Vivian A. Fonseca, MD, FRCP Professor of Medicine and Pharmacology - PowerPoint Presentation

Vivian A. Fonseca, MD, FRCP Professor of Medicine and PharmacologyTullis Tulane Alumni Chair in Diabetes Chief, Section of Endocrinology Tulane University School of MedicineNew Orleans, Louisiana Key Concepts of Type 2 Diabetes Mellitus Jonathan D. Leffert, MD, FACP, FACE, ECNUManaging Partner, North Texas Endocrine CenterPresident, American Association of Clinical EndocrinologistsDallas, Texas Dallas, Texas

Decline in -Cell Function with Diabetes Progression: UKPDS Lebovitz H. Diabetes Rev. 1999;7(3):139-153.UKPDS 16. Diabetes. 1995;44(11):1249-1258. Rx: Insulin, Metformin, Sulfonylurea  -Cell Function (%) Postprandial Hyperglycemia IGT Type 2 Diabetes Phase II Type 2 Diabetes Phase III 25 100 75 0 50 -12 -10 -6 -2 0 2 6 10 14 Years from Diagnosis Type 2 Diabetes Phase I Dashed line shows extrapolation forward and backward from years 0 to 6 based on HOMA data from UKPDS.

Basal vs Mealtime Hyperglycemia in T2DM Polonsky KS, et al. N Engl J Med . 1988;318(19):1231-1239. 100 200 300 400 0600 1000 1800 1400 0200 2200 0600 Time of day Breakfast Lunch Supper Basal hyperglycemia Incremental hyperglycemia after meals Blood Glucose (mg/dL)

HbA1C target should be individualized based on numerous factors, including age, life expectancy, comorbid conditions, duration of diabetes, risk of hypoglycemia or adverse consequences from hypoglycemia, patient motivation, and adherence 1,2 Test Glycemic Control Targets ADA AACE HbA1c <7% ≤6.5% 3 FPG 80-130 mg/dL <110 mg/dL 3 PPG <180 mg/dL (measured within 1 to 2 hours after the start of a meal) <140 mg/dL 3 (2-hour value) AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; FPG, fasting plasma glucose; PPG, postprandial glucose. 1. American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S135. 2. Garber AJ, et al. Endocr Pract. 2017;23(2):207-238. 3. Handelsman Y et al. Endocr Pract. 2015;21(suppl 1):1-87. ADA and AACE Glycemic Targets

When To Start Insulin in T2DM Patients withhyperglycemic emergenciessymptomatic hyperglycemia and/or markedly high HbA1chepatic or renal diseasecoronary artery disease, ↑ triglyceride level When combination oral/injectable agents become inadequateUnacceptable side effects of oral/injectable agents Patient wants more flexibilitySpecial circumstances (ie, steroid use, infection, pregnancy)Holman RR, et al. NEJM. 2009; 361(18):1736-1747. Lebovitz HE. Diabetes Rev. 1999;7(3):139-153 .

1. Riddle M, et al. Diabetes Care. 2003;26(11):3080-3086. 2. Gerstein HC, et al. Diabetes Med. 2006;23(7):736-742 3. Bretzel RG, et al. Lancet. 2008;371(9618):1073-1084.4. Yki-Järvinen H, et al. Diabetes Care. 2007;30(6):1364-13695. Schreiber SA, et al. Diabetes Obes Metab. 2007;9(1):31-38. Baseline Study end 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 T-T-T 1 n = 367 INSIGHT 2 n = 206 APOLLO 3 n = 174 INITIATE 4 n = 58 HbA1c (%) 8.6 8.6 8.7 8.7 8.8 7.0 7.0 7.0 6.8 7.0 ∆ -1.6 ∆ -1.6 ∆ -1.7 ∆ -2.0 ∆ -1.7 Observational 5 n = 11,511 Typically ~50% of people attain HbA1c <7% → ~50% do not Approximately Half of Patients Do Not Attain Target HbA1c After Initiating Titrated Insulin Glargine Similar results are obtained with insulin detemir

Hypoglycemia with Glargine Is Common in 11 Treat-to-Target Studies 2251 participants with systematically titrated glargine added to 1 or 2 oral agents Karl DM, et al. Diabetes Obes Metab . 2013;15(7):622-628. ≥ 1 symptomatic event ≥ 1 event confirmed <50 mg/dL ≥ 2 event confirmed <50 mg/dL ≥ 1 severe event 1.5 % 52% 17% 7% Percentage of Participants Affected Non-severe hypoglycemia Severe hypoglycemia

Both Fasting and Postprandial Glucose Contribute to HbA1c FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; PPG, postprandial plasma glucose1N=290 Non–insulin-using patients with type 2 diabetes2N=1699 Participants with type 2 diabetes on oral antidiabetic drugs. Mean age 59 years; mean duration of diabetes 9 years; mean FPG=194 mg/dL, mean HbA1c=8.7%. Hyperglycemia was defined as plasma glucose >100 mg/dL. 1. Monnier L, et al. Diabetes Care . 2003;26(3):881-885. 2. Riddle M, et al. Diabetes Care . 2011;34(12):2508-2514. FPG PPG 76% 78% 79% 79% 80% 24% 22% 21% 21% 20% Contribution to overall hyperglycemia (%) Baseline HbA1c category (%) 0 20 40 60 80 100 <8.0 8.0-<8.5 8.5-<9.0 9.0-<9.5 ≥9.5 Contribution to overall hyperglycemia (%) HbA1c value quintiles (%) 0 20 40 60 80 100 <7.3 7.3-8.4 8.5-9.2 9.3-10.2 >10.2 30% 70% 49% 51% 55% 45% 60% 40% 70% 30% Monnier et al (2003) 1 Riddle et al (2011) 2

Postprandial Hyperglycemia Independently Predicts CVD Risk Clinical Trial Association of PPG with CVD Honolulu Heart Program (1987)1-h glucose predicts coronary heart diseaseDIS (1996)Postmeal, not FPG, is associated with CHD Chicago Heart Study (1997) 2-h postchallenge glucose predicts all-cause mortality Whitehall Study, Paris Prospective Study, & Helsinki Policemen Study (1998) 2-h postchallenge glucose predicts all-cause and CHD mortality Coutinho et al (1999) 2-h glucose associated with CHD Hoom Study (1999) 2-h glucose better predicts all-cause and CV mortality than HbA1C DECODE (1999; 2004) High 2-h postload blood glucose associated with increased risk of death, independent of FPG; predicts cardiovascular death Cavalot (2006) Postprandial, not FPG, independently predicts CV events, particularly in women, in DM Adapted from Home P. Curr Med Res Opin . 2005;21(7):989-998. CHD, coronary heart disease; CV, cardiovascular; DM, diabetes mellitus; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin

Do We Have Evidence that Targeting Postprandial Hyperglycemia Reduces CV Risk? Clinical Trial Description Outcomes [HR (95% CI)]STOP-NIDDMAcarbose in IGT (N=1368)MI: 0.09 (0.01-0.72)Any CV event: 0.51 (0.28-0.95) Acarbose meta-analysis N=2180 MI: 0.36 (0. 16-0.80) Any CV event : 0.65 ( 0.48-0.88) NAVIGATOR Nateglinide in IGT (N=9306); 6 y CV outcomes: 0.94 (0.82-1.09) Heart2D Lispro TID vs Glargine/NPH BID (N=1115); 2.6 y CV event: 0.98 (0.8-1.21) BID, two times daily; CV, cardiovascular; IGT, impaired glucose tolerance; MI, myocardial infarction; NPH, neutral protamine Hagedorn; TID, three times daily 1. Chiasson JL, et al. JAMA. 2003;290(4):486-494.2. Hanefeld M. Eur Heart J . 2004;25(1):10-16.3. Navigator Study Group. N Engl. J Med. 2010;362(16):1463-1476.4. Raz I, et al. Diabetes Care . 2009;32:381-386.

Innovations in Basal Insulin Analogs Vivian A. Fonseca, MD, FRCP Professor of Medicine and PharmacologyTullis Tulane Alumni Chair in Diabetes Chief, Section of Endocrinology Tulane University School of MedicineNew Orleans, Louisiana Jonathan D. Leffert, MD, FACP, FACE, ECNU Managing Partner, North Texas Endocrine Center President, American Association of Clinical Endocrinologists Dallas, Texas

  NPH Insulin Insulin Glargine U-100Insulin DetemirFollow-on Insulin Glargine Insulin Glargine U-300 Insulin Degludec Insulin type Human; intermediate-acting Analog; long-acting Analog; long-acting Analog; long-acting Analog; long-acting Analog; long-acting Onset 2-4 hours 1.3 hours 1.3 hours 6 hours 1 hour Peak 4-10 hours No pronounced peak Relatively flat No pronounced peak Flat Flat Effective duration 10-16 hours Up to 24 hours Up to 24 hours Up to 24 hours ≤ 36 hours ≤42 hours Half-life Unknown* 14 hours 5-7 hours ~23 hours ~25 hours Time to steady-state Unknown 2 days 2 days 4 days 2-3 days Basal Insulins Currently Available Porcellati F, et al. Diabetes Ca re. 2007;30(10):2447-2452. Lucidi P, et al. Diabetes Care . 2011;34(6):1312-1314. Niswender K. Clin Diabetes . 2009;27:60-68. Novolin N [package insert]. Indianapolis, IN: Eli Lilly & Co.; January 2017. Lantus [package insert] Bridgewater, NJ: sanofi-aventis US LLC; August 2015. Basaglar [package insert]. Indianapolis, IN: Eli Lilly & Co.; April 2017. Levemir [package insert]. Princeton, NJ: Novo Nordisk US; February 2015. Toujeo [package insert]. Bridgewater, NJ: sanofi-aventis US LLC; October 2015. Becker RH, et al. Diabetes Care . 2015;38:637-643. Tresiba [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; December 2016. Heise T, et al. Diabetes Obes Metab . 2012;14(10):944-950.

Efficacy and Safety of Follow-on Glargine U-100 (Basaglar ®) vs Glargine U-100 (Lantus®) in Insulin-naïve Patients with T2DM1 Endpoint (N=455)Insulin Glargine U-100Follow-on Insulin Glargine U-100HbA1c (%), change from baseline-1.54-1.48Insulin dose (units/kg-day)0.440.42Weight gain (kg)2.22.0 Rosenstock J, et al. Diabetes Obes Metab . 2015;17:734-741. 1 Mean age = 58 years; duration of diabetes = 11 years; Baseline: HbA1c = 8.4% to 8.5%, weight = 89-91 kg, BMI = 32 kg/m 2 2 Overall (plasma glucose ≤70 mg/dL or sign or symptom of hypoglycemia) and nocturnal hypoglycemia (between bedtime and waking) are expressed as events/patient-year (EPY). Severe hypoglycemia (requiring assistance, baseline to month 6) is number of patients.

Ultralong-Acting Basal Insulins 1. Becker RH, et al. Diabetes Care . 2015;38:637-643. 2. Heise T, et al. Diabetes Obes Metab . 2012;14(10):944-950.   Glargine U-300 1 Degludec 2 Insulin Type Analog Analog Onset 6 hours 1 hour Peak Flat Flat Half-Life ~23 hours ~ 25 hours Time to Steady State 4 days 2-3 days Effective Duration ≤36 hours ≤42 hours

Pharmacokinetics of Insulin Glargine U-300 in Type 1 Diabetes Becker RHA, et al. Diabetes Care. 2015;38:637-643.

Insulin Glargine U-300: EDITION Program Anderson JE. J Fam Pract. 2016;65(10 Suppl):S23-S28.

Insulin Glargine U-300 vs U-100: Glycemic Efficacy* Ritzel R, et al. Diabetes Obes Metab . 2015;17(9):859-867 * Meta-Analysis of EDITION 1, 2, 3; N=2496 Time Time

Insulin Glargine U-300 vs U-100: Other Outcomes* Ritzel R, et al. Diabetes Obes Metab . 2015;17(9):859-867 * Meta-Analysis of EDITION 1, 2, 3; N=2496

Insulin Glargine U-300 vs U-100: Hypoglycemia Yki-Jarvinen H, et al. Diabetes Care . 2014;37:3235-3243.Glargine U-100 Glargine U-300 48% lower with U-300 P =0.001 Cumulative mean number of nocturnal severe or confirmed (≤70 mg/dL) events/participant Patients with T2DM using basal insulin + oral agent(s) (N=811) Difference mostly up to 12 wk

Insulin Degludec: BEGIN Program Philis-Tsimikas. J Fam Pract . 2016;65(10 Suppl):S14-S22.

Insulin Degludec vs Insulin Glargine U-100: Glycemic Efficacy N=725 52-week Core Trial 52-week Extension Phase 52-week Core Trial 52-week Extension Phase Rodbard HW, et al. Diabet Med . 2013;30:1298-1304.

Insulin Degludec vs Insulin Glargine U-100: Other Outcomes Rodbard HW, et al. Diabet Med . 2013;30:1298-1304.N=1023

Hypoglycemia with Degludec and Glargine U-300 vs Glargine U-100 1. Ratner RE, et al. Diabetes Obes Metab . 2013;15(2):175-184.2. Ritzel R, et al. Diabetes Obes Metab. 2015;17(9):859-867.Meta-analyses of phase 3 clinical studies in T2DM With both insulins, ~15% fewer overall and ~30% fewer nocturnal events vs glargine U-100 Degludec 1 Glargine U-300 2 # Studies 5 3 # Participants 3372 2496Definition of confirmed hypoglycemia<56 mg/dL and severe≤70 mg/dL or severe Anytime events [Rate ratio vs glargine U-100 (95% CI)]0.83 (0.74-0.94)0.86 (0.77-0.97)Nocturnal events [Rate ratio vs glargine U-100 (95% CI)] 0.68 (0.57-0.82)0.69 (0.57-0.84)

Zinman B, et al. Diabetes Care. 2012;35:2464-2471. Nocturnal events/patient Anytime events/patient 36% lower with degludec P =0.04 2.0 1.6 0.4 1.2 0.8 0.40 0.32 0.80 0.40 0.60 12 24 36 48 12 24 36 48 Weeks of treatment Weeks of treatment Cumulative hypoglycemic events (confirmed <56 mg/dL) Insulin Degludec vs Insulin Glargine U-100 Glargine U-100 Degludec Degludec 1023 insulin-naïve patients with T2DM Glargine U-100 18% lower with degludec P =0.11

Cardiovascular Safety of Insulin Glargine U-100*: ORIGIN Study Composite of MI, Stroke, CV Death Composite of Revascularization or Heart Failure Hospitalization ORIGIN Investigators. N Engl J Med . 2012;367():319-328. *12,537 people with increased CV risk plus impaired fasting glucose, impaired glucose tolerance, or T2DM were randomized to insulin glargine U-100 vs standard care. Mean follow-up was 6.2 years.

Cardiovascular Safety of Insulin Degludec: DEVOTE Study 7637 people with T2DM at high CV risk were randomized to standard care plusInsulin degludec orInsulin glargine U-100Target: FPG 71 to 90 mg/dLFollow-up ~2 yearsAt baselineAge (mean): 65.0 yHbA1c (mean): 8.4%Duration of T2DM (mean): 16.4 y85.2% established CVD or moderate CKD83.9% receiving insulin 54.8% basal-bolus Marso SP, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615692.

Cardiovascular Safety of Insulin Degludec: DEVOTE Study (cont) Outcome Hazard Ratio95% CI Primary composite10.910.78-1.06Expanded composite20.920.80-1.05All-cause death0.910.76-1.11Non-CV death0.840.60-1.16CV death0.960.76-1.21Nonfatal MI0.850.68-1.06Nonfatal stroke0.900.65-1.23 UA → hospitalization 0.95 0.68-1.31 Severe hypoglycemia 0.60 0.48-0.76 Nocturnal severe hypoglycemia 0.47 0.31-0.73 Marso SP, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615692. 1CV death, nonfatal MI, nonfatal stroke2CV death, nonfatal MI, nonfatal stroke, unstable angina leading to hospitalizationDegludec non-Inferior to glargine for major CV events

Flexible Dosing with Glargine U-300 Sub-study of pooled data from EDITION 1 and 2 (N=194)Glargine U-300 once daily for 3 monthsFixed: same time each dayFlexible: same time each day ± 3hChange from baseline to 3 monthsFlexibleFixed Daily basal insulin dose (units/kg)0.030.03HbA1c* (%)0.050.00FPG (mg/dL)6.63.9Confirmed or severe hypoglycemia (events/patient-year)10.4414.81Confirmed or severe nocturnal hypoglycemia (events/patient-year)2.301.95 Riddle MC, et al. Diabetes Technol Ther . 2016;18(4):252-257. *HbA1c 7.30% at baseline 64% of fixed-dose and 15% of flexible-dose participants reported all intervals within 23-25h range

Flexible Dosing with Degludec 26-wk randomized, open-label, treat-to-target trial (N=687)Glargine once daily at same time each dayDegludec once dailyFixed: same time each dayFlexible: schedule to create 8-40 hour dosing intervals Change from baseline* to 26 weeksDegludec GlargineFlexibleFixedHbA1c (%)-1.28-1.07-1.26FPG (mg/dL)-58-54-50Confirmed or severe hypoglycemia (events/patient-year)3.63.6 3.5 Confirmed or severe nocturnal hypoglycemia (events/patient-year) 0.6 0.6 0.8 Meneghini L, et al. Diabetes Care . 2013;36:858-864. *HbA1c 8.4-8.5% at baseline

Escalation vs Intensification of Basal Insulin Vivian A. Fonseca, MD, FRCP Professor of Medicine and Pharmacology Tullis Tulane Alumni Chair in Diabetes Chief, Section of Endocrinology Tulane University School of MedicineNew Orleans, Louisiana Jonathan D. Leffert, MD, FACP, FACE, ECNU Managing Partner, North Texas Endocrine Center President, American Association of Clinical Endocrinologists Dallas, Texas

Case Scenario: George 56 yo white male with a 7-y history of T2DMTitrates glargine U-100 with a mean FPG 130-145 mg/dLHbA1c 7.8%SMBG 2-3 days/weekHas occasional night sweats and restless sleep at 2-3 amCurrent medicationsMetformin 1000 mg bidPioglitazone 30 mg qAMGlargine U-100 65 units qHSVital signs: 5’10”; weight 216 lbs; BMI 31.0 kg/m2What considerations do you have?

When to Stop Titrating Basal Insulin and Consider Prandial Control Options 1. Skyler JS. In: Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related Disorders. Alexandria, VA: American Diabetes Association, Inc.; 2004:207-223. 2. American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers . 3rd ed. 2011:1-68.3. Inzucchi S, et al. Diabetes Care. 2012;35:1364-1379. 4. Davidson MB, et al. Endocr Pract. 2011;17:395-403.

Options for Intensifying Basal Insulin

American Diabetes Association. Diabetes Care. 2017;40(suppl 1):S1-S135. Therapeutic Options in Patients Not Achieving Glycemic Goals with Basal Insulin

24-week randomized study; N = 4823 Tanenberg RJ, et al. Diabetes. 2006;55(suppl 1):A135 [abstract 567-P]. Mean Insulin Dose, units/day FPG Goal, mg/dL Mean HbA1c, % Severe Hypoglycemia, rate / year 0.13 0.08 0.05 0.03 0.02 80 60 40 0 120 110 10090 80678 9 00.050.1 0.1578.274.969.662.2 59.4 7.67.57.4 7.47.3Mean basal insulin dose, units/dayMean HbA1C, %Severe hypoglycemia, rate/year Aggressive Basal Dose Titration May Increase Severe Hypoglycemia Without Improving HbA1c

Efficacy and Safety of Analog vs RHI Prandial Insulin Injections—Meta-Analysis Meta-analysis of 13 trials of 4361 individuals with T2DM. Mannucci E, et al. Diabetes Obes Metab. 2009;11:53-59.

Added Effect of a Single Mealtime Insulin Dose Owens DR, et al. Diabetes Obes Metab . 2011;13:1020-1027. Dominant breakfast (n=10; 20%) Dominant dinner (n=25; 51%) Dominant lunch (n=14; 29%) Mean rapid insulin 10.9 units Mean rapid insulin 12.2 units Mean rapid insulin 14.2 units ‘Basal-plus’ proof-of-concept study SMPG profiles before and 3 mos after addition of glulisine at the patient-identified dominant meal after optimized basal insulin (Mean HbA1c change vs placebo: -0.26%)

Basal-Plus Mealtime Insulin Use rapid-acting analogs (Aspart, Lispro, Glulisine), not RHIEasier timing, less postprandial hypoglycemiaStart with 1 injection at largest meal:4 units and titrate, ORBy weight: 0.1 unit/kgTitrate to:< 140 mg/dL 2 hours postprandial OR< 110 mg/dL next meal or bedtime Garber AJ, et al. Endocr Pract. 2016;22:84-113.

Basal-Plus Mealtime Insulin (cont) Consider decreasing dose or stopping oral secretagoguesCan continue metformin, TZD, AGI, GLP-1RA, DPP-4iBasal-bolus dosing~50% basal insulin and ~50% bolus insulinGarber AJ, et al. Endocr Pract. 2016;22:84-113.

Quality of Life Improves in T2DM With Intensification of Insulin TherapyMulticenter study of 447 patients with insulin-treated T2DM and HbA1c >7% Patients were transitioned from baseline insulin regimens to basal-bolus using glargine + rapid-acting insulinHbA1c declined from 8.8% to 7.7% over 6 months (P <.001)Nonsevere hypoglycemic episodes decreased Small but significant improvements with no significant change in hypoglycemia fear Emotional well-being (P<.001)Diabetes symptom distress (P<.001)Hypoglycemia fear (P =.61) Hajos TR, et al. Qual Life Res. 2012;21:1359-1365.

INNOVATIONS IN PRANDIAL INSULINS Vivian A. Fonseca, MD, FRCP Professor of Medicine and Pharmacology Tullis Tulane Alumni Chair in Diabetes Chief, Section of Endocrinology Tulane University School of MedicineNew Orleans, Louisiana Jonathan D. Leffert, MD, FACP, FACE, ECNU Managing Partner, North Texas Endocrine Center President, American Association of Clinical Endocrinologists Dallas, Texas

Current and Emerging Prandial Insulins a Not currently approved by the US FDA.US Food and Drug Administration. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.

Inhaled Technosphere Insulin in T2DM 1. Rave K, et al. J Diabetes Sci Technol. 2008;2:205-212.2. Rosenstock J, et al. Diabetes Care. 2015; 38(12):2274-2281. Inhaled TI (48 units) SC RHI (24 units) 5.0 3.0 1.0 Glucose Infusion Rate, mg/kg/min 0 60 120 180 Time, min 4.0 2.0 0.0 240 300 360 420 480 540 Duration of action for inhaled insulin is much shorter than for RHI 1 Almost complete PPG suppression has been observed in a double-blind, placebo-controlled trial in insulin-naive patients with T2DM using OADs 2

Inhaled Human Insulin Limitations of useAdultsIn T1DM, use with basal insulinNot for diabetic ketoacidosis, persons who smoke Contraindicated in chronic lung diseaseAssess lung function prior to and during treatmentHypokalemia- monitor at-risk personsFluid retention/Heart failure with concomitant TZDMost common adverse eventsHypoglycemia, cough, throat pain/irritationAfrezza [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; January 2016

U-200 Lispro* PharmacokineticsPharmacodynamics*PK/PD data generated from a study of 10 patients with T1DM.Potentially offers the advantage of a smaller injection volume for patients with high prandial insulin requirements 0 240 360 480 300 420 Time, min 120 180 60 250 200 150 100 0 Blood Glucose, mg/dL 50 LISPRO 0.2 U/kg (n = 10) RHI (n = 10); mean dose, 15.4 U 0 240 360 480 300 420 Time, min 120 180 60 80 70 50 30 0 10 20 40 60 Serum Free Insulin Concentration, mU/L LISPRO 0.2 U/kg (n = 10) RHI (n = 10); mean dose, 15.4 U Humalog [package insert]. Indianapolis, IN: Eli Lilly and Company; January 2017.

Insulin Lispro U-200 Same dose as U-100, but half the volumeHypokalemia- monitor at-risk personsFluid retention/Heart failure with concomitant TZDMost common adverse eventsHypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rashHumalog [package insert]. Indianapolis, IN: Eli Lilly and Company; January 2017.

Regular Human Insulin U-500 Limitations of useUse in adults/children requiring >200 units insulin/daySafety/efficacy in combination with other insulins has not been determinedIf using vial/syringe, use only U-500 syringeHypokalemia- monitor at-risk personsFluid retention/Heart failure with concomitant TZDMost common adverse eventsHypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rashHumulin R U-500 [package insert]. Indianapolis, IN: Eli Lilly and Company; March 2017.

PUTTING IT ALL TOGETHER Vivian A. Fonseca, MD, FRCP Professor of Medicine and Pharmacology Tullis Tulane Alumni Chair in Diabetes Chief, Section of Endocrinology Tulane University School of MedicineNew Orleans, Louisiana Jonathan D. Leffert, MD, FACP, FACE, ECNU Managing Partner, North Texas Endocrine Center President, American Association of Clinical Endocrinologists Dallas, Texas

Case Scenario: Maria 62-yo Hispanic female with a 10-y history of T2DMStarted glargine U-300 6 months ago as an add-on to oralsTitrated glargine; FPG 110-120 mg/dL; HbA1c 7.5%Works in a busy call center; has a very light breakfast, snack at lunchAdmits to being hungry at night; eats largest meal of the day

Case Scenario: Maria (cont) Current medicationsMetformin 1000 mg bidGlimepiride 4 mg qAMGlargine U-300 34 units qHSVital signs: height 5’2”; weight 156 lbs; BMI 28.5 kg/m2What are the options for achieving her HbA1c goal?

Case Scenario: Steven 42-yo African-American male with a 3-y history of T2DMInitially did well on oral agentsInitiated basal insulin due to a relatively rapid rise in blood glucose and worsening glycemic controlTravels frequently for work; demanding and unpredictable work scheduleHas been fatigued and frustrated managing his diabetesHbA1c 9.1%

Case Scenario: Steven (cont) Current medicationsMetformin 1000 mg bidGlimepiride 2 mg bidLinagliptin 5 mg qAMDegludec 40 units qHSVital signs: 6’0”; weight 184 lbs; BMI 25.0 kg/m2What is your clinical impression?