Quando l insulina basale non basta più: differenti e nuove strategie terapeutiche

Size: px

Start display at page:

Download "Quando l insulina basale non basta più: differenti e nuove strategie terapeutiche"

Anabel Logan
5 years ago
Views:

1 Quando l insulina basale non basta più: differenti e nuove strategie terapeutiche Giorgio Sesti Università Magna Graecia di Catanzaro

2 Potenziali conflitti di interesse Il Prof Giorgio Sesti dichiara di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche: Novo Nordisk, MSD, Boehringer Ingelheim, Eli Lilly, Janssen, Astra Zeneca, Theras Lifetech e Novartis per attività di Relatore ad eventi. Servier, Intarcia, Novo Nordisk, Janssen, Boehringer Ingelheim, Eli Lilly, Astra Zeneca, MSD Italy, Sanofi, Pfizer e Abbott per attività di Consulenza.

3 Ringrazio caldamente la SID per lo straordinario contributo alla mia formazione culturale, scientifica e clinica.

4 Antihyperglycemic therapy in type 2 diabetes: general recommendations Standards of Medical Care in Diabetes 2017, Diabetes Care, 40:S1-S135, 2017

5 Antihyperglycemic therapy in type 2 diabetes: general recommendations Standards of Medical Care in Diabetes 2017, Diabetes Care, 40:S1-S135, 2017

7 What next???? Basal insulin Once-daily Diet and exercise Oral monoor combination therapy HbA1c uncontrolled HbA1c uncontrolled, FBG on target, PPBG >160 mg/dl Time Modified from Raccah d et al. Diabetes Metab Res Rev 23: , 2007

8 Basal Plus Diet and exercise Oral monoor combination therapy HbA1c uncontrolled Basal insulin Once-daily Basal Plus One prandial for largest glucose? excurtion 2 prandial for? largest glucose excurtions HbA1c uncontrolled, FBG on target, PPBG >160 mg/dl Time Modified from Raccah d et al. Diabetes Metab Res Rev 23: , 2007

9 Basal Plus: One prandial for largest glucose excurtion OPAL: blood glucose profile of patients with type 2 diabete inadequately controlled with OADs+Glargine Lankisch M et al. Diabetes Obes Metab 10: , 2008

10 Basal Plus: One prandial for largest glucose excurtion OPAL: blood glucose profile of patients with type 2 diabete inadequately controlled with OADs+Glargine Lankisch M et al. Diabetes Obes Metab 10: , 2008

11 Basal Plus: One prandial for largest glucose excurtion OPAL: blood glucose profile of patients with type 2 diabete inadequately controlled with OADs+Glargine Lankisch M et al. Diabetes Obes Metab 10: , 2008

12 HbA1c (%) Basal Plus: One prandial for largest glucose excurtion OPAL: Change in HbA1c after 24 weeks NS difference between breakfast and main meal groups 7,5 7,35 P< ,29 P< ,0 7,03 6,94 6,5 6,0 Breakfast Group Main meal Group Lankisch M et al. Diabetes Obes Metab 10: , 2008

Basal Bolus Basal Plus 3 prandial Diet and exercise Oral monoor combination therapy HbA1c uncontrolled Basal insulin Once-daily Basal Plus One prandial for largest glucose?

13 Basal Bolus Basal Plus 3 prandial Diet and exercise Oral monoor combination therapy HbA1c uncontrolled Basal insulin Once-daily Basal Plus One prandial for largest glucose? excurtion 2 prandial for? largest glucose excurtions HbA1c uncontrolled, FBG on target, PPBG >160 mg/dl Time Modified from Raccah d et al. Diabetes Metab Res Rev 23: , 2007

Patient-cited issues with insulin treatment Insulin-treated diabetes controls their life 66,7% Insulin regimen can be restrictive 59,8% Hard to live normal life while managing diabetes 54,4% Wish

14 Patient-cited issues with insulin treatment Insulin-treated diabetes controls their life 66,7% Insulin regimen can be restrictive 59,8% Hard to live normal life while managing diabetes 54,4% Wish insulin regimen would fit daily life changes 81,4% Number of daily injections 23,1% Taking insulin at prescribed time/meals everyday 27,6% GAPP A global internet survey of patient and physician beliefs regarding insulin therapy n=1530 insulin treated patients with diabetes 0% 20% 40% 60% 80% 100% Percentage Peyrot et al. Diabetic Med 29:682 9, 2012

16 Consequences of delayed intervention in patients with T2DM Paul, SK et al.cardiovasc. Diabetol. 14: 100, 2015

Rationale for combination of SGTL2 inhibitors with insulin SGTL2 inhibitors Insulin-independent glucose reduction Reduction in FPG and PPG Low risk of hypoglycaemia Weight loss Blood pressure

18 Rationale for combination of SGTL2 inhibitors with insulin SGTL2 inhibitors Insulin-independent glucose reduction Reduction in FPG and PPG Low risk of hypoglycaemia Weight loss Blood pressure lowering CV benefit Complementary actions Additive effects Insulin therapy Increased doses to ensure glycemic control Chronic hyperinsulinemia (atherogenesis?) Increased risk of hypoglycaemia Weight gain Fluid retention

78-week study with empagliflozin as add-on to long-acting insulin HbA 1c change from baseline over time to Week 78-0.43 (95% CI: -0.67, -0.19) p = 0.0005-0.71 (95% CI: -0.96, -0.46) p < 0.

19 78-week study with empagliflozin as add-on to long-acting insulin HbA 1c change from baseline over time to Week (95% CI: -0.67, -0.19) p = (95% CI: -0.96, -0.46) p < N/Week BL Placebo mg QD mg QD Rosenstock J, et al. Diabetes Obes Metab 17: , 2015

78-week study with empagliflozin as add-on to long-acting insulin Change from baseline in body weight over time Rosenstock J, et al. Diabetes Obes Metab 17: 936 948, 2015-3.63 (95% CI: -5.81, -1.

20 78-week study with empagliflozin as add-on to long-acting insulin Change from baseline in body weight over time Rosenstock J, et al. Diabetes Obes Metab 17: , (95% CI: -5.81, -1.45) p = (95% CI: -5.39, -0.05) p = N/Week BL Placebo mg QD mg QD

78-week study with empagliflozin as add-on to long-acting insulin Change in basal insulin dose over time -6.04 (95% CI: -10.69, -1.39) p = 0.0112-5.96 (95% CI: -10.79, -1.13) p = 0.

21 78-week study with empagliflozin as add-on to long-acting insulin Change in basal insulin dose over time (95% CI: , -1.39) p = (95% CI: , -1.13) p = N/Week BL mg QD mg QD BL, baseline; CI, confidence interval; IU, insulin dose; QD, once daily; SE, standard error. MMRM. FAS (OC-78). Rosenstock J, et al. Diabetes Obes Metab 17: , 2015

22 78-week study with empagliflozin as add-on to long-acting insulin Change in SBP at Week 78 Empagliflozin -4.0 p < NS Mean baseline Rosenstock J, et al. Diabetes Obes Metab 17: , 2015

23 78-week study with empagliflozin as add-on to long-acting insulin Frequency of patients with hypoglycaemia* at Week 78 *Plasma glucose 3.9 mmol/l ( 70 mg/dl) and/or requiring assistance. Rosenstock J, et al. Diabetes Obes Metab 17: , 2015

24 Dapagliflozin vs. palcebo as add-on to insulin: Mean change in HbA1c from baseline at week 104 Wilding JPH et al. Diabetes Obes Metab 16: , 2014 Mean daily insulin dose was 77.1 U, with 17% using only basal insulin and 83% using bolus regimen

25 Dapagliflozin vs. palcebo as add-on to insulin: Mean change in total body weight from baseline at week 104 Wilding JPH et al. Diabetes Obes Metab 16: , 2014 ST= short term LT= long term

26 Dapagliflozin vs. palcebo as add-on to insulin: Mean change in mean daily insulin dose from baseline at week 104 Wilding JPH et al. Diabetes Obes Metab 16: , 2014

Canagliflozin add-on to insulin (>20 IU/day) substudy from CANVAS: HbA1c changes over 52 weeks Baseline (%) 8.2 8.3 8.3 LS mean Difference change vs PBO 0.2 0 0.03% 0.2 0.4 0.6 0.8 0.55% 0.

27 Canagliflozin add-on to insulin (>20 IU/day) substudy from CANVAS: HbA1c changes over 52 weeks Baseline (%) LS mean Difference change vs PBO % % 0.69% 0.58% (95%CI 0.68, 0.48) 0.81% (95%CI 0.83, 0.63) Time (weeks) PBO = 690 subjects 100 CANA= 692 subjects 300 CANA= 690 subjects Neal B. et al. Diabetes Care 38: , 2015

1 kg Difference vs PBO 1,0 1,5 2.4 kg (95%CI: 2.9, 1.

28 Canagliflozin add-on to insulin (>20 IU/day) substudy from CANVAS: body weight changes over 52 weeks Baseline (kg) 0,5 0 0, LS mean % change 0.1 kg Difference vs PBO 1,0 1,5 2.4 kg (95%CI: 2.9, 1.9) 2,0 2,5 3,0 3, Time (weeks) 2.3 kg 3.0 kg 3.0 kg (95%CI: 3.5, 2.6) Neal B. et al. Diabetes Care 38: , 2015

Canagliflozin add-on to insulin (>20 IU/day) substudy from CANVAS: Blood pressure changes over 52 weeks Systolic BP Diastolic BP Baseline (mmhg) 138.2 137.0 138.2 76.

29 Canagliflozin add-on to insulin (>20 IU/day) substudy from CANVAS: Blood pressure changes over 52 weeks Systolic BP Diastolic BP Baseline (mmhg) mmhg (95%CI : 4.8; 1.7) 6.2 mmhg (IC 95% : 7.7; 4.6) 1.2 mmhg (95%CI : 2.1; 0.3) 2.3 mmhg (95%CI : 3.2; 1.4) Neal B. et al. Diabetes Care 38: , 2015

Combination of basal insulin with a DPP-4 inhibitor has a scientific logic Complementary actions Basal insulin analogs Simple to initiate Control nocturnal and FPG Inhibition of HGP Lower

31 Combination of basal insulin with a DPP-4 inhibitor has a scientific logic Complementary actions Basal insulin analogs Simple to initiate Control nocturnal and FPG Inhibition of HGP Lower hypoglycaemia risk vs NPH Modest weight increase (1 3 kg) Achieve A1C targets in ~50 60% DPP-4I Simple to initiate Effect on FPG and PPG Reduction in glucagon release No increase in hypoglycaemia Weight neutral CV safety Additive effects

32 The efficacy and safety of combined DPP-4 inhibitor and insulin treatment in patients with type 2 diabetes: a meta-analysis Chen C et al. Int J Clin Exp Pathol 8(11): , 2015

33 The efficacy and safety of combined DPP-4 inhibitor and insulin treatment in patients with type 2 diabetes: a meta-analysis Chen C et al. Int J Clin Exp Pathol 8(11): , 2015

34 The efficacy and safety of combined DPP-4 inhibitor and insulin treatment in patients with type 2 diabetes: a meta-analysis Chen C et al. Int J Clin Exp Pathol 8(11): , 2015

35 The efficacy and safety of combined DPP-4 inhibitor and insulin treatment in patients with type 2 diabetes: a meta-analysis Chen C et al. Int J Clin Exp Pathol 8(11): , 2015

36 Linagliptin as add-on to insulin therapy: effects on insulin titration Mean (SE) insulin dose change (IU), FAS (OR) Stable insulin dose Free insulin dose Placebo Linagliptin Treatment weeks Placebo, n Linagliptin, n Baseline doses: Linagliptin group 41.5 IU; Placebo group, 40.1 IU Yki-Järvinen H et al. Diabetes Care 36: , 2013

Rationale for combining GLP-1RA and basal insulin analogs Basal insulin analogs Control nocturnal and FPG Inhibition of HGP Modest weight increase (1 3 kg) Achieve A1C targets in ~50 60%

38 Rationale for combining GLP-1RA and basal insulin analogs Basal insulin analogs Control nocturnal and FPG Inhibition of HGP Modest weight increase (1 3 kg) Achieve A1C targets in ~50 60% Complementary actions Additive effects GLP-1R agonists Pronounced FPG and PPG control Reduction in glucagon release Increase portal insulin delivery No increase in hypoglycaemia Weight lowering or neutral Achieve A1C targets in ~40 60% CV benefit (Liraglutide)

Combined use of a GLP-1RA and basal insulin Trials where basal insulin started first Study name Background therapy Added at randomisation Buse et al, 2011 ± Metformin ± pioglitazone Insulin glargine

placebo) LIRA-ADD2BASAL ± Metformin Insulin glargine or detemir Liraglutide 1.8 mg (vs. placebo) BEGIN: LIRAGLUTIDE ADD-ON ± Metformin Insulin degludec Liraglutide 1.

39 Combined use of a GLP-1RA and basal insulin Trials where basal insulin started first Study name Background therapy Added at randomisation Buse et al, 2011 ± Metformin ± pioglitazone Insulin glargine Exenatide BID (Vs. placebo) GetGoal-Duo-1 ± Metformin Insulin glargine Lixisenatide (vs. placebo) GetGoal-L ± Metformin Basal insulin Lixisenatide (vs. placebo) LIRA-ADD2BASAL ± Metformin Insulin glargine or detemir Liraglutide 1.8 mg (vs. placebo) BEGIN: LIRAGLUTIDE ADD-ON ± Metformin Insulin degludec Liraglutide 1.8 mg or Insulin aspart OD The FLAT-SUGAR Trial Metformin Insulin glargine Exenatide BID or Insulin basal-bolus BID, twice daily; OD, once daily; OW, once weekly; TID, three-times daily Ahmann et al. Diabetes Obes Metab 2015; Riddle et al. Diabetes Care 2013;36: ; Riddle et al. Diabetes Care 2013;36: ; Buse et al. Ann Intern Med 2011;154:103 12; Mathieu et al. Diabetes Obes Metab 2014;16:636 44; Rosenstock et al. Diabetes Care 2014;37: ; The FLAT-SUGAR Trial Investigators Diabetes Care 2016;39:

40 Change in HbA 1c (%) Addition of GLP-1RA to basal insulin Change in HbA 1c Vs. placebo Vs. bolus insulin dose(s) Buse et al. 30 wk GetGoal-L 24 wk GetGoal-Duo 24 wk LIRA-ADD2BASAL 26 wk LIRA ADD-ON 26 wk The FLAT-SUGAR 26 wk Baseline HbA 1c (%): n=137 n= n=327 n= n=223 n= n=225 n= n= n= n= n= ,0-0, ,4-0, ,8-1,0 0.7** 0.7** 0.7* , ,4 1.3*** -1,6-1,8 1.7** GLP-1RAs: Exenatide BID Lixisenatide OD Liraglutide OD Comparators: Placebo Basal/bolus IAsp OD (largest meal) Treatment difference for GLP-1 vs. comparator: *p<0.005; **p<0.001; p=ns; ***p< NS, not significant Ahmann et al. Diabetes Obes Metab 2015; Riddle et al. Diabetes Care 2013;36: ; Riddle et al. Diabetes Care 2013;36: ; Buse et al. Ann Intern Med 2011;154:103 12; Mathieu et al. Diabetes Obes Metab 2014;16:636 44; Rosenstock et al. Diabetes Care 2014;37: ; The FLAT-SUGAR Trial Investigators Diabetes Care 2016;39:

41 Change in weight (kg) Addition of GLP-1RA to basal insulin Change in body weight Vs. placebo Vs. bolus insulin dose(s) Baseline weight (kg): Buse et al. 30 wk n=137 n= GetGoal-L 24 wk n=327 n= GetGoal-Duo 24 wk n= n= LIRA-ADD2BASAL 26 wk n= n= LIRA ADD-ON 26 wk n= n= The FLAT-SUGAR 26 wk n= n= ,0 1,0 0, ** ,0-2,0-3,0 1.8* 1.8*** *** -4,0 3.5*** -5,0-6,0 GLP-1RAs: 4.8* Exenatide BID Lixisenatide OD Liraglutide OD Albiglutide OW Comparators: Placebo Lispro TID IAsp OD (largest meal) Treatment difference for GLP-1 vs. comparator: *p<0.001; **p=0.0012; ***p< Ahmann et al. Diabetes Obes Metab 2015; Riddle et al. Diabetes Care 2013;36: ; Riddle et al. Diabetes Care 2013;36: ; Buse et al. Ann Intern Med 2011;154:103 12; Mathieu et al. Diabetes Obes Metab 2014;16:636 44; Rosenstock et al. Diabetes Care 2014;37: ; The FLAT-SUGAR Trial Investigators Diabetes Care 2016;39:

43 Lixisenatide plus basal insulin vs. insulin glulisine either as basal-plus or basal-bolus in T2DM: The GetGoal Duo-2 Trial. Change over time from baseline to week 26 in HbA1c RosenstockJ et a. Diabetes Care 39: , 2016

44 Lixisenatide plus basal insulin vs. insulin glulisine either as basal-plus or basal-bolus in T2DM: The GetGoal Duo-2 Trial. Change over time from baseline to week 26 in body weight RosenstockJ et a. Diabetes Care 39: , 2016

45 Lixisenatide plus basal insulin vs. insulin glulisine either as basal-plus or basal-bolus in T2DM: The GetGoal Duo-2 Trial. Patients achieving composite end points at week 26 RosenstockJ et a. Diabetes Care 39: , 2016

Visit 29 Week 2 0 26 27 Inclusion criteria Type 2 diabetes Metformin + IGlar (20 50 units) HbA 1c 7 10% Age 18 years BMI 40 kg/m 2 Randomised 1:1 Open

48 DUAL V Study design Subjects with type 2 diabetes (N=557) Screening Visit 1 Randomisation Visit 2 IDegLira + metformin (n=278) IGlar + metformin (n=279) End of trial Visit 28 IDegLira Starting dose: 16 dose steps Maximum dose: 50 dose steps IGlar Starting dose: Pre-trial dose Maximum dose: Follow-up None Visit 29 Week Inclusion criteria Type 2 diabetes Metformin + IGlar (20 50 units) HbA 1c 7 10% Age 18 years BMI 40 kg/m 2 Randomised 1:1 Open label BMI, body mass index; HbA 1c, glycosylated haemoglobin; IDegLira, insulin degludec/liraglutide; IGlar, insulin glargine Lingvay et al. JAMA 2016;315:

Change in HbA 1c, % DUAL V Trial: patients uncontrolled on insulin Key clinical findings Change in Weight, kg Hypoglycaemia Rate, events/patient-year HbA 1c Weight Confirmed

23 p<0.001 5.05 n = 278 n = 279 IDegLira IGlar U100 (no max.) EOT HbA 1c 6.6% 7.1% Severe hypoglycaemia in one IGlar U100 subject *Hypoglycemia was defined as severe or <3.1 mmol/l.

49 Change in HbA 1c, % DUAL V Trial: patients uncontrolled on insulin Key clinical findings Change in Weight, kg Hypoglycaemia Rate, events/patient-year HbA 1c Weight Confirmed Hypoglycaemia * 0,0-0,5-1,0-1,5-2,0 IDegLira 1.81 IGlar U100 (no max.) n = 278 n = 279 p< ,0 1,5 1,0 0,5 0,0-0,5-1,0-1,5-2,0 IDegLira IGlar U100 (no max.) 1.4 p< n = 278 n = p< n = 278 n = 279 IDegLira IGlar U100 (no max.) EOT HbA 1c 6.6% 7.1% Severe hypoglycaemia in one IGlar U100 subject *Hypoglycemia was defined as severe or <3.1 mmol/l. Severe: An episode requiring assistance from another person to actively administer carbohydrate, glucagon, or other resuscitative actions Lingvay I, et al. JAMA 315: , 2016

50 Dose, Units DUAL V Trial: Patients Uncontrolled on Insulin Daily Insulin Dose Over Time IDegLira (n=278) IGlar U100 (n=279) Difference: 25.5 U, P< U U Time, weeks IDegLira dose capped at 50 dose steps; there was no maximum dose for IGlar U100. Lingvay I, et al. JAMA 315: , 2016

51 Fixed Ratio Basal Insulin/GLP-1 RA Combinations iglarlixi Components Ratio Maximum dose Development studies Regulatory status Basal insulin glargine GLP-1 RA lixisenatide 2 U insulin glargine/1 µg lixisenatide 3 U insulin glargine/1 µg lixisenatide 40 U insulin glargine/20 µg lixisenatide 60 U insulin glargine/20 µg lixisenatide Phase 2: Proof of concept randomised trial [a] Phase 3: LixiLan-O [b] and LixiLan-L [c] LixiLan-G (upcoming) [d] Approved for use in the US Submitted for approval in EU a. Rosenstock J, et al. Diabetes Care. 2016;39: ; b. Rosenstock J, et al. Diabetes Care Aug 15. [Epub ahead of print]; c. Aroda VR, et al. Diabetes Care Sep 20. [Epub ahead of print]; d. Clinicaltrials.gov. NCT ;

52 A titratable fixed-ratio combination of insulin glargine plus lixisenatide in T2DM inadequately controlled on basal insulin and metformin. The LixiLan-L randomized trial Aroda V et al. Diabetes Care 39: , 2016

53 A titratable fixed-ratio combination of insulin glargine plus lixisenatide in T2DM inadequately controlled on basal insulin and metformin. The LixiLan-L randomized trial Aroda V et al. Diabetes Care 39: , 2016

54 A titratable fixed-ratio combination of insulin glargine plus lixisenatide in T2DM inadequately controlled on basal insulin and metformin. The LixiLan-L randomized trial Aroda V et al. Diabetes Care 39: , 2016

57 with higher percentages of patients achieving Hb1Ac targets associated with 1. A lower risk for hypoglycemia (vs insulin alone) 2. Potential for weight loss 3. Lower doses of insulin Novel combination options are useful in poorly controlled T2DM patients on insulin and in those in whom it is difficult to escalate/intensify insulin therapy

58 THANK YOU! Now it s time for discussion. Sesti lecture

razionale della combinazione insulina/glp-1 RAs

Insulina e GLP-1 RAS: insieme o separati? razionale della combinazione insulina/glp-1 RAs Catania Mercure Catania Excelsior 10 ottobre 2017 Andrea Giaccari andrea.giaccari@unicatt.it Centro per le Malattie