What s New in Diabetes: Egils Bogdanovics M.D. Hungerford Diabetes Center

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1 What s New in Diabetes: 2017 Egils Bogdanovics M.D. Hungerford Diabetes Center

3 Insulin: January 11, year old Leonard Thompson, on a starvation diet for 2 years received his first insulin injection A thick brown muck prepared by Banting and Best 7.5cc in each buttock lowered glucose from 440 to 320 and resulted in an abscess at each injection site

4 Diabetes 2017 Type 2: SGLT-2i and GLP1RA Type 2: Cardiovascular Outcome Trials Type 1 and 2: Insulin and Hypoglycemia Type 1 and 2: Continuous Glucose Monitoring

5 2017: 12 Classes of Drugs for Diabetes Medication Route of Administration Year of approval HbA1c reduction with monotherapy Insulin Parenteral 1921 >2.5 Sulfonylureas Oral Metformin Oral Alpha-glucosidase inhibitors Oral Thiazoladenediones Oral Metiglinides Oral GLP-1 analogs Parenteral Amylin Analogs Parenteral DPP-IV inhibitors Oral Colesevelam Oral Bromocriptine Oral SGLT2 inhibitors Oral

6 The Ominous Octet Islet b-cell Impaired Insulin Secretion Decreased Incretin Effect Increased Lipolysis Islet a-cell Increased Glucagon Secretion Increased Glucose Reabsorption Increased HGP Neurotransmitter Dysfunction Decreased Glucose Uptake DeFronzo RA Diabetes 2009

7 Phlorizin 1835

10 Renal Threshold for Glucose Excretion in Healthy Subjects

11 Renal Threshold for Glucose Excretion in T2DM: Increased

12 SGLT2 Inhibition Lowers Renal Threshold for Glucose Excretion

13 SGLT2 Inhibitors INVOKANA canagliflozin FARXIGA dapagliflozin JARDIANCE empagliflozin sotagliflozin

14 Guidelines

Approach to the Management of Hyperglycemia Patient/Disease Features Risks associated with hypoglycemia & other drug adverse effects Disease Duration Life expectancy Important

severe Patient attitude & expected treatment efforts Resources & support system highly motivated, adherent, excellent self-care capabilities readily available less motivated,

15 Approach to the Management of Hyperglycemia Patient/Disease Features Risks associated with hypoglycemia & other drug adverse effects Disease Duration Life expectancy Important comorbidities Established vascular complications more stringent low newly diagnosed long absent absent A1C 7% Few/mild Few/mild less stringent high long-standing short severe severe Patient attitude & expected treatment efforts Resources & support system highly motivated, adherent, excellent self-care capabilities readily available less motivated, nonadherent, poor self-care capabilities limited American Diabetes Association Standards of Medical Care in Diabetes. Glycemic targets. Diabetes Care 2016; 39 (Suppl. 1): S39-S46

17 Trends in Age-Standardized Rates of Diabetes-Related Complications among U.S. Adults with and without Diagnosed Diabetes, : Residual Risk Gregg EW et al. N Engl J Med 2014;370:

18 Evolution of FDA CV Safety Concerns 1992 Human Proinsulin: trials and development suspended due to increased risk acute MI 2005 Muraglitazar: increased risk of death, major CV events, CHF 2007 Rosiglitazone: increased CV risk; withdrawn from market in many countries* 2008: FDA Guidance

19 Cardiovascular Outcome Trials December 2008

20 3 point MACE : Major Adverse Cardiovascular Event Cardiovascular Death Non-Fatal Myocardial Infarction Non-Fatal Stroke

21 Original Article Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes Bernard Zinman, M.D., Christoph Wanner, M.D., John M. Lachin, Sc.D., David Fitchett, M.D., Erich Bluhmki, Ph.D., Stefan Hantel, Ph.D., Michaela Mattheus, Dipl. Biomath., Theresa Devins, Dr.P.H., Odd Erik Johansen, M.D., Ph.D., Hans J. Woerle, M.D., Uli C. Broedl, M.D., Silvio E. Inzucchi, M.D., for the EMPA-REG OUTCOME Investigators N Engl J Med Volume 373(22): November 26, 2015

22 Zinman B et al. N Engl J Med 2015;373: Glycated Hemoglobin Levels.

23 Cardiovascular Outcomes and Death from Any Cause. Zinman B et al. N Engl J Med 2015;373:

25 EMPA-REG CV death, MI and stroke Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/ / (0.74, 0.99)* CV death 172/ / (0.49, 0.77) < Non-fatal MI 213/ / (0.70, 1.09) Non-fatal stroke 150/ / (0.92, 1.67) Favours empagliflozin Favours placebo Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI 25

26 Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk Simvastatin 1 for 5.4 years Ramipril 2 for 5 years Empagliflozin for 3 years High CV risk 5% diabetes, 26% hypertension Pre-statin era High CV risk 38% diabetes, 46% hypertension Pre-ACEi/ARB era <29% statin T2DM with high CV risk 92% hypertension >80% ACEi/ARB >75% statin S investigator. Lancet 1994; 344: , 2. HOPE investigator N Engl J Med 2000;342:145-53, 26

27 Original Article Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes Bruce Neal, M.B., Ch.B., Ph.D., Vlado Perkovic, M.B., B.S., Ph.D., Kenneth W. Mahaffey, M.D., Dick de Zeeuw, M.D., Ph.D., Greg Fulcher, M.D., Ngozi Erondu, M.D., Ph.D., Wayne Shaw, D.S.L., Gordon Law, Ph.D., Mehul Desai, M.D., David R. Matthews, D.Phil., B.M., B.Ch., for the CANVAS Program Collaborative Group N Engl J Med Volume 377(7): August 17, 2017

28 Effects of Canagliflozin on Glycated Hemoglobin Level, Body Weight, and Systolic and Diastolic Blood Pressure in the Integrated CANVAS Program. Neal B et al. N Engl J Med 2017;377:

29 Cardiovascular Outcomes in the Integrated CANVAS Program. Neal B et al. N Engl J Med 2017;377:

30 Cardiovascular Outcomes in the Integrated CANVAS Program

31 Adverse Events. Neal B et al. N Engl J Med 2017;377:

32 Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal.

34 Incretin 1932 La Barre proposed the name Incretin for an intestinal derived factor which lowered glucose La Barre J. Sur les possibilites d'un traitement du diabete par l'incretine. Bull Acad R Med Belg 1932;12:

35 Patients with an event (%) LEADER trial: Primary Outcome First occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke in the time-to-event analysis in patients with type 2 diabetes and high CV risk Hazard ratio, 0.87 (95% CI, ) P<0.001 for noninferiority P=0.01 for superiority 10 5 Placebo Liraglutide Months since randomisation Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial Adapted from: Marso SP et al., NEJM 2016

007 15 10 Placebo Liraglutide 5 0 0 6 12 18 24 30 36 42 48 54 Months since

36 Patients with an event (%) LEADER trial: Death from Cardiovascular Causes 20 Hazard ratio, 0.78 (95% CI, ) P= Placebo Liraglutide Months since randomisation Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial Adapted from: Marso SP et al., NEJM 2016

38 Marso SP et al. N Engl J Med DOI: /NEJMoa Semaglutide Cardiovascular Outcomes.

39 Original Article Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes Rury R. Holman, F.Med.Sci., M. Angelyn Bethel, M.D., Robert J. Mentz, M.D., Vivian P. Thompson, M.P.H., Yuliya Lokhnygina, Ph.D., John B. Buse, M.D., Ph.D., Juliana C. Chan, M.D., Jasmine Choi, M.S., Stephanie M. Gustavson, Ph.D., Nayyar Iqbal, M.D., Aldo P. Maggioni, M.D., Steven P. Marso, M.D., Peter Öhman, M.D., Ph.D., Neha J. Pagidipati, M.D., M.P.H., Neil Poulter, F.Med.Sci., Ambady Ramachandran, M.D., Bernard Zinman, M.D., Adrian F. Hernandez, M.D., M.H.S., for the EXSCEL Study Group N Engl J Med Volume 377(13): September 28, 2017

40 Holman RR et al. N Engl J Med 2017;377: EXCEL Trial Outcomes

41 CV risk in T2D: summary of large randomized trials with respect to CV events (MACE), CV mortality, and heart failure. Bernard Zinman et al. Dia Care 2017;40: by American Diabetes Association

43 Insulin

44 Pancreatic Poop-Out intype 2 Diabetes Glucose (mg/dl) Obesity IGT* Diabetes Postmeal Glucose Uncontrolled Hyperglycemia Fasting Glucose Relative Function (%) b-cell Failure Insulin Resistance *IGT=impaired glucose tolerance. International Diabetes Center, Years of Diabetes

45 Decline in b Cell Function in UKPDS Rx:Insulin, metformin, sulfonylurea b-cell function (%) Years from diagnosis Dashed line shows extrapolation forward and backward from years 0 to 6 based on HOMA data from UKPDS. Lebovitz H. Diabetes Rev. 1999;7:

46 Insulin 1928

47 Insulin concentrations 1922 U U-10 and U U U U-100 adopted 1958 U-500 Reg Beef 1998 U-500 Reg Hum 2015 U-200 Lispro 2015 U-300 Glargine 2015 U-200 Degludec

49 New Basal Insulins

50 Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs Plasma insulin Breakfast Lunch Dinner Novolog, Humalog or Apidra Aspart, Lispro or Glulisine Aspart, Lispro or Glulisine Basal Insulin 4:00 8:00 12:00 16:00 20:00 24:00 4:00 Time 8:00

51 Basal Insulin NPH Glargine: Lantus and Toujeo Detemir: Levemir Degludec: Tresiba

52 Contribution to overall hyperglycemia (%) FPG and PPG Contribution to 100 A1C Management PPG FPG < >10.2 A1C value quintiles (%) Findings revealed that as A1C improves, the relative contribution of PPG becomes increasingly important in maintaining overall glycemic control N=290 non insulin-using patients with type 2 diabetes. Monnier L et al. Diabetes Care. 2003;26:

53 Glucose concentration (mg/dl) Progressive Deterioration of PPG and FPG Is Characteristic of Type 2 Diabetes Breakfast Lunch Dinner Fasting (nocturnal period) Postprandial (daytime period) % 8.0% to <9.0% Morning period Time (hours) Diabetes duration (years) 7.0% to <8.0% 6.5% to <7.0% <6.5% A1C% Monnier L et al. Diabetes Care. 2007;30(2):

54 Insulin Glargine U-300

55 Glargine U-300

58 Insulin Degludec

60 Degludec MOA

62 Degludec Titration

BG (mmol/l) Glycaemic control: variability 18 16 Hyperglycaemia 324 288 14 Patient A Patient B 252 12 Low

7 mmol/mol) Hypoglycaemia 108 72 36 0 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 Time

64 BG (mmol/l) Glycaemic control: variability Hyperglycaemia Patient A Patient B Low variability High variability BG (mg/dl) Mean BG HbA 1c 7.8% (61.7 mmol/mol) Hypoglycaemia Time (hours) 0 BG, blood glucose Image adapted from Penckofer et al. Diabetes Technol Ther 2012;14:303 10; Vora & Heise. Diabetes Obes Metab 2013;15:701 12

Pathophysiological cardiovascular consequences of

days 2 Inflammation Persists for up to 48 hours 1

abnormalities HYPOGLYCAEMIA Endothelial dysfunction

Sympathoadrenal response Epinephrine Rhythm

changes Heart workload Contractility Output CRP,

vascular endothelial growth factor; Adapted from

Diabetes Care 2010;33:1389; Frier et al.

65 Pathophysiological cardiovascular consequences of hypoglycaemia CRP VEGF IL-6 Effects last up to 7 days 2 Inflammation Persists for up to 48 hours 1 Neutrophil activation Blood coagulation abnormalities HYPOGLYCAEMIA Endothelial dysfunction Vasodilatation Platelet activation Factor VIII Sympathoadrenal response Epinephrine Rhythm abnormalities Heart rate variability Haemodynamic changes Heart workload Contractility Output CRP, C-reactive protein; IL-6, interleukin 6; VEGF, vascular endothelial growth factor; Adapted from Desouza et al. Diabetes Care 2010;33:1389; Frier et al. Diabetes Care 2011;34 (Suppl. 2):S132; 1. Wright et al. Diabetes Care 2010;33:1591; 2. Chow et al. Diabetologia 2013;56 (Suppl. 1):S243

66 ECG (mv) Hypoglycaemia is associated with ECG abnormalities Baseline Hypoglycaemic hyperinsulinaemia Abnormalities in: 3 R Atrioventricular conduction Ventricular repolarisation 2 Catecholamine release leads to: K+ R-wave amplification 1 T T-wave flattening Depression of ST segment 0 P Q Prolongation of QT interval Risk of cardiac arrhythmia S Time (seconds) ECG, electrocardiogram Laitinen et al. Ann Noninvasive Electrocardiol 2008;13:

DEVOTE summary 3-point MACE (primary) Severe hypoglycaemia HR: 0.91 [0.78; 1.

001 Nocturnal severe hypoglycaemia Rate ratio: 0.47 [0.31; 0.73] 95% CI p<0.

DEVOTE reported 752 adjudication-confirmed severe hypoglycaemic events in a blinded head-to-head trial A 40% lower

hypoglycaemia was confirmed at a lower fasting plasma glucose CI, confidence interval; EAC, Event Adjudication

67 DEVOTE summary 3-point MACE (primary) Severe hypoglycaemia HR: 0.91 [0.78; 1.06] 95% CI Non-inferiority confirmed p<0.001 Rate ratio: 0.60 [0.48; 0.76] 95% CI Superiority confirmed p<0.001 Nocturnal severe hypoglycaemia Rate ratio: 0.47 [0.31; 0.73] 95% CI p<0.001 DEVOTE confirmed the cardiovascular safety of insulin degludec in comparison with insulin glargine (both U100) DEVOTE reported 752 adjudication-confirmed severe hypoglycaemic events in a blinded head-to-head trial A 40% lower rate of severe hypoglycaemia was confirmed at similar levels of HbA 1c A 53% lower rate of nocturnal severe hypoglycaemia was confirmed at a lower fasting plasma glucose CI, confidence interval; EAC, Event Adjudication Committee; HR, hazard ratio; IGlar U100, insulin glargine U100; MACE, major adverse cardiovascular events; N, number of patients at risk; PYO, patient-years of observation Marso et al. N Engl J Med 2017;377:723 32

68 New Basal Insulins Reduced Intrasubject Variability True 24 Hour Duration Reduced Nocturnal Hypoglycemia Reduced Injection Burden in T2DM

69 Detecting Glucose Variability with SMBG SMBG testing is associated with improved A1C levels in patients with T1DM and patients with T2DM treated with insulin Efficacy of SMBG depends on the patient s willingness and ability to perform several finger sticks throughout the day Even when SMBG frequency is high, it still provides only a few snapshots from a complex and variable environment, and provides no information about glucose levels when a patient is sleeping

70 BG level (mg/dl) BG level (mg/dl) Blood Glucose Fluctuations in Patients with Similar Average Blood Glucose Values Patient A Patient B Days of study Mean BG=144; A1C=6.5% 2 Hypoglycemia: 70 mg/dl Mean BG=144; A1C=6.5% 2 Hypoglycemia: 70 mg/dl 1. Kovatchev BP et al. Diabetes Care. 2006;29(11): ; 2. Nathan DM et al. Diabetes Care. 2008;31(8):

71 Continuous Glucose Monitoring (CGM)

72 Continuous Glucose Monitor Sensor

73 Where is the ball going?

74 HbA1c 7.3 Sensor Modal Day Report

75 Hypoglycemia Unawareness with Freddie, no reaction occurred after a blood sugar of 60 mg/dl and with Alice S., none occurred when the blood sugar was as low as 40 Dangerous hypoglycemia may occur without warning symptoms. Joslin, E 1924

76 Trend Arrow

77 T1D Exchange % of CGM users openly admitted to using CGM glucose values for determining insulin doses

78 Decision Making with CGM CGM number Trend Arrow Alert/Alarm Trend Graph

79 Trend Arrows

82 Hypoglycemia

83 Hypoglycemia Are you low or just stupid?

84 Median % Change Using a CGM: Change in Time Spent Within Various Glucose Ranges 125% 100% 75% Subjects with Baseline A1C > 9% *p < %* Subjects with Baseline A1C < 7% 125% 100% 75% 50% 25% 0% 27.4% 0.8% 8.8% 50% 25% 0% -25% -50% -75% -31.1% -36.4% < >240 Glucose Range (mg/dl) -46.4%* *p < % -8.5% -14.2% < >240 Glucose Range (mg/dl) -25% -50% -75%

87 Therapeutic CGM 12/20/16 FDA expanded indication Dexcom G5 CGM to replace FSBG testing for treatment decisions: non-adjunctive use 1/12/17 CMS ruling 1682R classified Therapeutic vs Non-Therapeutic CGM systems for Medicare patients

88 Medicare Therapeutic CGM Have Type 1 or Type 2 Diabetes Currently use a Home Blood Glucose Monitor and perform at least 4 fingersticks per day Take insulin, either with multiple daily injections or an insulin pump Have an insulin plan that requires frequent changes based on CGM readings

89 Dexcom

90 Freestyle Libre

91 Artificial Pancreas

92 Artificial Pancreas 670G

95 The person with diabetes who knows the most lives the longest Elliot Joslin

The Alphabet Soup of Diabetes. Egils Bogdanovics M.D. Hungerford Diabetes Center

The Alphabet Soup of Diabetes. Egils Bogdanovics M.D. Hungerford Diabetes Center The Alphabet Soup of Diabetes Egils Bogdanovics M.D. Hungerford Diabetes Center Insulin: January 11, 1922 12 year old Leonard Thompson, on a starvation diet for 2 years received his first insulin injection