistent with the known effect of pump therapy in Nathan et al 1982 1.08 (-0.27 to 2.43) 11 improving insulin sensitivity and reducing insulin Schiffrin et al 1984 1.13 (0.52 to 1.74) 7 resistance in people with type 1 diabetes.27 28 Dahl-J�rgensen et al 1986 0.58 (-0.15 to 1.31) 12 We excluded from our analysis the few trials in Helve et al 1987 0.58 (0.23 to 0.93) 13 Marshall et al 1987 0.94 (0.10 to 1.79) patients with newly diagnosed type 1 diabetes29 14 Bak et al 1987 0.46 (-0.17 to 1.09) because the likely remaining endogenous cell 17 Schmitz et al 1989 0.46 (-0.43 to 1.35) function would favour good control in any type of 18 D�sseldorf study 1990 -0.06 (-0.46 to 0.34) insulin therapy30 and obscure differences between 19 Hannaire-Broutin et al 2000 0.70 (0.25 to 1.14) pump and injection treatment. We also did not analyse trials in pregnant women because the number of stud- Overall (95% CI) 0.58 (0.34 to 0.83) ies is small31 33 and because we considered them to be a -2 -1 0 1 2 special group of patients, with changing control Favours injection Favours pump throughout pregnancy and a high level of motivation therapy therapy generally unrepresentative of most people with type 1 Fig 3 Standardised mean differences (95% confidence interval) in total daily insulin dose diabetes. during insulin pump compared with optimised insulin injection therapy Clinical significance of improved control What is the clinical significance of the small difference control than optimised insulin injection therapy but between the strict glycaemic control of pump and opti- that the difference is relatively small about 1 mmol/l mised injection therapy? Analysis of the results of the for blood glucose concentration and 0.5% for percent- diabetes control and complications trial34 has shown age of glycated haemoglobin. The main inclusion that the risk of development and progression of micro- criterion in the studies was that patients should agree vascular complications extends over the entire range of to and be capable of using the pump and its associated glycated haemoglobin values and there is no threshold procedures. As this is the prerequisite of pump therapy (short of normoglycaemia) below which there is no in clinical practice20 the results of our meta-analysis are risk. The standardised mean difference for glycated applicable to the general population of people with haemoglobin of 0.44 in this meta-analysis corresponds type 1 diabetes, though few of the participants in these to a reduction in HbA1c of about 0.5% in the diabetes studies had severe complications such as clinical neph- control and complications trial (where the SD for ropathy (with persistent proteinuria shown by positive HbA1c in the intensively managed group was 1.1-1.3%). result on dipstick testing). This degree of improvement in control was associated with a reduction in risk of retinopathy of about 25%. Potential influences on glycaemic control However, the relation between the absolute risk Our results of meta-analysis were not modified by the (hazard rate per 100 patient years of treatment) and publication date of the trials, though there are several HbA1c was curvilinear, with a smaller rate at a lower potential reasons why insulin pump therapy in the than at a higher HbA1c. In people with intensively con- early 1980s might have been less effective than modern trolled glycaemia the absolute risk reduction for practice. Early pumps had few or no alarm features for sustained progression in retinopathy (three steps on events such as low battery or occlusion of delivery and the early treatment of diabetic retinopathy scale) asso- no facility for automatic change in basal rate of ciated with a difference in HbA1c of 0.5% was about 0.5 infusion. The type of insulin used in the pump might cases per 100 patient years. Thus, maintaining this dif- also be important as unbuffered short acting insulin, ference in control between insulin pump and injection used particularly in North America in the first years therapy for 10 years would reduce the number of after the introduction of insulin pumps, was more patients developing retinopathy of this degree by likely than buffered insulins to occlude the delivery about 5%. The cost effectiveness of insulin pump cannula and disrupt control.21 22 The most recent trial versus insulin injections for this degree of benefit will in this survey used the monomeric insulin analogue, need to be assessed. lispro, in the pump.19 This is now considered to be the pump insulin of choice,23 26 but the results of the one Hypoglycaemia and variability of glycaemic control lispro pump study in this meta-analysis were broadly A weakness of our study is that because of poor report- consistent with the overall result of our analysis (stand- ing and short duration of studies we could not assess ardised mean differences with lispro were 0.30 ( - 0.13 the relative frequencies of potential side effects, to 0.74) for blood glucose concentration and 0.37 particularly severe hypoglycaemia, ketoacidosis, and ( - 0.06 to 0.81) for glycated haemoglobin, favouring weight gain. For hypoglycaemia, for example, many pump treatment19). studies were too short in duration to have more than Glycaemic control during optimised injection one episode of severe hypoglycaemic reported on therapy may be affected by the regimen used and the either treatment.5 6 8 11 16 17 However, as well as the lower intensity of its application. There were many different mean blood glucose concentration, we found that injection regimens used in the trials reported here, and oscillations in blood glucose concentration, as we cannot make judgments about their appropriate- measured by SD, were also significantly less during ness. Though this introduces some uncertainty into the pump treatment. This may contribute to the lower fre- conclusions, the results were surprisingly consistent quency of hypoglycaemia reported in other studies35 38 across trials. The only identified source of heterogen- and is probably related to the lower variability in 4 BMJ VOLUME 324 23 MARCH 2002 bmj.com Papers 6 Home PD, Capaldo B, Burrin JM, Worth R, Alberti KGMM. A crossover What is already known on this topic comparison of continuous subcutaneous insulin infusion (CSII) against multiple insulin injections in insulin-dependent diabetic subjects: improved control with CSII. Diabetes Care 1982;5:466-71. Continuous subcutaneous insulin infusion (insulin 7 Dahl-J�rgensen K, Brinchman-Hansen O, Hanssen KF, Ganes T, Kierulf pump therapy) produces good long term control P, Smeland E, et al. Effect of near-normoglycaemia for two years on pro- gression of early diabetic retinopathy, nephropathy, and neuropathy: the of blood glucose concentrations in people with Oslo study. BMJ 1986;293:1195-9. type 1 diabetes 8 Schiffrin A, Belmonte MM. Comparison between continuous subcutan- eous insulin infusion and multiple injections of insulin. A one-year pro- spective study. Diabetes 1982;31:255-64. Control of blood glucose concentration is 9 Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis substantially better on pump therapy than detected by a simple graphical test. BMJ 1997;315:629-34. 10 Sutton AJ, Abrams KR, Jones DR, Sheldon T, Song F. Methods for conventional (non-optimised) injection therapy meta-analysis in medical research. Chichester: Wiley, 2000. 11 Schiffrin AD, Desrosiers M, Aleyassine H, Belmonte MM. Intensified insu- It is unclear how glycaemic control on pump lin therapy in the type 1 diabetic adolescent: a controlled trial. Diabetes Care 1984;7:107-13. therapy compares with modern optimised insulin 12 Helve E, Koivisto VA, Lehtonen A, Pelkonen R, Huttunen JK, Nikkil� EA. injection regimens A crossover comparison of continuous insulin infusion and conventional injection treatment of type 1 diabetes. Acta Med Scand 1987;221:385-93. What this study adds 13 Marshall SM, Home PD, Taylor R, Alberti KGMM. Continuous subcutan- eous insulin infusion versus injection therapy: a randomized cross-over trial under usual diabetic clinic conditions. Diabetic Med 1987;4:521-5. Though glycaemic control was better during 14 Bak JF, Nielsen OH, Pedersen O, Beck-Nielsen H. Multiple insulin injec- continuous subcutaneous insulin infusion than tions using a pen injector versus insulin pump treatment in young diabetic patients. Diabetes Res 1987;6:155-8. optimised insulin injection therapy, the difference 15 Nosadini R, Velussi M, Fioretto P, Doria A, Avogaro A, Trevisan R, et al. was relatively small Frequency of hypoglycaemic and hyperglycaemic-ketotic episodes during conventional and subcutaneous continuous insulin infusion therapy in IDDM. Diabetes Nutr Metab 1988;1:289-96. Continuous subcutaneous insulin infusion is an 16 Saurbrey N, Arnold-Larsen S, M�ller-Jensen B, K�hl C. Comparison of effective form of intensive insulin therapy that continuous subcutaneous insulin infusion with multiple insulin injections using the NovoPen. Diabetic Med 1988;5:150-3. should lower the risk of microvascular 17 Schmitz A, Sandahl-Christiansen J, Kjeldahl-Christiansen C, Hermansen complications K, Mogensen CE. Effect of pump versus pen treatment on glycaemic con- trol and kidney function in long-term uncomplicated insulin-dependent diabetes mellitus (IDDM). Danish Med Bull 1989;36:176-8. Insulin pump therapy is unnecessary for most 18 D�sseldorf Study Group. Comparison of continuous subcutaneous insulin people with type 1 diabetes and should be infusion and intensified conventional therapy in the treatment of type 1 reserved for those with special problems with diabetes: a two-year randomised study. Diabetes Nutr Metab 1990;3:203-13. 19 Hannaire-Broutin H, Melki V, Bessieres-Lacombe S, Tauber J. optimised insulin injections Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens using insulin lispro in type 1 diabetic patients on intensified treatment: a randomized study. Diabetes Care 2000;23:1232-5. 20 Pickup JC, Keen H. Continuous subcutaneous insulin infusion in type 1 subcutaneous insulin absorption during pump infu- diabetes. BMJ 2001;322:1262-3. 21 Mecklenburg RS, Guinn TS. Complications of insulin pump therapy: the sion compared with injection treatment.39 effect of insulin preparation. Diabetes Care 1985;8:367-70. 22 Eichner HL, Selam J-L, Woertz LL, Cornblath M, Charles MA. Improved Conclusions and recommendations metabolic control of diabetes with reduction of occlusions during We conclude that continuous subcutaneous insulin continuous subcutaneous insulin infusion. Diabetes Nutr Metab 1988;1:283-7. infusion is an effective form of intensive insulin therapy 23 Melki V, Renard E, Lassman-Vague V, Boivin S, Guerci B, Hanaire- for people with type 1 diabetes as glycaemic control is Broutin H, et al. Improvement of HbA1c and blood glucose stability in IDDM patients treated with lispro insulin analogue in external pumps. slightly but significantly better than during optimised Diabetes Care 1998;21:977-81. insulin injections. However we consider that in general 24 Renner R, Pf�tzner A, Trautman M, Harzer O, Sauter K, Landgraf R. Use insulin pump should be reserved for those with special of insulin lispro in continuous subcutaneous insulin infusion treatment. Diabetes Care 1999;22:784-8. problems such as unpredictable hypoglycaemia or a 25 Zinman B, Tildesley H, Chiasson J-L, Tsui E, Strack T. Insulin lispro in marked increase in blood glucose concentration at CSII: results of a double-blind crossover study. Diabetes 1997;46:440-3. 26 Schmauss S, K�nig A, Landgraf R. Human insulin analogue dawn, despite best attempts to improve control with [LYS(B28),PRO(B29)]: the ideal pump insulin? Diabetic Med optimised injection regimens.20 40 1998;15:247-9. 27 Beck-Nielsen H, Richelsen B, Hasling C, Nielsen OH, Hedding L, S�rensen NS. Improved in vivo insulin effect during continuous subcutaneous insulin infusion in patients with IDDM. Diabetes Contributors: JP initiated the study, analysed the data, wrote the 1984;33:832-37. first draft of the paper, and is guarantor. MM analysed the data. 28 Simonson DC, Tamborlane WV, Sherwin RS, Smith JD, DeFronzo RA for SK performed the statistical analyses. All authors collaborated the Kroc Collaborative Study Group. Improved insulin sensitivity in on the final version of the paper. patients with type 1 diabetes mellitus after CSII. Diabetes 1985;34(suppl Funding: None. 3):80-6. Competing interests: King s College London has received 29 De Beaufort CE, Houtzagers CMGJ, Bruining GJ, Aarsen RSR, den Boer NC, Grose WFA, et al. Continuous subcutaneous insulin infusion (CSII) financial support for some studies on continuous subcutaneous versus conventional injection therapy in newly diagnosed diabetic insulin infusion from MiniMed, a manufacturer of insulin children: two-year follow-up of a randomized, prospective trial. Diabetic pumps. Med 1989;6:766-71. 30 Gonen B, Goldman J, Baldwin D, Goldberg RB, Ryan WG, Blix PM, et al. Metabolic control in diabetic patients. Effects of insulin-secretory reserve 1 Pickup JC, Keen H, Parsons JA, Alberti KGMM. Continuous (measured by plasma C-peptide levels) and circulating insulin antibodies. subcutaneous insulin infusion: an approach to achieving normoglycae- Diabetes 1979;28:749-53. mia. BMJ 1978;i:204-7. 31 Coustan DR, Reece EA, Sherwin RS, Rudolf MCJ, Bates JE, Sockin SM, et 2 Lauritzen T, Frost-Larsen K, Larsen HW, Deckert T. Effect of 1 year of al. A randomized clinical trial of the insulin pump vs intensive near-normal blood glucose levels on retinopathy in insulin-dependent conventional therapy in diabetic pregnancies. JAMA 1986;255:631-6. diabetics. Lancet 1983;i:200-4. 32 Carta Q, Meriggi E, Trossarelli GF, Catella G, Dal Molin V, Menato G, et 3 Kroc Collaborative Study Group. Blood glucose control and the evolution of diabetic retinopathy and albuminuria. A preliminary multi- al. Continuous subcutaneous insulin infusion versus intensive conven- tional insulin therapy in type I and type II diabetic pregnancy. Diabete center trial. N Engl J Med 1984;311:365-72. Metabolisme 1986;12:121-9. 4 Diabetes Control and Complications Trial Research Group. The effect of 33 Nosari I, Maglio ML, Lepore G, Cortinovis F, Pagani G. Is continuous intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J subcutaneous insulin infusion more effective than intensive conventional Med 1993;329:977-86. insulin therapy in the treatment of pregnant diabetic women? Diabetes 5 Nathan DM, Lou P, Avruch J. Intensive conventional and insulin pump Nutr Metab 1993;6:33-7. therapy in adult type 1 diabetes. A crossover study. Ann Intern Med 34 Diabetes Control and Complications Trial Research Group. The absence 1982;97:31-6. of a glycemic threshold for the development of long-term complications: BMJ VOLUME 324 23 MARCH 2002 bmj.com 5 Papers the perspective of the diabetes control and complications trial. Diabetes 38 Boland EA, Grey M, Oesterle A, Fredrickson L, Tamborlane WV. 1996;45:1289-98. Continuous subcutaneous insulin infusion. A new way to lower risk of 35 Ng Tang Fui S, Pickup JC, Bending JJ, Collins ACG, Keen H, Dalton N. severe hypoglycemia, improve metabolic control and enhance coping in Hypoglycemia and counterregulation in insulin-dependent diabetic adolescents with type 1 diabetes. Diabetes Care 1999;22:1799-84. patients: a comparison of continuous subcutaneous insulin infusion and 39 Lauritzen T, Pramming S, Deckert T, Binder C. Pharmacokinetics of con- conventional insulin therapy. Diabetes Care 1986;9:221-7. tinuous subcutaneous insulin infusion. Diabetologia 1983;24:326-9. 36 Bending JJ, Pickup JC, Keen H. Frequency of diabetic ketoacidosis and 40 Pickup JC. Is insulin pump treatment justifiable? In: Gill GV, Pickup JC, hypoglycemic coma during treatment with continuous subcutaneous Williams G, eds. Difficult diabetes. Oxford: Blackwell Science, 2001:205-23. insulin infusion. Am J Med 1985;79:685-91. 37 Bode BW, Steed RD, Davidson PC. Reduction in severe hypoglycemia with long-term continuous subcutaneous insulin infusion in type 1 diabetes. Diabetes Care 1996;19:324-7. (Accepted 5 November 2001) 6 BMJ VOLUME 324 23 MARCH 2002 bmj.com

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