Insulin and Incretins: - PowerPoint Presentation

Insulin and Incretins:the perfect Partnership? Stephen Colagiuri, MDProfessor of Metabolic HealthBoden Institute of Obesity, Nutrition and ExerciseUniversity of Sydney Sydney, Australia Moderator

Stephen C. Bain, MD Professor of Medicine (Diabetes) Institute of Life ScienceSwansea University Medical School Swansea, United KingdomAndreas Liebl, MDMedical Director Center for Diabetes and Metabolism Fachklinik Bad Heilbrunn Bad Heilbrunn, Germany Luc Martinez, MD Former Professor of Family Medicine University Pierre et Marie CurieVice President, French Society of General MedicineExecutive Member, Primary Care Diabetes EuropeParis, France Panelists

Intensification of Insulin Therapy in T2DM Delays in the intensification of insulin therapyTreatment options for patients uncontrolled on basal insulinPractical aspects of how to intensify basal insulin therapy with a GLP-1 RA

Fewer T2DM Patients at Target W hen T reated With Insulin/Injectables: PANORAMA Study de Pablos-Velasco P, et al. Clin Endocrinol. 2014;80:47-56. *Insulin or GLP-1 RA

Insulin Therapy Needs to Control Both FPG and PPG a. Monnier L, et al. Diabetes Care. 2003;3:881-885; b. Riddle M, et al. Diabetes Care. 2011;34:2508-2514. FPG ( b asal h yperglycemia) Postprandial h yperglycemia Total Hyperglycemia, % Treated With OADs [a] Treated With Basal Insulin [b] n = 290 n = 1699

Why Does Intensification of Insulin Therapy Not Happen in Many Patients With T2DM? Clinical inertiaPhysician barriersInexperience with using insulin; lack of resources/trainingFear 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 increasesProgressive 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 OADDPP-4 or SGLT2 inhibitor  limited glucose-lowering potency Add a short-acting insulin at mealtime S tepwise 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 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. IDegAsp twice a day (n=138) IDeg once daily + IAsp (n=136) 0.0 Time, weeks Treatment difference: 0.18%-points (– 0.04; 0.41) 7.0 % 6.8 % M ean 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 P roportion 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)

Lower Total Daily Dose of IDegAsp vs Basal Bolus 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 IDegAsp twice a day vs IDeg once daily + IAsp Mean Ratio (U/kg) Basal insulin dose 1.05 Bolus insulin dose 0.55 Total insulin dose 0.83 Total Daily Insulin Dose Over Time Insulin Dose, U Time, weeks Estimated ratio: 0.88 (95% CI: 0.78, 1.00) P< .05 Cooper J, et al. EASD 2014. Abstract 147 .

Rationale for Basal Insulin/GLP-1 RA Combination Basal insulin improves FPG levelsGLP-1 RA reduces PPG levelsComplementary efficacy and mitigated side effects when combined Now available as titratable fixed-ratio combinations

Complementary Effects of Basal Insulin and GLP-1 RA Therapy For illustrative purposes only; not meant to quantify or imply magnitude of change in either direction HbA1c FPG PPG Weight Hypoglycemia Basal insulin GLP-1 RA monotherapy + GLP-1 RA/insulin combined Increased Decreased - Efficacy Side effects Nausea

Fixed-Ratio Combinations of Basal Insulin and GLP-1 RAs GLP-1 RA Lixisenatide Insulin Glargine IGlarLixi GLP-1 RA Liraglutide Insulin Degludec IDegLira

Fixed Ratio Basal Insulin/GLP-1 RA Combinations Components Ratio Development studies Regulatory status iGlarLixi Basal insulin glargine GLP-1 RA lixisenatide 2 U insulin glargine /1 µg lixisenatide 3 U insulin glargine /1 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 Maximum dose 40 U insulin glargine /20 µg lixisenatide 60 U insulin glargine/20 µg lixisenatide 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;

Severe hypoglycaemia in 4 IGlarLixi subjects and 1 Gla-100 subject HbA 1c Weight Documented symptomatic Hypoglycaemia LixiLan -L Trial: Patients Uncontrolled on Insulin Key Clinical Findings Change in Weight, kg Hypoglycaemia Rate, events/patient-year P <.0001 Change in HbA 1c, % EOT HbA 1c 6.94% 7.48% P <.0001 n = 367 n = 367 n = 367 n = 369 n = 369 n = 369 * Max . dose 60 U. Documented symptomatic hypoglycemia (PG ≤ 70 mg/dL). Aroda VR, et al. Diabetes Care. 2016 Sep 20. [Epub ahead of print ].

LixiLan-L Trial: Patients Uncontrolled on Insulin Insulin Dose Over Time 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 Mean Daily IGlar U100 Dose ± SE, Units Study Week Aroda VR, et al. Diabetes Care. 2016 Sep 20. [Epub ahead of print ] * n = 367 n = 369

Fixed Ratio Basal Insulin/GLP-1 RA Combinations Components Ratio Development studies Regulatory status IDegLira Basal insulin degludec GLP-1 RA liraglutide 1 U insulin degludec / 0.036 mg liraglutide 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 Maximum dose 50 dose steps (50 U IDeg and 1.8 mg Lira) [a] 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 O ver T ime 7.1% 6.6% HbA1c , % Time, weeks EOT Difference ∆Hb A1c –1.81% –1.13% 0.0 –0.59% [–0.74; –0.28 ] 95 % CI P <.001 Lingvay I, et al. JAMA. 2016;315:898-907.

Severe hypoglycaemia in one IGlar U100 subject ‡ Change in Weight, kg Hypoglycaemia Rate, events/patient-year IDegLira IGlar U100 (no max.) IDegLira IGlar U100 (no max.) HbA 1c Weight Confirmed Hypoglycaemia * p <0.001 p <0.001 Change in HbA 1c, % IDegLira IGlar U100 (no max.) EOT HbA 1c 6.6% 7.1% –1.13 p <0.001 –1.4 1.8 2.23 5.05 DUAL V Trial: Patients Uncontrolled on Insulin Key Clinical Findings n = 278 n = 279 n = 278 n = 279 n = 278 n = 279 Lingvay I, et al. JAMA. 2016;315:898-907. *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

Time, weeks Dose, Units 41 U 66 U Difference: – 25.5 U, P <.001 IDegLira dose capped at 50 dose steps; there was no maximum dose for IGlar U100. DUAL V Trial: Patients Uncontrolled on Insulin Daily Insulin Dose Over Time Lingvay I, et al. JAMA. 2016;315:898-907.

GI Adverse Events Post hoc analysis of nausea in blinded studies (DUAL II and IV)Post hoc analysis of two double-blinded, Phase 3, 26-week trials Liraglutide arm from DUAL I included for visual comparison onlyNon-GLP-1 RA comparator arms were pooled for analysis Adapted from Aroda et al . Diabetes 2015;64(Suppl . 1): A257 P Patients With Nausea, % n = 289 n = 199 n = 415 n = 345

Utility of Fixed-Ratio B asal 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 RAIncreased 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 alreadyInsulin 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: Basal insulin—FPG controlled but suboptimal postprandial control GLP-1 RA Oral glucose-lowering medications (single/dual)

IDegLira Titration 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 Titration Algorithm in Clinical Trials [a] EU Label [b] MEAN PREBREAKFAST PG mmol/L (mg/dL) < 4.0 (<72) –2 > 5.0 (>90) +2 DOSE CHANGE dose steps or U 4.0 - 5.0 (72-90) 0 Titrated twice weekly based on the mean of 3 measurements TARGET * *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.

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: t itrated once weekly based on the mean of 2 consecutive prebreakfast SMPGs †IDegLira twice-weekly titration: t itrated 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. DUAL VI Study: Once- vs Twice-Weekly Titration Titration Algorithm

Patient and Physician Perspectives PatientSimplicity—1 injection per day, easy to self-titrateWeight loss Improved glycemic control 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 insulinThose 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 lossLower doses of insulinFewer GI side effects due to slow titration with low initial doses of GLP-1 RA

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