Insulin pump treatment compared with multiple daily injections for treatment of type 2 diabetes (OpT2mise): a randomized open-label controlled trial Yves Reznik, Ohad Cohen, Ronnie Aronson, Ignacio Conget, Sarah Runzis, Javier Castaneda, Scott W Lee, for the OpT2mise Study Group Published online July R3 박소영 / Prof. 오승준

INTRODUCTION Many patients with advanced type 2 diabetes require treatment with insulin. →Addition of basal insulin →Multiple daily injection However, such intensified regimens →Do not meet glycated haemoglobin targets in about 30% patients →Be associated with increased risks of hypoglycaemia and weight gain These limitations of multiple daily injection treatment show the need for new treatments for this group of patients.

AIM To further assess the potential benefits of pump treatment for type 2 diabetes For patients with type 2 diabetes who had not responded to a basal-bolus regimen after active insulin titration. To compare the efficacy and safety of pump treatment and multiple daily injection treatment A randomized, controlled trial (OpT2mise)

METHODS Randomized, parallel-group study 36 hospitals, tertiary care centers, referal centers –8 in Canada, 23 in Europe and Israel, 2 in South Africa, and 3 in the USA December 2010 ~ February 2014 Enrolled patients (age 30–75 years) with investigator-diagnosed type 2 diabetes. Exclusion: Pregnancy, ≥2 hypoglycaemia-related seizures or comas within the past 6 months, or significant diabetic complications 2-month run-in period, 6-month randomized phase, 6-month continuation phase

To stop all other antidiabetes drugs other than metformin To regulary monitor blood glucose with a minimum of three measurements per day (excluded if they checked their glucose fewer than 2.5 times per day) On completing the run-in phase, – glycated hemoglobin % ( mmol/mol) – daily insulin requirements of units per kg (maximum 220 units per day) Randomly assigned (1:1) On completing the randomized phase, –Follow-up was continued for a further 6 months

Primary end points –The between-group difference in change in mean glyceted hemglobin from baseline to the end of the randomized phase Secondary end points –Changes from baseline to 6 months of continuous glucose monitoring data –Mean 24-h glucose concentrations –The area under the curve (AUC) for hypoglycemia and hyperglycemia –The time spent in hypoglycemia and hyperglycemia Safety endpoints –The number of severe hypoglycemic events –The number of ketoacidosis events

RESULTS Figure 1: Trial profile

Changes in glycated hemoglobin 8.6 % 7.9 % 9.0 % -0.7 %, (p<0.0001)

Cumulative distribution of glycated hemoglobin at 6 months 55% 28%

Changes in total daily insulin dose 122 units 97 units (p<0.0001)

Univariate assessment of baseline factors and decreases in glycated hemoglobin

Pump treatment Mutiple Daily injections DifferenceP value SD of glycemic values change (mmol/L)-0.2 (0.8) Mean basal daily insulin dose change (U)-5.6 (18.7)7.0 (29.2)-12.6< Lipid parameters HDL-cholesterol increase (%)8%-7%15% LDL-cholesterol increase (%)5%0%5% Triglyceride increase (%)-17%0%-17% Cholesterol increase (%)-2% 0% Weight gain (Kg)1.5 (3.5)1.1 (3.6)-0.4% Additional secondary endpoints in each treatment group

Pump- therapy Event Injection- therapy Events Injection or infusion site problem (sensor and infusion set) Bleeding31 Cellulitis7 Folliculitis2 Infection7 Inflammation3 Pain21 Site irritation / allergy61 Hyperglycemia5 Severe hypoglycemia1 Digestive disorders11 Pump- therapy Event Injection- therapy Events Hyperglycemia and/or ketosis Without acidosis 21 Digestive disorder1 Cardiac disorder Acute coronary syndrome1 Chest pain1 Coronary artery surgery1 Heart failure1 Eye disorders1 Infection2 Hypertension1 Device or study related adverse events reported by the subjects during the study phase Diabetes, device or study related serious adverse events reported by the subjects during the study phase

CONCLUSION Insulin pump treatment Significantly improved glycaemic control compared with multiple daily injection. Be considered a valuable therapeutic option for patients who are unable to reach glycated haemoglobin targets with multiple daily injection regimens.