CAN WE IMPROVE POSTPRANDIAL GLUCOSE CONTROL WITH FAST-ACTING INSULINS? Faculty Antonio Ceriello, MD, PhD Professor of Medicine Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain Bruce W. Bode, MD Associate Professor of Medicine Emory University School of Medicine; President and CEO Atlanta Diabetes Associates Piedmont Hospital Atlanta, USA

Controlling Glucose in T1DM 415 million adults worldwide have diabetes > 540,000 children have T1DM Significant morbidity and mortality in people with elevated glucose levels Improving glucose control improves outcomes Guideline-Recommended Glycemic Targets   ADA, 2017[a,b] IDF, 2012[c] HbA1c 53 mmol/mol (< 7%) FPG 4.4 to 7.2 mmol/mol (80-130 mg/dL) 6.5 mmol/mol (115 mg/dL) PPG 10.0 mmol/mol (< 180 mg/dL) 9.0 mmol/mol (< 160 mg/dL) International Diabetes Federation. Diabetes Atlas - 7th edition, 2015. http://www.diabetesatlas.org. Accessed February 21, 2017. International Diabetes Federation Clinical Guidelines Task Force. Global guideline for type 2 diabetes. http://www.idf.org/guideline-type-2-diabetes. Accessed February 21, 2017. ADA = American Diabetes Association FPG = fasting plasma glucose HbA1c = glycated hemoglobin IDF = International Diabetes Federation PPG = postprandial glucose T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus * More or less stringent targets may be set according to patient or disease factors. ADA. Diabetes Care. 2017;40(suppl 1):S1-S135. IDF website. Diabetes atlas. IDF website. Global guidelines for T2DM.

Patient Case: Profile Gender, age Female, 22 Duration of T1DM Diagnosed 3 years ago Current medication Insulin glargine once daily Insulin aspart with each meal HbA1c Current 56.3 mmol/mol (7.3%) Target < 53 mmol/mol (< 7%) FPG 5.1 to 6.7 mmol/L (92-120 mg/dL) PPG 9.9 to 11.3 mmol/L (178-204mg/dL) Monitoring Checks FPG most mornings and PPG 2 to 3 times per week

The Importance of Controlling PPG Normal HbA1c Controlled FPG Controlled PPG PPG after 2 hours is a risk factor for overall mortality and CVD in diabetes[a,b] Treatment guidelines recommend:[c,d] Food with low glycemic index in diet Adding specific glucose-lowering agents for targeting elevated PPG International Diabetes Federation. 2011 Guideline for management of post meal glucose in diabetes. http://www.idf.org/2011-guideline-management-postmeal-glucose-diabetes. Accessed February 21, 2017. CVD = cardiovascular disease a. Cavalot F, et al. Diabetes Care. 2011;34:2237-2243; b. Raz I, et al. Diabetes Care. 2009;32:381-386; c. ADA. Diabetes Care. 2017;40(suppl 1):S1-S135; d. IDF website. Postmeal glucose management guidelines.

Insulins That Target PPG: Aspart 4 9 Time, min Time, min Pooled analysis of 6 randomized, double-blind, crossover trials Adults aged 18 to 64 with T1DM; treated with insulin ≥ 12 months; HbA1c ≤ 86 mmol/mol (≤ 10%); BMI 18 to 28 kg/m2 PK analysis: n = 218; PD analysis: n = 119 BMI = body mass index GIR = maximum glucose infusion rate PD = pharmacodynamics PK = pharmacokinetics Newer insulin aspart vs regular aspart Onset twice as fast 2-fold higher insulin exposure after 30 minutes 74% greater action within first 30 minutes Heise T, et al. ADA 2016. Poster 929-P.

Onset® 1 Trial: Faster Aspart Effective Whether Given Before or After a Meal -0.32% -0.17% -0.13% Change in HbA1c (%) ETD: -0.15%* (95% CI: -0.23, -0.07) ETD: 0.04% (95% CI: -0.04, 0.12) Study Design: T1DM ≥ 12 months Male or female ≥ 18 years Basal-bolus insulin ≥ 12 months Insulin detemir or insulin glargine ≥ 4 months HbA1c 53 to 80 mmol/mol (7.0%-9.5%) BMI ≤ 35.0 kg/m2 Primary endpoint: change in HbA1c after 26 weeks CI = confidence interval ETD = estimated treatment difference * Weeks *Statistically significant Russell-Jones D, et al. Diabetologia. 2016;59(suppl 1):S6.

Onset 1 Trial: Faster Aspart Controlled 1-Hour and 2-Hour PPG 2-hour ETD:* -0.67 mmol/L (95% CI: -1.29, -0.04) -12.0 mg/dL (95% CI: -23.3, -0.7) 126 108 † 90 * 72 PPG Increment (mmol/L) PPG Increment (mg/dL) 54 1-hour ETD:† -1.18 mmol/L (95% CI: -1.65, -0.71) -21.2 mg/dL (95% CI: -29.7, -12.8) 36 18 Time (min) Bolus dose 0.1 U/kg No significant differences in the overall rate of hypoglycemia Similar overall safety profiles *P = .0375; †P < .0001 Standardized meal test: mealtime comparison Russell-Jones D, et al. Diabetologia. 2016;59(suppl 1):S6.

Onset® 2: Mean Change in HbA1c Over Time Basal optimization Bolus intensification Patients with T2DM: Basal insulin (glargine 100) and metformin ± other glucose-lowering agents Basal insulin dose optimization Bolus intensification for 26 weeks with insulin aspart (n = 344) or faster aspart (n = 345) HbA1c 7.0% to 9.5% (53-80 mmol/mol) HbA1c, % 0.0 Time Since Randomization, Weeks Bowering K, et al. Diabetologia. 2016;59(suppl 1):S399.

Related Agents in Development Afrezza® (insulin human) - inhaled insulin (United States only) BioChaperone® - molecular delivery system Hylenex® - hyaluronidase adjuvant Others - eg, hepatic specific insulins Note to CME - I checked with the lead SD, Anne, and she said it is ok to use trade names here. Afrezza website. https://www.afrezza.com/. Accessed February 28, 2017. BioChaperone website. http://www.adocia.fr/WP/technology/biochaperone-technology-2/. Accessed February 28, 2017. Hylenex website. http://hylenex.com/. Accessed February 28, 2017. Afrezza website. BioChaperone website. Hylenex website. Madsbad S. Diabetes. 2014;63:390-392.

Patient Case: Progression Continued with insulin regimen Focused on changing her diet to include foods with a low glycemic index But her PPG remains elevated after 6 months 1-hour PPG 11.2 to 13.3 mmol/L (202-242 mg/dL) Insulin dose needs to increase Using an insulin pump will reduce the risk for hypoglycemia Grunberger G, et al. Endocr Pract. 2014;20:463-489.

Earlier Insulin Exposure and Action With Faster Aspart in CSII Cmax 1.11 [1.03, 1.19]a† AUC0-30 min 2.95 [2.32, 3.73]a* AUCTotal 0.97 [0.90, 1.05]a Randomized, double-blind, crossover trial CSII in 48 patients with T1DM receiving faster aspart or insulin aspart as a CSII bolus dose in addition to basal CSII AUC0-1 h 1.52 [1.37, 1.69]a* AUC0-2 h 1.18 [1.10, 1.26]a* Onset of action (t50%Cmax) 0.64 [0.57, 0.71]a* AUC = area under the concentration-time curve Cmax = maximum concentration CSII: continuous subcutaneous insulin infusion 21 32 *P < .001; †P = .01; a Treatment ratio, 95% CI Onset of action ~3-fold greater insulin exposure within the first 30 minutes, with faster aspart vs insulin aspart Study also found greater glucose-lowering effect with faster aspart in first 2 hours; similar total glucose-lowering effect Heise T, et al. Diabetes. 2015;64(suppl 1):A256.

Better PPG Control in CSII With Faster Aspart Double-blind, randomized, 14-day crossover trial of 43 adults with T1DM Improved PPG after a meal test in CSII with faster aspart vs insulin aspart ∆PPG0-2 h† -0.99 [-1.95, -0.03] mmol/L*‡ ∆PPG0-1 h† -0.50 [-1.07, 0.07] mmol/L‡ *P < .05 † PPGav,0-1 (2)h calculated as AUCPG,0-2 h / 2 h - PPGPre-dose where AUCPG,0-2h was the area under the plasma glucose concentration time profile based on observed values and actual measurement times in relation to injection time between 0 and 2 h ‡ Treatment difference, 95% CI Bode B, et al. Diabetes. 2015;64(suppl 1):A253.

Other Trials With Faster Aspart Onset® 4[a] 37 patients with T1DM 6-week pump compatibility Faster aspart vs insulin aspart Onset® 5[b] Phase 3B T1DM pump ClinicalTrials.gov. Efficacy and safety of continuous subcutaneous insulin infusion of faster-acting insulin aspart compared to NovoRapid® in adults with type 1 diabetes (Onset® 5). https://www.clinicaltrials.gov/ct2/show/NCT02825251. https://www.clinicaltrials.gov/ct2/show/NCT02825251. Accessed February 28, 2017. EASD = European Association for the Study of Diabetes a. Bode B, et al. EASD 2016. Abstract 39. b. ClinicalTrials.gov. NCT02825251.

Conclusions FPG and PPG need to be controlled in order to get HbA1c to goal Several methods available for achieving this Fast-acting insulin aspart is available in many countries It can be used in T1DM and T2DM with no increased risk for hypoglycemia Several clinical trials with faster aspart completed Can be used with pump therapy and as a post-meal bolus

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Abbreviations ADA = American Diabetes Association AE = adverse event AUC = area under the concentration-time curve BMI = body mass index CI = confidence interval Cmax = maximum concentration CSII = continuous subcutaneous insulin infusion CVD = cardiovascular disease EASD = European Association for the Study of Diabetes ETD = estimated treatment difference FPG = fasting plasma glucose GIR = glucose infusion rate HbA1c = glycated hemoglobin IDF = International Diabetes Federation

Abbreviations (cont) PD = pharmacodynamic PK = pharmacokinetic PPG = postprandial glucose SC = subcutaneous T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus t50%Cmax = time to 50% of maximum insulin concentration