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INSULIN AND INCRETINS: THE PERFECT PARTNERSHIP? Moderator Stephen Colagiuri, MD Professor of Metabolic Health Boden Institute of Obesity, Nutrition and Exercise University of Sydney Sydney, Australia Panelists Stephen C. Bain, MD Luc Martinez, MD Professor of Medicine (Diabetes) Institute of Life Science Swansea University Medical School Swansea, United Kingdom Former Professor of Family Medicine University Pierre et Marie Curie Vice President, French Society of General Medicine Executive Member, Primary Care Diabetes Europe Paris, France Andreas Liebl, MD Medical Director Center for Diabetes and Metabolism Fachklinik Bad Heilbrunn Bad Heilbrunn, Germany Intensification of Insulin Therapy in T2DM • Delays in the intensification of insulin therapy • Treatment options for patients uncontrolled on basal insulin • Practical aspects of how to intensify basal insulin therapy with a GLP-1 RA Fewer T2DM Patients at Target When Treated With Insulin/Injectables: PANORAMA Study Diet/Exercise HbA1c <7% 1 OAD 12.1% HbA1c ≥7% 23.9% 76.1% 87.9% 2 OADs Insulin/Injectables* ≥3 OADs 36.1% 38.6% 50.1% 61.4% de Pablos-Velasco P, et al. Clin Endocrinol. 2014;80:47-56. 49.9% 63.9% *Insulin or GLP-1 RA Insulin Therapy Needs to Control Both FPG and PPG Total Hyperglycemia, % Treated With OADs[a] 80% 60% Treated With Basal Insulin[b] 80% 70% 60% 60% 40% 20% 48% 52% 40% 42% 43% 48% 0% <7.3 7.3-8.4 8.5-9.2 9.3-10.2 <6.5 ≥10.2 6.5-<7.0 7.0-<7.5 7.5-<8.0 ≥8 80% 80% 60% 70% 58% 40% 59% 58% 57% 40% 50% 42% 52% 40% 20% 30% 20% 0% 0% <7.3 n = 290 42% 20% 30% 0% 60% 41% 7.3-8.4 8.5-9.2 9.3-10.2 FPG (basal hyperglycemia) ≥10.2 <6.5 6.5-<7.0 7.0-<7.5 7.5-<8.0 Postprandial hyperglycemia a. Monnier L, et al. Diabetes Care. 2003;3:881-885; b. Riddle M, et al. Diabetes Care. 2011;34:2508-2514. ≥8 n = 1699 Why Does Intensification of Insulin Therapy Not Happen in Many Patients With T2DM? • Clinical inertia – Physician barriers • Inexperience with using insulin; lack of resources/training • Fear of hypoglycemia • Not buying into HbA1c targets; don’t want to be too aggressive – Patient barriers • Insulin carries “baggage” (eg, negative family experience, “end of the road” perception) • Educational issues about insulin dose increases • Progressive nature of disease Higher doses of insulin and/or addition of other therapies will be needed Intensification Options for T2DM Patients Uncontrolled on Basal Insulin • Add an OAD – DPP-4 or SGLT2 inhibitor limited glucose-lowering potency • Add a short-acting insulin at mealtime – Stepwise addition: small dose with largest meal, uptitration, add to 3 meals/day up to 4 injections, weight increase and hypoglycemia risk • Switch to premixed insulins – Only 2 injections limited flexibility • Novel insulin combinations – Modern short-acting plus long-acting insulin analog combination • Basal insulin/GLP-1 RA combinations IDegAsp Fixed-Ratio Combination vs Basal Bolus: HbA1c Reduction IDegAsp twice a day (n=138) IDeg once daily + IAsp (n=136) 9.0 Mean HbA1c, % 8.5 Treatment difference: 0.18%-points (–0.04; 0.41) 8.0 7.5 7.0% 6.8% 7.0 6.5 6.0 0.0 0 10 14 18 22 26 Time, weeks • • • Mean HbA1c decreased by 1.31% in the IDegAsp group and by 1.50% in the basal bolus group Noninferiority of IDegAsp vs basal bolus (IDeg + IAsp) not confirmed Proportion of patients achieving HbA1c <7.0% (53 mmol/mol) after 26 weeks was similar for IDegAsp and basal bolus (56.5% and 59.6%, respectively) Calculated, not measured; Data are mean (SEM) in the FAS (LOCF); Comparisons: estimates adjusted for multiple covariates. Rodbard HW, et al. Diabetes Obes Metab. 2015;18:274-280. Lower Total Daily Dose of IDegAsp vs Basal Bolus Estimated ratio: 0.88 Total Daily Insulin Dose Over Time 140 IDegAsp twice a day (n=136) (95% CI: 0.78, 1.00) P<.05 Ideg once daily + IAsp (n=135) Insulin Dose, U 120 100 80 60 40 20 0 2 4 6 8 10 12 14 Time, weeks IDegAsp twice a day vs IDeg once daily + IAsp • • 16 18 20 Mean Ratio (U/kg) Basal insulin dose 1.05 Bolus insulin dose 0.55 Total insulin dose 0.83 IDegAsp twice a day, 70% of IDegAsp dose is basal and 30% is bolus IDeg once daily + IAsp, sum of single IDeg dose and all IAsp doses Comparisons: estimates adjusted for multiple covariates; SAS; LOCF Cooper J, et al. EASD 2014. Abstract 147. 22 24 26 Rationale for Basal Insulin/GLP-1 RA Combination • Basal insulin improves FPG levels • GLP-1 RA reduces PPG levels • Complementary efficacy and mitigated side effects when combined • Now available as titratable fixed-ratio combinations Complementary Effects of Basal Insulin and GLP-1 RA Therapy Increased + Side effects Efficacy Decreased GLP-1 RA monotherapy Basal insulin GLP-1 RA/insulin combined - HbA1c FPG PPG Weight Hypoglycemia Nausea For illustrative purposes only; not meant to quantify or imply magnitude of change in either direction Fixed-Ratio Combinations of Basal Insulin and GLP-1 RAs GLP-1 RA GLP-1 RA Liraglutide Lixisenatide Insulin Glargine Insulin Degludec IDegLira IGlarLixi Fixed Ratio Basal Insulin/GLP-1 RA Combinations iGlarLixi Components Basal insulin glargine GLP-1 RA lixisenatide Ratio 2 U insulin glargine/1 µg lixisenatide 3 U insulin glargine/1 µg lixisenatide Maximum dose 40 U insulin glargine/20 µg lixisenatide 60 U insulin glargine/20 µg lixisenatide Development studies Regulatory status 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;39:1579-86; b. Rosenstock J, et al. Diabetes Care. 2016 Aug 15. [Epub ahead of print]; c. Aroda VR, et al. Diabetes Care. 2016 Sep 20. [Epub ahead of print]; d. Clinicaltrials.gov. NCT02787551; LixiLan-L Trial: Patients Uncontrolled on Insulin Key Clinical Findings HbA1c Weight Change in HbA1c, % 0 -0.2 n = 367 n = 369 -0.4 -0.62 -0.6 -0.8 -1 EOT HbA1c *Max. n = 367 6.94% n = 369 1.5 0.7 1 0.5 0 -1 P<.0001 IGlar U100* 2 -0.5 -1.13 -1.2 iGlarLixi Hypoglycaemia -0.7 P<.0001 7.48% dose 60 U. Documented symptomatic hypoglycemia (PG ≤70 mg/dL). Aroda VR, et al. Diabetes Care. 2016 Sep 20. [Epub ahead of print]. Hypoglycaemia Rate, events/patient-year IGlar U100* Change in Weight, kg IGlarLixi Documented symptomatic IGlarLixi IGlar U100* n = 367 n = 369 6 5 4 3 2 4.22 3.03 1 0 Severe hypoglycaemia in 4 IGlarLixi subjects and 1 Gla-100 subject LixiLan-L Trial: Patients Uncontrolled on Insulin Mean Daily IGlar U100 Dose ±SE, Units Insulin Dose Over Time 45 40 IGlarLixi IGlar U100 * 35 n = 367 n = 369 30 25 20 15 10 5 0 0 3 5 7 9 11 15 18 21 24 27 30 LOCF Study Week The HbA1c-over-time plot includes all scheduled measurements obtained during the study, including those obtained after study drug discontinuation or introduction of rescue therapy *Max. dose 60 U Aroda VR, et al. Diabetes Care. 2016 Sep 20. [Epub ahead of print] Fixed Ratio Basal Insulin/GLP-1 RA Combinations IDegLira Components Basal insulin degludec GLP-1 RA liraglutide Ratio 1 U insulin degludec/ 0.036 mg liraglutide Maximum dose 50 dose steps (50 U IDeg and 1.8 mg Lira)[a] Development studies Regulatory status Phase 3 complete: DUAL I, II, III, IV, V, VI[b] Phase 3 ongoing: DUAL VII, VIII, IX[b] Approved in EU, US and Switzerland a. Gough et al. Lancet Diabetes Endocrinol 2014;2:885–93; b. Clinicaltrials.gov; NCT01336023, NCT01392573, NCT01676116, NCT01952145, NCT02501161, NCT02298192, NCT02100475, NCT02911948, NCT02607306 DUAL V Trial: Patients Uncontrolled on Insulin HbA1c Over Time IDegLira (n=278) 9.0 Difference –0.59% IGlar U100 (n=279) 8.5 [–0.74; –0.28] 95% CI P<.001 HbA1c, % 8.0 ∆HbA1c 7.5 EOT 7.0 7.1% –1.13% 6.5 6.6% –1.81% 6.0 5.5 0.0 0 4 8 12 Time, weeks Lingvay I, et al. JAMA. 2016;315:898-907. 16 20 26 DUAL V Trial: Patients Uncontrolled on Insulin Key Clinical Findings 0.0 n = 278 n = 279 -0.5 –1.13 -1.0 -1.5 –1.81 2.0 1.8 1.0 n = 278 n = 279 0.0 -1.0 –1.4 6.6% 7.1% p<0.001 6 5 5.05 4 3 2 1 0 p<0.001 p<0.001 Hypoglycaemia* IGlar U100 (no max.) -2.0 -2.0 EOT HbA1c IDegLira IGlar U100 (no max.) Change in Weight, kg Change in HbA1c, % IDegLira Confirmed Weight Hypoglycaemia Rate, events/patient-year HbA1c 2.23 n = 278 n = 279 IDegLira IGlar U100 (no max.) 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. 2016;315:898-907. DUAL V Trial: Patients Uncontrolled on Insulin Daily Insulin Dose Over Time 80 Difference: –25.5 U, IDegLira (n=278) IGlar U100 (n=279) P<.001 70 66 U Dose, Units 60 50 40 41 U 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Time, weeks IDegLira dose capped at 50 dose steps; there was no maximum dose for IGlar U100. Lingvay I, et al. JAMA. 2016;315:898-907. P GI Adverse Events Post hoc analysis of nausea in blinded studies (DUAL II and IV) 12 • Liraglutide arm from DUAL I included for visual comparison only • Non-GLP-1 RA comparator arms were pooled for analysis 10 Patients With Nausea, % • Post hoc analysis of two double-blinded, Phase 3, 26-week trials 8 6 4 2 0 1 2 4 6 8 10 12 14 16 18 20 22 24 26 n = 415 Liraglutide 1.8 mg (DUAL I) Non-GLP-1 RA comparators (DUAL II+IV Ideg+placebo) n = 345 IDegLira (DUAL II) IDegLira (DUAL IV) Adapted from Aroda et al. Diabetes 2015;64(Suppl. 1):A257 n = 199 n = 289 Utility of Fixed-Ratio Basal Insulin/GLP-1 RA Combinations in Clinical Practice High percentage of patients achieving HbA1c target with – Lower risk for hypoglycemia (compared with insulin alone) – Weight loss (vs weight gain with insulin) – Reduced frequency of GI side effects due to slow titration with low initial dose of GLP-1 RA – Increased patient acceptability T2DM Patients Suitable for a Fixed-Ratio Basal Insulin/GLP-1 RA Combination • HbA1c above 7% or even 8% • Advanced T2DM, some complications already • Insulin therapy delayed for some time • At higher risk for hypoglycemia • Overweight T2DM Patients Suitable for a Fixed-Ratio Basal Insulin/GLP-1 RA Combination (cont) Patients not at HbA1c target treated with: 1. Basal insulin—FPG controlled but suboptimal postprandial control 2. GLP-1 RA 3. Oral glucose-lowering medications (single/dual) IDegLira Titration Titration Algorithm in Clinical Trials[a] MEAN PREBREAKFAST PG mmol/L (mg/dL) DOSE CHANGE dose steps or U Titrated twice weekly based on the mean of 3 measurements >5.0 (>90) 4.0-5.0 (72-90) <4.0 (<72) +2 TARGET* 0 –2 *DUAL IV target was 4-6 mmol/L as add-on to sulfonylurea a. Lingvay I, et al. JAMA. 2016;315:898-907. b. Xultophy® Summary of Product Characteristics. EU Label[b] IDegLira is to be dosed in accordance with the individual patient’s needs. It is recommended to optimize glycemic control via dose adjustment based on FPG DUAL VI Study: Once- vs Twice-Weekly Titration Titration Algorithm Mean Prebreakfast (Fasting) SMPG*† Dose Change mmol/L mg/dL Dose steps <4.0 <72 –2 4.0-5.0 72-90 0 >5.0 >90 +2 *IDegLira once-weekly titration: titrated once weekly based on the mean of 2 consecutive prebreakfast SMPGs †IDegLira twice-weekly titration: titrated twice weekly based on the mean of 3 consecutive prebreakfast SMPGs 1 IDegLira dose step = 1 U IDeg/0.036 mg liraglutide Harris SB, et al. EASD 2016. Abstract P-908. Patient and Physician Perspectives • Patient 1. Simplicity—1 injection per day, easy to self-titrate 2. Weight loss 3. Improved glycemic control 4. Well tolerated • Physician: easy to manage and explain to patient Conclusions • Novel fixed-ratio basal insulin/GLP-1 RA combinations provide an opportunity for – Poorly controlled T2DM patients on insulin – Those in whom it is difficult to escalate/intensify insulin therapy • Higher percentages of patients achieving Hb1Ac targets with – A lower risk for hypoglycemia (vs insulin alone) – Potential for weight loss – Lower doses of insulin – Fewer GI side effects due to slow titration with low initial doses of GLP-1 RA Thank you for participating in this activity. To proceed to the online CME test, click on the Earn CME Credit link on this page.