Impact des nouvelles insulines dans la prise en charge du DT2

Transcription

1 Impact des nouvelles insulines dans la prise en charge du DT2 Pr. A Avignon CHU Montpellier, Nutrition Diabète Université Montpellier 1, UFR Médecine INSERM U1046, CNRS Antoine Avignon

2 Disclosures: Novo Nordisk, MSD, Eli lilly, Sanofi, AstraZeneca,

3 The consequences of hyperglycaemia Brain Heart Eyes Kidneys Pregnancy and birth Nervous system Circulation DCCT N Engl J Med 1993;329:977-86; Stratton et al. BMJ 2000;321:405 12

4 % of patients who progressed p<0.05; intensive vs. conventional treatment; DCCT, Diabetes Control and Complications Trial; EDIC, European Diploma in Intensive Care Medicine; T1D, type 1 diabetes; T2D, type 2 diabetes; UKPDS, UK Prospective Diabetes Study. 1. DCCT/EDIC Group. JAMA 2002;287:2563 9; 2. Martin et al. Diabetes Care 2006;29:340 4; 3. UKPDS Study Group. Lancet 1998;352:837 53; 4. Holman et al. N Engl J Med 2008;359: Intensive vs. conventional treatment in T1D and T2D DCCT/EDIC and UKPDS follow-up data T1D DCCT/EDIC microvascular complications 1,2 (4-years post-edic trial) *p=0.006 **p=0.002 ***p<0.001 ****p< Conventional Retinopathy Neuropathy Renal ****36 % Intensive Randomisation T2D UKPDS macrovascular complications 3,4 UKPDS original results: Intensive vs. conventional treatment 1997 (20 years) 10-years post-trial follow-up period (non-interventional) 2007 (30 years) *66% ***76 % **53% 12% 16% 9% 15% 5 0 ****62 % ***86% 25% 24% Any diabetes-related endpoint Microvascular disease Myocardial infarction Improvements in glycaemic control reduce the risk of complications

5 Glycaemic control recommendations ADA/EASD, AACE and IDF guidelines HbA 1c recommendations (ADA/EASD) FPG recommendations Age group T1D 1 T2D 2 Young (<18 years) <7.5% 7.0% Adult <7.0% 7.0% Older adults Healthy* Complex/intermediate Very complex/poor health <7.5% <8.0% <8.5% 7.0% Association ADA/EASD 2,3 AACE 4 IDF 5 FPG target <7.2 mmol/l <130 mg/dl <6.1 mmol/l <110 mg/dl <6.5 mmol/l <115 mg/dl *No comorbidities, long life expectancy Depending on disease duration, life expectancy, important comorbidities, patient attitudes and resource or support targets can be set more or less stringent AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes; FPG, fasting plasma glucose; IDF, International Diabetes Federation; T1D, type 1 diabetes; T2D, type 2 diabetes. 1. Chiang et al. Diabetes Care 2014;37: ; 2. Inzucchi et al. Diabetologia 2015;58:429 42; 3. ADA Guidelines Diabetes Care 2015;38:33 40; 4. Garber et al. Endocr Pract 2016;22;84 113; 5. IDF 2012 Global Guideline for Type 2 Diabetes. Diabetes.pdf

6 The worldwide challenge of glycaemic control HbA 1c in T1D and T2D T1D 1* T2D 2 4 Sweden: 8.7% 2 Sweden: 8.0% Netherlands: 7.5% Norway: 7.9% Denmark: 7.9% UK: % Ukraine: 7.4% France: 8.0% Greece: 7.6% USA: 7.5% Italy: 7.5% Poland: 9.0% 2 Russia: 7.7% 3 Canada: 7.9% 3 UK: 8.4% 3 Turkey: % 2,3 Portugal: 9.7% 2 Romania: 9.9% 2 USA: 8.0% 3 South Korea: 8.0% 3 Greece: 9.0% 2 China: 7.6% 3 India: 8.6% 3 Latin America: 8.5% 4 New Zealand: 8.3% *Data are median and in adults (25+ years) T1D, type 1 diabetes; T2D, type 2 diabetes 1. McKnight et al. Diabet Med 2015;32: ; 2. Oguz et al. Curr Med Res Opin 2013;29:911 20; 3. Polinski et al. BMC Endocr Disord 2015;15:46; 4. Mendivil et al. Curr Med Res Opin 2014;30:

7 Proportion of patients (%) Mean HFS II worry score Challenges of maintaining glycaemic control Surveys identifying challenges with rigid regimens and the fear of hypoglycaemia Complex and inflexible regimens 1 Fear of hypoglycaemia % 80% 60% 40% 20% 0% 27,6% Taking insulin at prescribed time/meals everyday 23,1% 81,4% Number of Wish insulin daily injections regimen would fit daily life changes 54,4% Hard to live normal life while managing diabetes All comparisons significant 27,5 20,1 12,3 6,2 Increasing severity of hypoglycaemia HFS, Hypoglycaemia Fear Survey; 2. Total patient sample, n= Peyrot et al. Diabet Med 2012;29:682 9; 2. Marrett et al. Diabetes 2008;57(Suppl. 1):A174

8 Patients modifying insulin dose Fear of hypoglycaemia conflicts with treatment success for both patients and clinicians Percentage of patients decreasing their insulin dose following a hypoglycaemic event I would treat my patients more aggressively if there was no concern about hypoglycaemia 100% T1D T2D Primary care physicians Diabetes specialists 80% 60% 40% 20% 74% 43% 79% 58% 72% 79% 0% Non-severe episodes Severe episodes Percentage Total patient sample, n=335 (T1D, n=202; T2D, n=133) GAPP (A global internet survey of patient and physician beliefs T1D, type 1 diabetes; T2D, type 2 diabetes regarding insulin therapy): n=1250 physicians Leiter et al. Can J Diabetes 2005;29: Peyrot et al. Diabet Med 2012;29:682 9

9 Hypoglycaemia incidence, events per patient-year Hypoglycaemia rates are higher than expected Results from the HAT study HAT study Non-interventional, global, 6-month retrospective and 1-month prospective study of patient self-reported hypoglycaemic events n=27,585 (T1D: 8,022; T2D: 19,563) ,1 4,9 0,9 Severe hypoglycaemia T1D, retrospective (n=8,022) T1D, prospective (n=7,108) T2D, retrospective (n=19,563) T2D, prospective (n=18,518) 2,5 Prospective data suggests higher than previously observed rates of hypoglycaemia in both T1D and T2D, in particular severe events HAT, Hypoglycaemia Assessment Tool; T1D, type 1 diabetes; T2D, type 2 diabetes Khunti et al. Diabetes Obes Metab 2016: 2016;18:907 15; Khunti et al. Poster presented at the 10th International Diabetes Federation-Western Pacific Region Congress, November 2014, Singapore

10 Need for innovation

11 Objectives of developing a new basal insulin Glycaemic control Once-daily administration Effectiveness (glucose-lowering effect) Flat time-action profile Low risk of hypoglycaemia Low variability Long duration of action Possibility of flexible dosing

12 Target profiles for new insulin analogues Mimicking physiological responses Action profile of today s modern insulins Targeted action profiles of future insulins For illustrative purposes only

13 Insulin degludec Rationally designed, beyond sequence modification Des(B30) LysB29(γ-Glu Nε-hexadecandioyl) human insulin A1 G I V E Q C s C T S s I C S L Y Q L E N Y C N A21 B1 F V N Q H L s s C G S H L V E A L Y L V s s C G E R G F F Y DesB30 T P K T DesB30 insulin Jonassen et al. Pharm Res 2012;29: HO O Hexadecandioyl Fatty diacid side chain O N H O O NH OH L-γ-Glu Glutamic acid spacer

14 Insulin degludec Mode of protraction [ Phenol; Zn 2+ ] Insulin degludec is administered with a pen device into the subcutaneous tissue Jonassen et al. Pharm Res 2012;29:

15 Insulin degludec Mode of protraction [ Phenol; Zn 2+ ] The stable dihexamers formed in solution in the pen are injected into the subcutaneous space fatty acid side-chains monomers Jonassen et al. Pharm Res 2012;29:

16 Insulin degludec Mode of protraction [ Phenol; Zn 2+ ] Jonassen et al. Pharm Res 2012;29:

17 Insulin degludec Mode of protraction [ Phenol; Zn 2+ ] After injection, the insulin degludec dihexamers adapt to an open conformation after phenol has rapidly diffused from the vehicle Jonassen et al. Pharm Res 2012;29:

18 Insulin degludec Mode of protraction [ Zn 2+ ] After the diffusion of phenol and conformation change, the dihexamers link together via single side-chain contacts. Long multihexamer chains assemble Jonassen et al. Pharm Res 2012;29:

19 Insulin degludec Mode of protraction [ Zn 2+ ] Zinc diffuses slowly causing Monomers are absorbed from individual hexamers to the depot into the circulation disassemble, releasing monomers Jonassen et al. Pharm Res 2012;29:

20 The pharmacokinetics and pharmacodynamics of insulin degludec

21 Insulin concentration (% of maximum) Half-life of IDeg is twice as long as that of IGlar U IDeg 0.8 U/kg IGlar U U/kg 10 * Time since injection (hours) IDeg IGlar U U/kg 0.6 U/kg 0.8 U/kg 0.4 U/kg 0.6 U/kg 0.8 U/kg Half-life (hours) Mean half-life *IGlar U100 was undectable after 48 hours. Results from 66 patients with T1D IDeg, insulin degludec; IGlar U100, insulin glargine U100; T1D, type 1 diabetes Heise et al. Diabetes 2011;60(Suppl. 1):LB11; Heise et al. Diabetologia 2011;54(Suppl. 1):S425; Heise et al. Expert Opin Drug Metab Toxicol 2015;11:

22 Serum IDeg concentration Proportion of Day 6 level (%) Serum IDeg concentration Proportion of Day 4 level (%) IDeg concentration reaches clinical steady state in 2 3 days T1D T2D Days since first dose Days since first dose T1D trial, n=66, 0.4, 0.6 or 0.8 U/kg; T2D trial, n=49, 0.4, 0.6 or 0.8 U/kg Estimated ratios and 95% CI CI, confidence interval; IDeg, insulin degludec; T1D, type 1 diabetes; T2D, type 2 diabetes Heise et al. Diabetes 2012;61(Suppl. 1):A259

23 Reaching steady state with IDeg without stacking Injected insulin Units added each day Insulin in s.c. depot Units remaining from prior injections Maximum units present in 24 h Insulin in circulation (t 1/2 ~24 h) interval Units absorbed into circulation Day 1 10 U 10 U 50% 5 U Day 50% U 5 U 15 U 7.5 U Day 50% U 7.5 U U ~9 U Day 50% U ~9 U ~10 U 19 U Day 50% U 10 U 20 U IDeg, insulin degludec; s.c., subcutaneous Figure adapted from Heise and Meneghini Endocr Pract 2014;20:75 83 ~10 U 10 U Elimination of any insulin follows first order kinetics. Therefore there is no stacking

24 GIR (mg/kg/min) GIR (mg/kg/min) Flat time-action profile in T1D and T2D at steady state 6 T1D at steady state 1 5 T2D at steady state U/kg 0.6 U/kg 0.4 U/kg Time (hours) IDeg Dose level AUC GIR,0 12h AUC GIR,12-24h 0.4 U/kg 51% 49% Time since injection (hours) 1. IDeg, n=66, 0.4 U/kg; 2. Randomised, 2-period, 12-day trial; n=49; Variability was assessed at steady state by clamps on days 6 and 12 AUC, area under the curve; GIR, glucose infusion rate; IDeg, insulin degludec; T1D, type 1 diabetes; T2D, type 2 diabetes 1. Heise et al. Expert Opin Drug Metab Toxicol 2015;11: ; 2. Heise et al. Diabetes Obes Metab 2012;14:944 50

25 Day-to-day variability in AUC GIR (CV%) Lower day-to-day variability in glucose-lowering effect for IDeg versus IGlar U100/U300 IDeg IDeg vs. IGlar U100** IDeg vs. IGlar U300* IGlar U300 IGlar U100 Time interval (hour) Time interval (hour) FAS AUC, area under the curve; CV, coefficient of variation; GIR, glucose infusion rate; IDeg, insulin degludec; IGlar U100, insulin glargine U100; IGlar U300, insulin glargine U300 *NN : Heise et al. Presented at Diabetes Technology Meeting, 16 th Annual Scientific Sessions, November 2016, Bethesda, MD, USA **NN : Heise et al. Diabetes Obes Metab 2012;14:859-64

26 Proportion of AUC GIR (%) Proportion of AUC GIR (%) Glucose-lowering effect is more consistent with IDeg than IGlar U IDeg 0.4 U/kg IGlar U U/kg Time intervals (hours) Time intervals (hours) Proportion of effect in 6-hour time intervals across one dosing interval (%) Patients with T1D (n=66) AUC, area under the curve; GIR, glucose infusion rate; IDeg, insulin degludec; IGlar U100, insulin glargine U100; T1D, type 1 diabetes Heise et al. Expert Opin Drug Metab Toxicol 2015;11:

27 Flexible administration of IDeg was tested in both T1D and T2D Two phase 3a clinical trials (6 and 12 months) 12am MON TUE WED THUR FRI SAT SUN 2am 4am Morning Morning Morning 6am 8am 10am 12pm 2pm 4pm 6pm 8pm Evening Evening Evening Evening 40h 8h 40h 8h 40h 24h 10pm IDeg, insulin degludec; T1D, type 1 diabetes; T2D, type 2 diabetes Meneghini et al. Diabetes Care 2013;36:858 64; Mathieu et al. J Clin Endocrinol Metab 2013;98:

28 Confirmed hypoglycaemia (cumulative events per patient) HbA 1c (%) Flexibility can benefit patients who find it challenging to inject at the same time each day 1,2 9,0 8,5 8,0 7,5 7,0 6,5 6,0 5,5 5,0 0.0 IDeg Flexible OD IDeg Fixed OD IGlar U100 OD HbA 1c Time (weeks) IDeg Flexible vs IGlar U100 Treatment difference: non-inferior IDeg Flexible vs IDeg Fixed Treatment difference: NS HbA 1c (mmol/mol) Flexibility in the timing of insulin administration can benefit patients who find it challenging to always inject insulin at the same time each day. 2 2,0 1,8 1,6 1,4 1,2 1,0 0,8 0,6 0,4 0,2 0,0 Confirmed hypoglycaemia Time (weeks) NS In particular, this could include individuals who travel regularly... Shift workers may also greatly benefit from the freedom to change their dosing schedule 1 IDeg, insulin degludec; IGlar U100, insulin glargine U100; NS, not significant; OD, once daily 1. Aye & Atkin. Drug, Healthcare and Patient Safety 2014;6:55 67; 2. Meneghini et al. Expert Rev Endocrinol Metab 2012;7:9 14; 3. Meneghini et al. Diabetes Care 2013;36:858 64

29 Insuline Degludec delivers significant reductions in severe hypoglycaemia vs IGlar U Insuline Degludec significantly reduces severe hypoglycaemia when compared with IGlar U100: 1-4 Reduction in severe hypoglycaemic events Estimated rate ratio [95% CI] Meta-analysis of patients with T2DM BOT (insulin naïve) 1 SWITCH 1 patients with T1DM with 1 risk factor for hypoglycaemia 2 SWITCH 2 patients with T2DM with 1 risk factor for hypoglycaemia 3 DEVOTE patients with T2DM and high CV risk [all severe] 4 86% * 0.14 [ ] FULL TREATMENT PERIOD 26% * 0.74 [0.61; 0.91] FULL TREATMENT PERIOD 51% * 0.49 [0.26; % * 0.60 [0.48; 0.76] *p < 0.05; # p= NS MAINTENANCE PERIOD 35% * 0.65 [0.48; 0.89] MAINTENANCE PERIOD 46% # 0.54 [0.21; 1.42] A significant reduction in severe hypoglycaemia not observed in T2DM B/B; Maintenance was the predefined period of analysis; Combined treatment period 1 and 2; B/B, basal bolus therapy; BOT, basal oral therapy; CI, confidence interval; CV, cardiovascular; NS, non-significant Reference: 1. Ratner et al. Diabetes Obes Metab. 2013;15: Lane et al. 87-LB. Presented at ADA June 2016, New Orleans. 3. Wysham et al. 90-LB. Presented at the ADA 76 th Annual Scientific Sessions, June 2016, New Orleans. 4. Marso et al. June 12, NEJM. DOI: /NEJMoa

30 Stable IDeg dihexamers can be co-formulated with insulin aspart IDeg with insulin aspart (IDegAsp) IDeg, insulin degludec

31 Absorbance units IDeg and IAsp exist separately in solution IDeg:IAsp IDeg dihexamer IAsp hexamer Minutes Size-exclusion chromatography of IDegAsp in conditions simulating the pharmaceutical formulation IAsp, insulin aspart; IDeg, insulin degludec Havelund et al. Pharm Res 2015;32:2250 8

32 Challenges with co-formulating IDet or IGlar U100 with rapid-acting analogues Insulin glargine IGlar U100 is soluble at ph 4 Rapid-acting analogue soluble at ph 7.4 ph IGlar U100 is soluble at ph 4 and designed to microprecipitate at neutral ph (7.4) in subcutaneous tissue, whereas commercially available rapid-acting analogues are soluble at ph Insulin detemir IDet Mixed hexamers IAsp When IDet is co-formulated with commercially available rapid-acting analogues under standard conditions, mixed hexamers form with unsuitable PK/PD profiles 2 IAsp, insulin aspart; IDet, insulin detemir; IGlar U100, insulin glargine U100; PD, pharmacodynamic; PK, pharmacokinetic 1. Lantus US Prescribing Information. Sanofi April 2010; 2. Jonassen et al. Pharm Res 2012;29:

33 IDegAsp is a unique combination of two soluble insulin analogues in one pen: 70% IDeg and 30% IAsp 1. Heller S, et al. Diabetes Metab Res Rev. 2012;28(1): Heise T, et al. Diabetes Care. 2011;34(3): Jonassen I, et al. Pharm Res. 2012;29(8):

34 BID OD IDegAsp phase 3 clinical trial programme overview Type 1 diabetes Insulin-naïve Phase 3a type 2 diabetes Insulin-experienced Phase 3b type 2 diabetes T1 Basal-bolus, n=548 INTENSIFY PREMIX I Intensify from premix, n=447 T1 paediatric Basal bolus, n=362 SIMPLE vs STEP-WISE Prior BOT, n=272 Simple vs. step-wise INTENSIFY ALL Intensify any insulin, n=424 START I Insulin-naïve, n=530 TWICE-DAILY vs BB Prior BOT, n=274 SIMPLE USE Basal start, n=276 Simple vs. step-wise INTENSIFY BASAL BOT, n=465 JAPAN Insulin-naïve, n=296 START TWICE DAILY Insulin start, n=394 INTENSIFY BID Intensify from IDegAsp, n=40 RAMADAN Insulin experienced, fasting, n=263 Comparators vs. insulin detemir vs. BIAsp 30 vs. IGlar U100 vs. IDeg + IAsp with meals vs. IDegAsp* *Simple vs. step-wise titration algorithm; BB, basal bolus; BIAsp 30, biphasic insulin aspart 30; BID, twice daily; BOT, basal-oral therapy; IAsp, insulin aspart; IDegAsp, insulin degludec/insulin aspart; IDeg, insulin degludec; IGlar U100, insulin glargine U100

35 Standards of Medical Care in Diabetes 2017 Considérer d emblée un schéma multi-injections si le patient est franchement déséquilibré * *Si la glycémie > 3g/l ou si l HbA1c > 10%. ADA. Diabetes Care 2017;40:S1 135

36 Insulin-experienced T2D BID: study design BOOST TWICE-DAILY vs BASAL-BOLUS Patients with type 2 diabetes (n=274) Inclusion criteria Type 2 diabetes 26 weeks Currently treated with basal insulin (IDet, IGlar U100, NPH) ± OADs for 12 weeks HbA 1c % BMI 40 kg/m 2 Age 18 years 0 IDegAsp BID ± OADs (n=138) Open-label IDeg OD + IAsp (2 4 injections/day) ± OADs (n=136) Primary endpoint Change from baseline in HbA1c after 26 weeks of treatment. Key secondary endpoints FPG 8-point SMPG profiles Insulin dose Number of daily insulin injections Body weight AEs Rate of severe, confirmed and nocturnal confirmed hypoglycaemia. 26 weeks Pre-trial OADs included metformin, DPP-4 inhibitor, sulphonylurea/glinides or α-glucosidase inhibitor. Basal insulin and sulphonylurea/glinides (if administered) were discontinued at randomisation. 64% of patients had been previously treated with IGlar U100 BID, twice daily; BMI, body mass index; IAsp, insulin aspart; IDeg, insulin degludec; IDegAsp, insulin degludec/insulin aspart; IDet, insulin detemir; IGlar U100, insulin glargine U100; NPH, neutral protamine Hagedorn; OAD, oral antidiabetic drug; OD, once daily; T2D, type 2 diabetes Rodbard et al. Diab Obes Metab 2016;18:274-80

37 TWICE DAILY vs BASAL-BOLUS Pays participants Norway Austria France United States Algeria Rodbard HW et al. Diabetes Obes Metab 2015; doi: /dom [Epub ahead of print]

38 Baseline Characteristic [IDegAsp] [IDeg+IAsp] N Female/male, % 47.1/ /63.2 Race: White/Black/Asian/Other, % 92.0/6.5/0.0/ /5.1/2.2/0.0 Ethnicity: Hispanic or Latin American, % Age, years 59.6 (8.3) 59.6 (9.2) Weight, kg 91.2 (17.7) 93.3 (15.2) BMI, kg/m (4.7) 32.0 (4.5) Duration of diabetes, years 13.5 (7.2) 11.7 (7.2) HbA 1c, % 8.3 (0.9) 8.3 (0.7) HbA 1c, mmol/mol* FPG, mmol/l FPG, mg/dl 9.0 (3.0) (54.0) *Calculated, not measured. FAS; Values are mean (SD) unless otherwise stated. BMI, body mass index; FAS, full analysis set; FPG, fasting plasma glucose; HbA 1c, glycated haemoglobin; IAsp, insulin aspart; IDeg, insulin degludec; IDegAsp, insulin degludec/insulin aspart; OAD, oral antidiabetic drug; SD, standard deviation Rodbard HW et al. Diabetes Obes Metab 2015; doi: /dom [Epub ahead of print] 8.8 (2.9) (52.7) With OAD at screening, n

39 Confirmed hypoglycaemia (cumulative events per patient) Nocturnal confirmed hypoglycaemia (cumulative events per patient) HbA 1c (%) FPG (mmol/l) Insulin-experienced T2D BID: results BOOST TWICE-DAILY vs BASAL-BOLUS 9,0 8,5 8,0 7,5 7,0 HbA 1c Treatment difference: non-inferiority not confirmed ETD: 0.18%-points [-0.04; 0.41] NS 6, , HbA 1c (mmol/mol) a 10,0 9,0 8,0 7,0 6,0 5,0 FPG IDegAsp BID (n=138) IDeg OD + IAsp (n=136) Treatment difference: ETD: mmol/l [-0.97; 0.34] NS 4, FPG (mg/dl) Time (weeks) Time (weeks) 8 Confirmed hypoglycaemia 0,8 Nocturnal confirmed hypoglycaemia 7 0,7 6 0,6 5 0, % lower rate with IDegAsp ERR: 0.81 [0.61; 1.07] NS 0,4 0,3 0,2 0,1 20% lower rate with IDegAsp ERR: 0.80 [0.50; 1.29] NS , Time (weeks) Time (weeks) a Calculated, not measured. BID, twice daily; ETD, estimated treatment difference; ERR, estimated rate ratio; FPG, fasting plasma glucose; IAsp, insulin aspart; IDeg, insulin degludec; IDegAsp, insulin degludec/insulin aspart; NS, not significant; OD, once daily; T2D, type 2 diabetes Rodbard et al. Diab Obes Metab 2016;18:274-80

40 SMPG (mmol/l) Insulin-experienced T2D BID: 8-point SMPG profile BOOST TWICE-DAILY vs BASAL-BOLUS Week 0 Week 26 IDegAsp BID (n=138) IDeg OD + IAsp (n=136) * SMPG (mg/dl) Pre BF 90 mins after BF Pre lunch 90 mins after lunch Pre dinner 90 mins after dinner Bedtime 0 Pre BF *p<0.05 FAS, full analysis set; LOCF, last observation carried forward. Comparisons: Estimates adjusted for multiple covariates BF, breakfast; BID, twice daily; IAsp, insulin aspart; IDeg, insulin degludec; IDegAsp, insulin degludec/insulin aspart; OD, once daily; SMPG, self-measured plasma glucose; T2D, type 2 diabetes Rodbard et al. Diab Obes Metab 2016;18:274-80

41 Total insulin dose (U) Insulin-experienced T2D BID: insulin dose BOOST TWICE-DAILY vs BASAL-BOLUS IDegAsp BID (n=136) IDeg OD + IAsp (n=135) ERR: 0.88 [95% CI 0.78; 1.00], p< Time (weeks) 1.34 (131) 1.11 (107) EOT U/kg (U) IDegAsp BID vs IDeg OD + IAsp Mean ratio (U/kg) Basal insulin dose 1.05 Bolus insulin dose 0.55 Total insulin dose 0.83 SAS, safety analysis set; LOCF, last observation carried forward. Comparisons: Estimates adjusted for multiple covariates BID, twice daily; ERR, estimated rate ratio; IAsp, insulin aspart; IDeg, insulin degludec; IDegAsp, insulin degludec/insulin aspart; OD, once daily; T2D, type 2 diabetes Rodbard et al. Diab Obes Metab 2016;18:274-80; Cooper et al. Diabetologia 2014;57(Suppl. 1):S69

42 Change in weight from baseline (kg) TWICE DAILY vs BASAL-BOLUS Poids 5 4 Treatment difference: 1.04 kg, p< IDegAsp BID (n=136) IDeg OD + IAsp (2 4) (n=135) SAS; LOCF Comparisons: Estimates adjusted for multiple covariates LOCF, last observation carried forward; SAS, safety analysis set Cooper J et al. EASD Oral presentation (abstract 147)

43 Conclusion les deux stratégies d'intensification à partir d une insuline basale avec IDegAsp, en co-formulation [IDegAsp] 2 fois/jour, ou sous forme de Basal-bolus [IDeg + IAsp], ont été aussi efficaces que sures de façon similaire et ont amélioré le contrôle glycémique Bien que la non-infériorité n'ait pas été confirmée pour l HbA 1C, il n'y avait pas de différence significative entre les groupes qui pourraient affecter l'utilité clinique Le schéma d'idegasp BID peut apporter une solution au besoin d'intensification de l'insuline chez de nombreux patients atteints de DT2 dont l'adhésion à des schémas plus complexes et exigeants est difficile BID, twice-daily; HbA 1c, glycated haemoglobin; IAsp, insulin aspart; IDeg, insulin degludec; IDegAsp, insulin degludec/insulin aspart; T2DM, type 2 diabetes mellitus Rodbard HW et al. Diabetes Obes Metab 2015; doi: /dom [Epub ahead of print]

44 Antoine Renseignements : fabienne.dubreuil@umontpellier.fr