What's New in Insulin Related Therapies 2018

Transcription

1 What's New in Insulin Related Therapies 2018 James Lenhard, MD Section Chief, Endocrinology and Metabolism Christiana Care Health System Newark, DE

2 Disclosures Speaker:Eli Lilly, Janssen

3 Prevalence of Diabetes Number of Persons with Diagnosed Diabetes, United States, Diabetes is becoming more common in the United States. In 2000, about 12 million persons in the United States reported that they had diabetes. As the detailed tables show, people aged 65 years or older account for almost 40% of the population with diabetes. Between 1996 and 1997 an unusually large increase occurred in the number of people with diagnosed diabetes. Most of this increase is likely due to changes in the survey used to measure diagnosed diabetes Estimates 18.8 million diagnosed 7.0 million undiagnosed 8.3% of our population 25.8 million Pre-diabetes = 79 million!

4 Prevalence of Diabetes Number of Persons with Diagnosed Diabetes, United States, Diabetes is becoming more common in the United States. In 2000, about 12 million persons in the United States reported that they had diabetes. As the detailed tables show, people aged 65 years or older account for almost 40% of the population with diabetes. Between 1996 and 1997 an unusually large increase occurred in the number of people with diagnosed diabetes. Most of this increase is likely due to changes in the survey used to measure diagnosed diabetes Estimates 21.0 million diagnosed 8.1 million undiagnosed 9.3% of our population 29.1 million Pre-diabetes = 86 million!

5 Prevalence of Diabetes Number of Persons with Diagnosed Diabetes, United States, Diabetes is becoming more common in the United States. In 2000, about 12 million persons in the United States reported that they had diabetes. As the detailed tables show, people aged 65 years or older account for almost 40% of the population with diabetes. Between 1996 and 1997 an unusually large increase occurred in the number of people with diagnosed diabetes. Most of this increase is likely due to changes in the survey used to measure diagnosed diabetes Estimates 23.1 million diagnosed 7.2 million undiagnosed 9.4% of our population 30.3 million Pre-diabetes = 84.1 million!

6 2015 Prevalence Report A study of US trends in total diabetes, diagnosed diabetes, and undiagnosed diabetes using National Health and Nutrition Examination Survey (NHANES) data. The prevalence of diabetes and prediabetes was defined by using hemoglobin A 1c, fasting plasma glucose (FPG), 2-hour plasma glucose (2-hour PG) level. Data was examined both adjusted to the average age of people in NHANES and unadjusted. Prevalence of and Trends in Diabetes Among Adults in the United States, Andy Menke, PhD 1 ; Sarah Casagrande, PhD 1 ; Linda Geiss, MA 2 ; Catherine C. Cowie, PhD 3 JAMA. 2015;314(10): doi: /jama

7 Age Adjusted The increase in diabetes has primarily been in the number of diagnosed cases. Undiagnosed diabetes is not increasing.

8 Conclusions In the overall population, the prevalence was 12.4% (adjusted)/14.3% (unadjusted) for total diabetes, and 38.0% for prediabetes. 50 to 52% of adults over age 20 have diabetes or prediabetes. Using a 2015 population of adults > age 20 in DE of 805,083, the number of people with diabetes is estimated to be 100,202. Using a 2015 population of adults > age 20 in the US of 235,183,899, the number of people with diabetes is estimated to be 29.2 million. US Census Bureau

9 Changes in Diabetes Prevalence The CDC predicted that a child born in the year 2000 had a two in five (40%) chance of developing diabetes in their lifetime. Gregg E et al, The Lancet Diabetes & Endocrinology, 2014, (Aug 13)

10 Diabetes and Hyperglycemia at CCHS 31% of all non-pregnant adult patients. Increasing by ~1% yearly. Confers ~ 1.1 extra day to the ALOS.

11 Insulin: Past, Present and Future Technosphere inhlaed insulin Combinations: IGlarLixi IDegAsp IdegLira

12 When do you generally start basal insulin? 1. After metformin 2. After two oral antihyperglycemic therapies 3. After three oral antihyperglycemic therapies 4. After basal insulin therapy

13 Sophie Sophie is a 62 year old woman with 15 year history of type 2 diabetes complicated by obesity, diabetic kidney disease and nonproliferative retinopathy. She is currently taking metformin 500 mg twice a day, detemir insulin 50 units AM and 20 units PM. She is intolerant of GLP-1 RA. She tests her BG three times per day. Her am BG are generally in the 150 s. She reports BG in the 200 s during the mid-day and overnight hypoglycemia three times per month. She admits to eating lunch at restaurants two three times per week. Her lipids and blood pressure are well controlled. Her A1c is 8.4% and egfr is 40 ml/min/1.73 m 2.

14 What do you think is the most likely reason for her poor glycemic control? 1. Poor dietary adherence 2. Poor absorption of detemir insulin 3. Poor adherence to BID dosing of detemir

15 What would you suggest for Sophie? 1. Sending her for diabetes education 2. Discontinue metformin 3. Increasing am dose of detemir 4. Add SGLT-2 inhibitor 5. Changing detemir insulin to U-300 glargine

16 What dose would you recommend? units units units units

17 ADA/EASD Approaches to Glycemic Treatment Uncontrolled hyperglycemia (catabolic features, BG mg/dl, HbA1c 10-12%) American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care 2017; 40 (Suppl. 1): S64-S74

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19 Plasma Glucose, mg/dl Basal Insulin Improves Fasting Plasma Glucose Without T2DM Basal insulin effect With T2DM 6:00 10:00 14:00 18:00 22:00 2:00 6:00 B L D Time Polonsky KS, et al. N Engl J Med. 1988;318:

20 Approved Basal Insulins: United States Human Insulin Analogue Insulins U-100 NPH Long-acting U-100 detemir U-100 glargine U-100 glargine equivalent a Ultralong-acting U-300 glargine a U-100 degludec a U-200 degludec a a Available only in prefilled pens. Drugs@FDA.

21 Evolution of basal insulin preparations

22 Less hypoglycemia with first generation basal analogues vs. NPH * * * * Riddle et al. Diabetes Care 2003; 26: Philis-Tsimikas et al. Clin Ther 2006; 28 (10). *P<0.05

23 Modeled risk of hypoglycemia based on achieved A1C levels Little S, et al. Diab Tech Ther 2011; 13 (S1)

24 Patients modifying insulin dose Fear of hypoglycemia conflicts with treatment success for both patients and clinicians Percentage of patients decreasing their insulin dose following a hypoglycemic event 1 I would treat my patients more aggressively if there was no concern about hypoglycemia 2 100% 80% 60% 40% 20% 74% 43% 79% 58% T1D (n=202) T2D (n=133) Primary care physicians Diabetes specialists 72% 79% 0% Non-severe episodes Severe episodes Percentage 1. Leiter et al. Can J Diabetes 2005;29:186 92; 2. Peyrot et al. Diabet Med 2012;29:682 9, GAPP (A global internet survey of patient and physician beliefs regarding insulin therapy): n=1250 physicians

25 U300 Glargine Has a Flatter, More Prolonged Time Action Profile than U100 Glargine Type 1 DM after 8 days of treatment

26 Confirmed Hypoglycemia: U-300 Gla vs U-100 Gla in T2DM Previously Treated with Basal Insulin At any time (24 h) Cumulative mean number of confirmed Cumulative ( 70 Cumulative mmean g/dl number [ 3 mean.9 mmol/l]) of number Estimated or of severe number events of 10 confirmed ( ( 3.9mmol/L 70 mg/dl( 3.9 [ 70 mmol/l mg/dl]) or or severe events Gla-300 Gla At At Any any Time time (24 Hour) h) Nocturnal (00:00 05:59 h) Cumulative mean number of co firm Cumulative ed ( 70 mmean g/dl number [ 3.9 mmol/l]) of Estimated or severe number events of 3 confirmed ( 3.9mmol/L [ 70 mg/dl]) or severe events Gla-300 Gla Nocturnal (00:00-05:59 Hour) Time, weeks Rate ratio 0.86 (0.77 to 0.97) P= Rate ratio 0.69 (0.57 to 0.84) P= Maintenance Time, weeks On average, doses of U300 were 10 17% higher than U100 Yki-Jarvinen H, et al. Diabetes Care. 2014;37:

27 Half-life of insulin degludec is twice as long as that of insulin glargine Insulin concentration (% of maximum) 100 IDeg 0.8 U/kg IGlar 0.8 U/kg 10 * Time since injection (hours) Insulin degludec Insulin glargine 0.4 U/kg 0.6 U/kg 0.8 U/kg 0.4 U/kg 0.6 U/kg 0.8 U/kg Half-life (hours) Mean half-life *Insulin glargine was undectable after 48 hours Results from patients with type 1 diabetes IDeg, insulin degludec; IGlar, insulin glargine Heise et al. Diabetologia 2011;54(Suppl. 1):S425

28 Hypoglycaemia with Degludec vs Glargine Type 1 DM Rate of overall symptomatic confirmed hypoglycaemia Rate of nocturnal symptomatic confirmed hypoglycaemia Rate of severe hypoglycaemia Maintenance period Full treatment period Type 2 DM Lane W et al JAMA 2017;318: Wysham C et al JAMA 2017;318:45-56

29 Number of hypoglycaemic events High variability in SMBG is associated with increased risk for hypoglycaemic events in Type 2 DM p< Variability tertile: 430 Low Medium High 258 p= p= Overall symptomatic Nocturnal symptomatic Severe Bailey et al. Presented at ADA 2017, poster number 404-P Bailey T et al Poster 404-P, Presented at 77th Annual ADA Scientific Sessions, June 2017

30 Variability of Effect Variability in effects of an insulin can cause unexplainable variations in glucose control from day to day Insulin Within Subject Variability (CV% of AUC GIR) NPH 68 Glargine U Detemir 27 Glargine U Degludec 20 Adapted from: Rossetti P, et al. Diabetes Obes Metab, 2014;16: ; Becker RHA, et al. Diabetes Obes Metab, 2015;17:261-7

31 Insulin Doses are Increasing

32 Glucose Infusion Rate (mg/min) Humulin R U-100: Increased Insulin Concentration Delays Absorption & Action This allows for coverage of prandial and basal with 2 3 injections/day U100 U500 Delayed Onset of action and longer duration De la Peña et al. Diabetes Care 2011;34:

33 U500 in MDI - A1c, Weight and TDD Change - U500 in CSII A1c Weight U-500R MDI; (A) Changes in A1c with a significant reduction of 1.59% (95% CI, ); (B), weight with a significant increase of 4.38 kg (95% CI, ); (C), TDD with a significant increase of 51.9 units (95% CI, ) A1c Weight TDD U-500R via CSII; (A) Changes in A1c with significant reduction of 1.64% (95% CI, ); (B), weight nonsignificant increase of 2.99 kg (95% CI, ); (C) and TDD with nonsignificant decrease of 13.6 units TDD JDST 2012

34 PK/PD of IDeg U200 and IDeg U100 are Bioequivalent

35 Transitioning Between Insulins* From To Consider dose change U100 glargine U300 glargine 10 15% more U300 glargine U100 glargine 10 15% less U300 glargine degludec 20 35% less U100 glargine degludec 10 15% less degludec U100 glargine 10% more BID NPH, detemir Any 20% less *Individualize by A1c and presence of hypoglycemia Fide C. Wysham MD

36 Switching Basal Insulin vs Intensifying Consider switch if: Patient close to goal, on < 0.5U/kg, but hypoglycemia limiting further titration Patient with high variability in SMBG readings Consider intensification if: Patient not at goal on dose > 0.5 U/kg Fasting glucose < 130 and A1c > 7% Experiencing nocturnal hypoglycemia

37 Advancing Beyond Basal Insulin in Type 2 Diabetes Mellitus

38 Richard Richard is a 55 year old white male with 10 year history of type 2 diabetes. He tries to eat healthy, but he eats out frequently. His weight has been increasing over the past five years. Current weight 100 kg, BMI 31. He is currently taking metformin 1000 mg BID and U100 glargine 50 units at HS.

39 Richard He usually performs SMBG once daily in the AM. His average fasting glucose is 123, with range between 72 and 217. When he tests at bedtime, he is usually > 200. He occasionally has hypoglycemia in the afternoon, if he misses lunch A1c 8%

40 What would you suggest to Richard? 1. Continue to titrate U100 glargine until AM BG < Add rapid acting insulin before each meal 3. Add rapid acting insulin before dinner 4. Add GLP-1 RA once daily 5. Add SGLT-2 inhibitor 6. Add DPP-4 inhibitor.

41 Why not just titrate basal insulin further Several clues in Richard s history suggest that titration of basal insulin is not optimal approach: His glargine dose is > 0.5 U/kg His A1c > 7%, with mean fasting BG < 130 His HS BG > AM BG He has hypoglycemia with missed meal He is probably over basalized

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

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44 Rule of Thirds for the Half Way Mark By the half way point of a lecture, 1/3 of the audience will be in REM, +/- snoring. 1/3 will be awake still, but teetering near sleep. 1/3 will be awake but daydreaming: 1/3 about vacation, 1/3 about finances and 1/3 about sex/romance. $$$$$$

45 Approved Prandial Insulins: United States Human Insulins Analogue Insulins U-100 RHI U-500 RHI Inhaled RHI U-100 aspart (Novolog) U-100 glulisine (Apidra) U-100 lispro (Humalog) U-200 lispro 2 (Humalog U200) Biosimilar lispro (Admelog) Fiasp ² Available only in prefilled pens. Drugs@FDA.

46 Premixed Insulins: United States Human Insulins Analogue Insulins Human Regular 70/30 Lispro 50/50 Lispro 75/24 Aspart 70/30 Ideg/Aspart 70/30

47 Mean GIR, mg/min Comparative Pharmacodynamics of U-200 and U-100 Insulin Lispro U-200 and U-100 lispro are bioequivalent 1,2 No dose conversion is needed 1 U-200 lispro is available only in pen injectors Time, h U-200 lispro (20 U) U-100 lispro (20 U) de la Peña A, et al. Clin Pharmacol Drug Dev. 2016;5: Drugs@FDA.

48 FIASP

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50 FIASP

51 FIASP Faster, but still not fast enough Faster clearance may be more important than faster onset Type 1 diabetes, especially CSII

52 Δ A1C From BL, % Comparing Basal-Bolus, Basal-Plus, and ASP Premixed Insulin Regimens Premix BID -2.0 Basal- Plus -2.3* -2.4 * P =.06 vs premix P <.01 vs premix Basal- Bolus A1C with basal-bolus vs premix (P <.01) A1C < 7% Basal-plus: 49% Premixed: 39% (P <.05) Hypoglycemia (BG < 50 mg/dl): incidence 30%-35% lower with basal-bolus vs premix (P <.01) Similar insulin doses and weight gain in all groups Open-label study of patients previously on oral agents (60 weeks; N = 582; BL A1C = 9.4%) started and optimized on GLAR followed by 1 injection of GLU (basal-plus), GLAR followed by stepwise addition of up to 3 injections of GLU (basal bolus), or twice-daily ASP 70/30 (premix BID). Riddle MC, et al. Diabetes Obes Metab. 2014;16:

53 Confirmed Hypoglycemia (cumulative events per patient), n Weight Change, kg Confirmed Hypoglycemia Degludec/Aspart Premixed Insulin DEG/ASP ASP 70/30 32% reduction P = Time Since Randomization, weeks Mean Weight Change P <.05 Similar A1C decrease in both groups (8.3%-8.4% to 7.1%) More patients reached A1C < 7% without hypoglycemia with DEG/ASP than with ASP 70/30 (21.8% vs 14.9%; P =.041) Premixed DEG + ASP ASP 70/ patients with T2DM previously using premixed or self-mixed insulin with or without oral agents. Both insulins were dosed twice daily. Confirmed hypoglycemia: plasma glucose < 56 mg/dl or assistance required. Fulcher GR, et al. Diabetes Care. 2014;37:

54 Recommended Alternatives to Bolus Prandial Insulin for Improving PPG in Patients on Basal Insulin ADA/EASD 1 GLP-1 RA Premixed insulin twice daily a AACE/ACE 2 GLP-1 RA SGLT2 inhibitor DPP-4 inhibitor a Before breakfast and dinner. 1. ADA. Diabetes Care. 2017;40(suppl 1):S1-S Garber AJ, et al. Endocr Pract. 2017;23:

55 GLP-1 Receptor Agonists with Basal Insulin FDA approved Exenatide BID (Byetta) Exenatide weekly (Bydureon) Liraglutide (Victoza) Albiglutide (Tamzeum) Withdrawn Dulaglutide (Trulicity) Semaglutide (Ozempic) Fixed ratio insulin + GLP-1 RA iglarlixi (Soliqua) ideglira (Xultophy)

56 Adding Exenatide BID to Glargine: Change in A1C From Baseline 0 Change in A1C % ±0.09% ±0.09% Treatment Week OG + exenatide BID (baseline, %) OG + placebo BID (baseline, %) A1C, glycosylated hemoglobin; OG, optimized glargine. Adapted from Buse JB et al. Ann Intern Med. 2011;154(2): Exenatide Placebo Weight (kg) Severe hypoglycemia 0 2 events/1 pt. Hypoglycemia (%) Hypo (events/pt-yr)

57 Exenatide BID Added to Basal Insulin Glargine Improves Post-Prandial Glucose Excursions in T2DM Buse, et al. Ann Intern Med. 2011;154: Rosenstock, et al. Diabetes Care 2012; 35(5): Epub 2012 Mar 19.

58 Intensifying Insulin Therapy With a GLP-1 RA vs Prandial Insulin Compared with adding prandial insulin, adding a GLP-1 RA 1,2 : Is equally, if not more, effective Has a lower risk of hypoglycemia Is less likely to cause weight gain Is associated with less glycemic variability throughout the day A1C 7.0% a Equivalent glycemic control (P = NS) 1,3,4 Hypoglycemia b 33% fewer events per patient-year with GLP-1 RA (P <.05) 1,3-5 Δ Weight a 5.66-kg more weight loss with GLP-1 RA (P <.05) 1,3-5 a Baseline to the end of the intervention. b Any hypoglycemic episode, as defined by the trial. 1. Eng C, et al. Lancet. 2014;384: FLAT-SUGAR Trial Investigators. Diabetes Care. 2016;39: Diamant M, et al. Diabetes Care. 2014;37: Rosenstock J, et al. Diabetes Care. 2014;37: Shao H, et al. Diabetes Metab Res Rev. 2014;30:

59 Percent Patients (%) Mean A1C (%) (%) Efficacy of Fixed-Ratio iglarlixi in T2DM Patients Not Controlled on Basal Insulin T2DM patients not controlled on basal insulin + Met ± 2 nd OAD % 8.1% iglarlixi (N = 366) Mean Difference p-value vs Glargine (N = 365) -0.52% < % iglarlixi Glargine % Patients with A1C < 7.0% at Week Screening Baseline 8 Glargine Week iglarlixi 6.9% A1C < 7.0% with No Wt Gain and No Symptomatic Hypoglycemia

60 Once Daily Lixisenatide vs. Prandial Insulin: HbA1C Reduction Mean (95% CI) HbA 1c (%) Lantus ± MET Insulin optimization Lixisenatide QD Glulisine QD Glulisine TID Week 26 (LOCF) Study week Lixisenatide Glulisine QD Glulisine TID Week 26 Δ Baseline, Mean Rosenstock J et al. Diabetes Care. 2016;39:

61 IDegLira in Patients Failing Basal Insulin: Changes in A1c, Body Weight and Hypoglycemia Lingvay I JAMA 2016;315:

62 DUAL-7: IDegLira vs Basal-Bolus Insulin in Type 2 DM Billings, L et al Presented at ADA 77 th Annual Scientific Sessions, San Diego, CA, 2017

63 Mean Change from Premeal Plasma Glucose (mg/dl) PPG Effect of Short- and Long-Acting GLP-1 RAs: LIXI vs LIRA Patients (%) Lixisenatide (Baseline) Liraglutide (Baseline) Meal Time after Study Drug Administration GLP-1 Agonist LIXI = lixisenatide; PPG = postprandial glucose. Kapitza C, et al. Diabetes Obes Metab. 2013;15(7): Lixisenatide (Day 28) Liraglutide (Day 28) p < Proportion of Patients with 2-h PPG < 140 mg/dl at Day Lixisenatide (n = 75) 29 Liraglutide (n = 68)

64 Jetta 49 year old woman with type 2 diabetes for 8 years. She works as a nursing supervisor covering the night shift at a large teaching hospital. She has two teenaged children and has variable sleeping schedule. She admits that the timing of her basal insulin is a challenge. She goes to the gym when she can. She tries to follow a low carbohydrate diet. Her weight is stable at 94 kg. She is very worried about hypoglycemia

65 Jetta Currently taking metformin 850 mg BID, liraglutide 1.2 mg daily, U100 glargine at 47 units at bedtime She performs SMBG 2 times daily. Her meter download: Mean BG with SD - 75, range # < 70 12, # < 50: 1. Most of her low blood glucose levels are at night when she worked and during the day, on her days off work. Her A1c is 7.8%

66 What would you recommend? 1. Lower her glargine insulin to 42 units 2. Change U100 glargine to U300 glargine 3. Change U100 glargine to Ideg/Lira 100/ Add liraglutide 5. Add SGLT-2 inhibitor

67 Jetta She was converted to Ideg/Lira 30 units daily*, with instructions to increase twice a week to am BG < 120 She returns for follow up in one month. She reports that, the first two weeks after the switch, her blood sugars were higher, but they subsequently improved Download of her meter revealed Mean of 149, with SD 54 and range between 63 and 294. She had 10 BG < 70 and none < 50.

68 Initial Doses and Titration of Fixed Dose Combinations of Insulin and GLP-1 RA Product Starting Dose Dose Range Titration Insulin degludec/ liraglutide 100/ Units/0.58 mg Lowest dose: 10 Units/0.36 mg Max dose: 50 Units/1.8 mg Every 3 to 4 days Above target: + 2 Units Within target: 0 Units Below target: -2 Units Insulin glargine/ lixisenatide 100/33 15 Units/5 mcg (If <30 Units basal insulin or lixisenatide) 30 Units/10 mcg (If Units basal insulin) Lowest dose: 15 Units/5 mcg Max dose: 60 Units/20 mcg Weekly Above target: + 2 Units Within target: 0 Units Below target: -2 Units Sanofi-Aventis U.S. LLC. insulin glargine/lixisenatide package insert. Bridgewater, NJ; Novo Nordisk A/S. insulin degludec/liraglutide package insert. Bagsvaerd, Denmark; 2016.

69 John is a 76 year old male with Type 2 DM Lipids and hypertension are well controlled Currently taking Metformin 500 mg BID and glargine insulin 44 units QAM A1c 8.2%, AM SMBG (average 129) egfr 42 ml/min

70 What would you suggest for improving John s glycemic control? Titrate basal insulin further Change to lixisenatide/glargine Change to degludec/liraglutide Add SGLT-2 inhibitor Add DPP-4 inhibitor

71 Mean Δ A1C From BL, % 0.5 Intensifying Insulin Therapy With a DPP-4 Inhibitor or an SGLT2 Inhibitor a DPP-4 inhibitors 1-4,b SITA SAXA LINA ALO SGLT2 inhibitors CANA DAPA EMPA 5-7,b P <.05 for all vs PBO. Impact on weight 1-7 DPP-4 inhibitors: considered to be weight neutral SGLT2 inhibitors: potential for weight loss a Basal/long-acting (all), intermediate-acting (SITA, SAXA), premixed (SITA, SAXA, ALO), short-acting (ALO, CANA, DAPA); b Outcomes with maximum recommended doses are presented Vilsbøll T, et al. Diabetes Obes Metab. 2010;12: ; 2. Barnett A, et al. Curr Med Res Opin. 2012;28: ; 3. Yki-Jarvinen H, et al. Diabetes Care. 2013;36: ; 4. Rosenstock J, et al. Diabetes Obes Metab. 2009; 11: ; 5. Neal B, et al. Diabetes Care. 2015;38: ; 6. Wilding JP, et al. Ann Intern Med. 2012;156: ; 7. Rosenstock J, et al. Diabetes Obes Metab. 2015;17: ; 8. Drugs@FDA. scripts/cder/daf/.

72 A1c Reduction (%) Linagliptin Added to Basal Insulin in Subjects 70 Years of Age and Older Sub-analysis to evaluate risk for hypoglycemia in older patients Baseline A1c 8.2% Plac Lina Inzucchi S et al. Diabetes Obes Metab 2015;17:

73 Some Clinical Considerations for Intensification Options CKD Exenatide not recommended for egfr < 30 ml/min/1.73 m 2 SGLT-2 inhibitors not recommended for egfr < 45 ml/min/1.73 m 2 Of DPP-4, all but Linagliptin require dose adjustment for CKD Acute Kidney Injury Reported with GLP-1 RA, SGLT-2, but not seen in CVOT Mitigate risk by avoiding dehydration and hypotension Gastrointestinal disease GLP-1 RA increase risk for nausea/vomiting short acting > long acting Cardiovascular disease consider SGLT-2 inhibitor or Liraglutide Peripheral vascular disease - Lower extremity amputations with canagliflozin Elderly -Consider DPP-4 as first step in intensification

74 Newer Basal Insulin and Combinations At same A1c, newer basal insulins are associated with lower rates of hypoglycemia compared with U100 glargine Have more flexibility in timing (+/- 3 hrs with U300 glargine, +/- 16 hours with degludec) Similar price as U100 glargine Insulin/GLP-1 RA combinations are indicated after treatment with either basal insulin or GLP-1 RA

75 Summary: Insulin Insulin is often needed to improve glycemic control in most patients with T2DM Basal insulin is typically initiated first, followed by addition of rapid-acting insulin or non-insulin agents to improve prandial control Ultralong-acting basal insulins may offer advantages such as dosing flexibility and lower hypoglycemia risk Advances in achieving prandial control include: Higher-concentration lispro New coformulations (aspart/degludec, liraglutide/degludec, lixisenatide/glargine) Recommendations for use of non-insulin agents

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77 Questions? Thank you!