Background Type 2 diabetes is a relentless progressive disease, characterized by ongoing decline in beta cell function. In advanced disease, many patients develop worsening diabetes control, unable to reach the glycaemic targets and ultimately require insulin. In addition, a growing number of insulin-treated patients require high doses of insulin. Opt2mise study demonstrated the efficacy of insulin pump therapy in long standing poorly controlled type 2 diabetes on multiple daily injections.1 In Malaysia, approximately 30% of insulin users were on premixed insulin regimen due to the cost and presumed convenience.2 Those patients who fail premixed insulin are usually intensified with multiple daily injections of insulin. Aim The purpose of this study was to evaluate the comparative efficacy of Continuous Subcutaneous Insulin Infusion(CSII) therapy versus multiple daily injections(MDI) in insulin resistant type 2 diabetes patients who were sub-optimally controlled with premixed insulin regimen. Methodology This was an ongoing 12 - months randomized, parallel-group, open-label trial with a single-arm cross-over in the continuation phase in subjects with Type 2 diabetes inadequately controlled with premixed insulin therapy. Participants were recruited from the Endocrine clinics and General Medical outpatient clinics, Putrajaya Hospital since January 2016. The participants were insulin-taking patients who were sub optimally controlled on premixed insulin regimen twice or three times daily(defined as having an HbA1c > 8%). The participants entered an 8-week dose optimisation run-in period and at the end of the run-in period, insulin dosage was at minimum 1.0U/kg/day. This was followed by randomisation into two interventional arms which were CSII and MDI. After 6 months, the participants on the MDI arm crossed over to CSII for another 6 months. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was change in mean glycated haemoglobin between baseline and 6 months for the intention-to-treat population. The secondary endpoints were safety, metabolic profiles, total insulin dosage, within group difference in HbA1c from 6 months to 12 months and the number of self-monitoring blood glucose(SMBG)/day. This study was registered with ClinicalTrials.gov, number NCT03112538 and NMRR-15-1449-26854. Results These were the results for the first 6 months. 56 patients entered the run-in period and 54 patients were randomised(29 to CSII and 25 to MDI). 25 in CSII group and 25 in MDI group completed 6 months of follow-up. The baseline demographic data were similar in both groups with the median age 52.0(IQR 14.50) and 56.0(IQR 16.50) in CSII and MDI group, respectively with mean duration of diabetes 13.8 years. Mean glycated haemoglobin at baseline was 10% in both groups. At 6 months, mean glycated haemoglobin had decreased by 2·1%(SD 1.17) in the CSII group and 1.2%(SD 1.74) in the MDI group, resulting in a between-group treatment diﬀerence of –0·92%(95% CI -1.766, -0.816 p=0.032). After 6 months, the median total daily insulin(TDD)/kg/day was 1.0(IQR 0.37) with CSII versus 1.2(IQR 0.35) for MDI(p=0.018). The total daily insulin dose was 91.3(SD 31.38) vs 110.9(SD 35.42) (95% CI -38.59,-0.53 p=0.044) between the 2 groups. 16% vs 4% achieved HbA1c<7%, 36% vs 4% achieved HbA1c<7.5% and 56% vs 20% achieved HbA1c<8% in the CSII group(p=0.349, p=0.005 and p=0.009, respectively). No signiﬁcant diﬀerence in bodyweight change between the two groups (2.1 kg(SD 3·0) vs 2.9 kg(SD 3·6), p=0·26). The change in blood pressure, lipid profiles and the number of SMBG/day were also not significant between the 2 arms. The incidents of hypoglycaemia < 3.9mmol/L were 3.68 vs 7.36 events-patient year, < 3.0mmol were 0.4 vs 2.4 events-patient year and severe hypoglycaemia were 0 vs 0.64 events-patient year in CSII and MDI group, respectively. 1 ketoacidosis occurred in the MDI group. Discussion Improvements in HbA1c were achieved in both groups, but with greater improvement observed with pump therapy. The improvement in HbA1c was observed with significantly reduced insulin requirement and less hypoglycaemia events compared to MDI. This was the first study to demonstrate insulin intensification with insulin pump therapy after failure of premixed insulin. The potential explanations of the improvements in glycaemic control achieved with pump therapy include a more physiological method of delivery, improved absorption of smaller subcutaneous insulin depots with continuous insulin infusion, prevention of the hyperglycaemia of the dawn phenomenon, prevention of hypoglycaemia that becomes a barrier to insulin intensification and improved adherence to insulin dosing. In conclusion, insulin pump therapy is effective and a safe treatment option for insulin resistant type 2 DM patients who have been on intensified premixed insulin and remained far from achieving target glycaemic control.
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