Individualizing Treatment in the Management of Type 2 Diabetes: Novel Therapies for Improved Patient Outcomes. Richard Pratley, M.D.

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1 Individualizing Treatment in the Management of Type 2 Diabetes: Novel Therapies for Improved Patient Outcomes. Richard Pratley, M.D. Samuel Crockett Chair in Diabetes Research Director, Florida Hospital Diabetes Institute Senior Investigator, Translational Research Institute Adjunct Professor, Sanford Burnham Medical Research Institute Orlando, Florida, USA Disclosures Research Support: Lexicon, Lilly, Merck, Novo Nordisk, Sanofi, Takeda Consultant: Astra-Zeneca, Boehringer, GSK, Lilly, Merck, Novo Nordisk, Sanofi, Takeda, All honoraria directed toward a non-profit which supports education and research MSB 1

2 Objectives Compare and contrast the safety, efficacy and mechanisms of action of current and emerging therapies for achieving individualized target goals in types 2 diabetes (T2DM) Apply newly released clinical data and guidelines on combination therapies to practice regarding glycemic management in patients with T2DM Assess the importance of customizing A1c goals based on individual patient characteristics Recognize the most effective place in the T2DM treatment continuum for GLP-1 agonists, newer insulins and SGLT-2 inhibitors Analyze barriers to effective and timely combination therapy initiation and implement strategies to overcome these barriers in T2DM management Examine recent clinical data on the use of combination therapy to improve glycemic control and other cardiovascular risk factors in patients with T2DM Multiple Metabolic Defects Contribute to Hyperglycemia in T2DM Islet -cell Impaired Insulin Secretion Decreased Incretin Effect Increased Lipolysis Islet -cell Increased Glucagon Secretion Increased Glucose Reabsorption Increased HGP From DeFronzo, Diabetes: 2009 Neurotransmitter Dysfunction Decreased Glucose Uptake MSB 2

3 Type 2 Diabetes: A Progressive Disease Normal IGT Type 2 Diabetes Complications Disability Death Prediabetes state Clinical disease Complications 86 million 29 million Primary Secondary Tertiary Prevention Prevention Prevention IGT = impaired glucose tolerance CDC National Diabetes Statistics Report, Microvascular Complications of T2DM In , of adults 40 years of age with diabetes, 4.2 million (28.5%) had diabetic retinopathy. 655,000 (4.4%) had advanced diabetic retinopathy In 2010, about 73,000 non-traumatic lower-limb amputations were performed in adults 20 years of age with diabetes. About 60% of non-traumatic lower-limb amputations among adults 20 years of age are in people with diabetes. Diabetes was listed as the primary cause of kidney failure in 44% of all new cases in Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, Atlanta, GA: U.S. Department of Health and Human Services; MSB 3

4 Diabetes Doubles the Risk for Vascular Outcomes Number of Cases Coronary heart disease* 26,505 Coronary death 11,556 Nonfatal MI 14,741 HR (95% CI) I 2 (95% CI) 2.00 ( ) 64 (54 71) 2.31 ( ) 41 (24 54) 1.82 ( ) 37 (19 51) Stroke subtypes* Ischemic stroke 3,799 Hemorrhagic stroke 1,183 Unclassified stroke 4,973 Other vascular deaths 3, ( ) 1 (0 20) 1.56 ( ) 0 (0 26) 1.84 ( ) 33 (12 48) 1.73 ( ) 0 (0 26) HR = hazard ratio; CI = confidence interval; MI = myocardial infarction. Emerging Risk Factors Collaboration. Lancet. 2010;375(9733): ADA-EASD Position Statement: Management of Hyperglycemia in T2DM Glycemic targets HbA1c < 7.0% (mean PG mg/dl [ mmol/l]) Pre-prandial PG <130 mg/dl (7.2 mmol/l) Post-prandial PG <180 mg/dl (10.0 mmol/l) Individualization is key: Tighter targets ( %) - younger, healthier Looser targets ( %+) - older, comorbidities, hypoglycemia prone, etc. Avoidance of hypoglycemia Diabetes Care 2012;35: Diabetologia 2012;55: PG = plasma glucose MSB 4

5 12 Classes of Antihyperglycemic Agents for T2DM Class A 1c Reduction Hypoglycemia Weight Change Dosing (times/day) Other Safety Issues Metformin 1.5 No Neutral 2 GI, lactic acidosis, B12 deficiency Basal insulin analog Yes Gain 1, injected Hypoglycemia Rapid-acting insulin Yes Gain 1-4,injected Sulfonylureas 1.5 Yes Gain 1 Allergies, secondary failure Thiazolidinediones No Gain 1 Edema, CHF, bone fractures Short-acting GLP-1 RAs No Loss 2, injected GI,? pancreatitis, ARF Long-acting GLP-1 RAs ~1.5 No Loss 1, injected GI,? pancreatitis,?mtc,?arf Repaglinide Yes Gain 3 Nateglinide Rare Gain 3 Alpha-glucosidase inhibitors No Neutral 3 GI Amylin mimetics No Loss 3, injected GI DPP-4 inhibitors No Neutral 1 Pancreatitis Bile acid sequestrant 0.5 No Neutral 1 or 2 GI Bromocriptine quick release 0.7 No Neutral 1 GI SGLT2s No Loss 1 Genital mycotic infections GI = gastrointestinal; GLP-1 = glucagon-like peptide-1; RA = receptor agonist; CHF = congestive heart failure; ARF = acute renal failure; MTC = medullary thyroid carcinoma; DPP-4 = dipeptidyl peptidase-4; SGLT2 = sodium-dependent glucose cotransporter -2. Adapted from: Nathan DM, et al. Diabetes Care. 2007;30(3): Nathan DM, et al. Diabetes Care. 2006;29(8): Nathan DM, et al. Diabetes Care. 2009;32(1): ADA. Diabetes Care. 2008;31:S12-S54. Buse J, et al. Lancet. 2009;374(9683): Complementary Mechanisms of Action of Current Diabetes Medications Insulin Sulfonylureas Megltinides Islet -cell Islet -cell Impaired Insulin Secretion GLP-1 RA DPP-4 inhibitors Increased Glucagon Secretion GLP-1 RA DPP-4 inhibitors Decreased Incretin Effect Increased Lipolysis SGLT-2 inhibitors Increased Glucose Reabsorption Metformin Increased HGP From DeFronzo, Diabetes: 2009 Bromocryptine Neurotransmitter Dysfunction TZDs Decreased Glucose Uptake MSB 5

6 ADA/EASD Position Statement: Managing Hyperglycemia in Type 2 Diabetes Monotherapy 2-drug combinations Efficacy ( A1C) Hypoglycemia Weight Side effects Costs Lifestyle Changes METFORMIN Efficacy ( A1C): High Weight: Neutral/loss Hypoglycemia: Low risk Proceed after 3 mo. if needed METFORMIN + SU TZD DPP4-I High Moderate risk Gain Hypoglycemia Low High Low risk Gain Edema, HF, Fx High Intermediate Low risk Neutral Rare High Side effects: GI/lactic acidosis Costs: Low Order does not indicate preference GLP-1-RA High Low risk Loss GI High Insulin Highest High risk Gain Hypoglycemia Variable 3-drug combinations or Proceed after 3 mo. if needed Order does not indicate preference METFORMIN + SU + TZD DPP4-I TZD + SU DPP4-I DPP4-I + SU TZD or GLP-1-RA Insulin or GLP-1-RA Insulin Insulin GLP-1-RA + Insulin + SU TZD TZD DPP4-I or or Insulin GLP-1-RA More complex insulin strategies Proceed after 3-6 mo. if needed Insulin usually in combination with 1-2 noninsulin agents Insulin (multiple daily doses) Inzucchi SE et al. Diabetologia. Published online April 19, doi: /s Garber et al. Endocrine Practice 22:1, 2016 MSB 6

7 Long Term Efficacy of Oral Hypoglycemic Agents: ADOPT Study 8.0 Treatment difference (95% CI) Rosiglitazone vs metformin, (-0.22 to -0.05); P=0.002 Rosiglitazone vs glyburide, (-0.50 to -0.33); P<0.001 Glycated Hemoglobin (%) Annualized slope (95% CI) Rosiglitazone, 0.07 (0.06 to 0.09) Metformin, 0.14 (0.13 to 0.16)* Glyburide, 0.24 (0.23 to 0.26)* Years No. of Patients *Significant difference rosiglitazone vs other treatment groups with Hochberg adjustment. Kahn SE, et al. N Engl J Med 2006;355: More Hypoglycemic Events With Glyburide Than Metformin or TZD ADOPT (patients with new-onset diabetes) 1 Patients Self-Reporting Hypoglycemic Events, % TZD (Rosiglitazone) 11.6 Metformin 1 ADOPT=A Diabetes Outcome Progression Trial; TZD=thiazolidinedione. a P 0.01 for the comparison between this treatment group and the rosiglitazone group. 1. Kahn SE et al. N Engl J Med. 2006;355(23): Bolen S et al. Ann Intern Med. 2007;147(6): a Sulfonylurea (Glyburide) Other studies have also shown an increased frequency of hypoglycemic events in patients with type 2 diabetes treated with a sulfonylurea compared with patients treated with metformin or a TZD. 2 MSB 7

8 Insulin, Sulfonylureas and TZDs Lead to Weight Gain Over Time Change in weight (Kg) UKPDS: up to 8 Kg in 12 years 1 ADOPT: up to 4.8 Kg in 5 years 2 Insulin (n=409) Glibenclamide (n=277) Metformin (n=342) Weight (Kg) Treatment difference (95% CI) Rosiglitazone vs metformin 6.9 (6.3 to 7.4); P<0.001 Rosiglitazone vs glibenclamide, 2.5 (2.0 to 3.1); P< Years from randomisation Years Conventional treatment (n=411); diet initially then sulphonylureas, insulin and/or metformin if FPG >15 Rosiglitazone, 0.7 (0.6 to 0.8) mmol/l Metformin, -0.3 (-0.4 to -0.2)** n=at baseline 1 Glibenclamide, -0.2 (-0.3 to 0.0)** 1. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352: Kahn SE, et al (ADOPT). N Engl J Med. 2006;355: Properties of Established Anti- Hyperglycemic Agents Class Mechanism Advantages Disadvantages Cost Biguanides (Metformin) Activates AMPkinase Hepatic glucose production Extensive experience No hypoglycemia Weight neutral? CVD events Gastrointestinal Lactic acidosis B-12 deficiency Contraindications Low SUs / Meglitinides Closes KATP channels Insulin secretion Extensive experience Microvascular risk Hypoglycemia Weight gain Low durability? Ischemic preconditioning Low TZDs Activates PPAR- Insulin sensitivity No hypoglycemia Durability TGs, HDL-C? CVD events (pio) Weight gain Edema / heart failure Bone fractures? MI (rosi)? Bladder ca (pio) Low Diabetes Care 2012;35: Diabetologia 2012;55: MSB 8

9 Pioglitazone After Ischemic Stroke or TIA: IRIS Trial Design Eligibility: Recent TIA or Ischemic Stroke Nondiabetic Insulin Resistant (HOMA >3.0) No HF R N = 3895* Pioglitazone 15 mg 45 mg 5 years 5 years Fatal/nonfatal MI Fatal/nonfatal stroke *90% power to detect a 20% RRR from 27% in the placebo group to 22% in the pioglitazone group at an alpha level of 0.05 HOMA = homeostasis model assessment; RRR = relative risk reduction; TIA = transient ischemic attack. Viscoli CM et al. Am Heart J. 2014;168:823 9.e6. IRIS: Primary Outcome* *Fatal or nonfatal stroke or MI. Cumulative Event-free Survival Probability Kernan WN et al. N Engl J Med. 2016;374: HR = % CI: 0.62, 0.93 P=0.007 Months in Trial Pioglitazone 11.8% MSB 9

10 SGLT-2 Inhibition Insulin-Independent Reversal of Glucotoxicity Proximal Tubule GLUT-2 ATP 3Na + 2K + Tubular Lumen SGLT-2 Insulin sensitivity in muscle 1,2 Insulin sensitivity in liver 2 Na + / Glucose GLUT-1 ATP 3Na + 2K + Glucose Glucose SGLT-1 Na + Gluconeogenesis 2,3 Improved β-cell function 4,5 Glucose GLUT-2, glucose transporter DeFronzo RA, et al. Diabetes Obes Metab. 2012;14(1):5-14; 2. Merovci A, et al. J Clin Invest. 2014;124(2): ; 3. Marsenic O. Am J Kidney Dis. 2009;53(5): ; 4. Ferrannini E, et al. J Clin Invest. 2014;124(2): ; 5. Polidori D, et al. Diabetologia. 2014;57(5): SGLT2 Inhibitors: FDA-Approved Agents FDA-approved SGLT2 Inhibitors Agent Administration Canagliflozin Oral, once daily Taken before the first meal of the day Dapagliflozin Oral, once daily Empagliflozin Taken in the morning with or without food MSB 10

11 SGLT-2 Inhibitors vs Sulfonylureas Added to Metformin A1c From Baseline, % Noninferior vs SU CANA (300 mg) 1,b GLIP Agent Weight, kg SGLT-2 Inhibitor SU Hypoglycemia, % of patients SGLT-2 Inhibitor SU CANA 1,a 4.0 a a 34 DAPA 2,b 3.2 a a 41 EMPA 3,c 3.2 a a 24 DAPA (10 mg) 2,c GLIM EMPA (25 mg) 3,d a P< vs SU. b CANA: 52-week trial of canagliflozin; baseline A1c, 7.8%; c DAPA: 52-week trial of dapagliflozin; baseline A1c, 7.7%; d EMPA:104-week trial of empagliflozin; baseline A1c, 7.9%. 1. Cefalu WT, et al. Lancet. 2013;382(9896): ; 2. Nauck MA, et al. Diabetes Care. 2011;34(9): ; 3. Ridderstråle M, et al. Lancet Diabetes Endocrinol. 2014;2(9): Glycemic Efficacy: SGLT2 Inhibitors vs Sitagliptin Added to Metformin Agent A1C, % Weight, kg Hypoglycemia, % SGLT2 SITA SGLT2 SITA SGLT2 SITA CANA (300 mg) 1 52 weeks EMPA (25 mg) 2 12 weeks 0.88 c d c Superior vs SITA. d P <.001 vs SITA. 1. LaValle Gonzalez et al. Diabetologia. 2013;56: Rosenstock et al. Diabetes Obes Metab. 2013;15: MSB 11

12 Effects of SGLT-2 Inhibitors on Blood Pressure and Cholesterol Canagliflozin 1 Dapagliflozin 2 Empagliflozin 3 Systolic BP change, mmhg 100 mg: 3.7 mmhg 300 mg: 5.4 mmhg (vs placebo) 5 mg: 4.5 mmhg 10 mg: 5.3 mmhg (vs placebo) 10 mg: 4.1 mmhg 25 mg 4.8 mmhg (vs placebo) LDL-C % change 100 mg: +4.5% 300 mg: +.0% (vs placebo) 10 mg: +2.9% vs 1.0% for placebo Dose-related increases % (vs placebo) 1. Canagliflozin prescribing information Dapagliflozin prescribing information Empagliflozin prescribing information. ingelheim.com/biwebaccess/ ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Jardiance/jardiance.pdf EMPA-REG OUTCOME Trial: Design (n = 2333) Screening (n = 11,531) Randomized and treated (n = 7020) Empagliflozin 10 mg (n = 2345) Key inclusion criteria: Adults with T2DM BMI <45 kg/m 2 A1C 7% 10% Established CVD Key exclusion criteria: egfr < 30 mg/min/1.73 m 2 (MDRD) Empagliflozin 25 mg (n = 2342) Median treatment duration = 2.6 years BMI = body mass index; egfr = estimated glomerular filtration rate; MDRD = Modification of Diet in Renal Disease Study equation. Zinman B et al. N Engl J Med. 2015;373: MSB 12

13 EMPA-REG Outcome Trial Patients With Event, % Patients With Event, % Patients With Event, % Cumulative Incidence of the Primary Outcome a P=0.04 for superiority Hazard ratio, 0.86 (95.02% CI, ) a Cumulative incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. N=7020 patients with T2DM at high risk of cardiovascular events. Zinman B, et al. N Engl J Med. 2015;373(22): Empagliflozin Cumulative Incidence of Death From CV Causes P<0.001 Hazard ratio, 0.62 (95% CI, ) Empagliflozin P=0.002 Hazard ratio, 0.65 (95% CI, ) Hospitalization for Heart Failure Empagliflozin Month Potential Mechanisms for the Beneficial Effect of Empagliflozin on CV Outcomes Insulin resistance BP Heart rate Plasma volume Glucose Weight loss and reduced visceral fat Uric acid Arterial stiffness SNS activity Ang 1-7 AT 2 receptor Ketones Albuminuria Inflammation and oxidative stress AT = angiotensin; SNS = sympathetic nervous system. DeFronzo RA et al. Nat Rev Nephrol. 2016;13: MSB 13

14 SGLT-2 Inhibitors and Diabetic Ketoacidosis Concerns 20 cases of DKA in patients with T2DM reported to the FDA Adverse Events Reporting System (3/2013 to 6/2014) 13 published cases of euglycemic DKA in patients with T1DM (9 cases) or T2DM (4 cases) Most patients were women Most cases linked to reduced insulin doses Possible links to increased activity, recent illness, alcohol use, and decreased food intake Some patients had no identifying cause All patients responded to IV rehydration and insulin Potential Mechanisms SGLT-2 Inhibition Increases glucose renal clearance Decreases renal clearance of ketone bodies Endogenous and/or exogenous insulin levels reduced + Dehydration or increased activity level + Increased α-cell secretion of glucagon (mediated by SGLT-2) Increased lipolysis Patients with T1DM should be counseled Eudiabetic Ketoacidosis when SGLT-2s are used off-label DKA, diabetic ketoacidosis; IV, intravenous. Taylor SI, et al. J Clini Enocrinol Metab. 2015;100(8): ; Peters AL, et al. Diabetes Care. 2015;38(9): Advantages and Disadvantages of SGLT2 Inhibitors Advantages Good efficacy Decreases glucotoxicity Weight loss Lower BP Low risk of hypoglycemia Quick onset Low risk of DDI Disadvantages Cost NOT effective in patients with moderate to severe renal impairment Genital mycotic infections Risk of DKA Unknown long-term safety Durability? Possible CVD benefits MSB 14

15 The Incretin Defect in T2DM Substantial impairment 40% of normal response Not due to impaired secretion of GLP-1 or GIP Absent insulinotropic response to GIP Beta-cell GIP receptor down-regulation Decreased response to GLP-1 Can be overcome by achieving higher than physiologic GLP-1 levels GLP-1 infusions that achieve higher levels effective at enhancing insulin secretion and suppressing glucagon in a glucose-dependent manner Nauck et al. Diabetologia. 1986;29: Laakso et al. Diabetologia. 2008;51: Nauck et al. Diabetologia. 2011;54:10 8. Højberg et al. Diabetologia. 2009;52: Vilsbøll et al. Diabetologia. 2002;45: Nauck et al. Diabetologia. 1993;36: Incretin Therapies to Treat T2DM Incretin effect is impaired in T2DM Natural GLP-1 has extremely short half-life Add GLP-1 analogues with longer half-life: Injectables Exendin-4 Based: Exenatide Exenatide QW Lixisenatide Human GLP-1: Liraglutide Albiglutide Dulagutide Block DPP-4, the enzyme that degrades GLP-1: Oral agents Sitagliptin Saxagliptin Linagliptin Alogliptin Drucker. Curr Pharm Des. 2001;7(14): Drucker. Mol Endocrinol. 2003;17(2): MSB 15

16 Comparison of DPP-4 Inhibitors Usual Phase 3 Dose Sitagliptin Alogliptin Saxagliptin Linagliptin 25, 50, 100 mg QD 6.25, mg QD 2.5, 5 mg QD 5 mg QD Half Life (t1/2) 12.4h 12.5 to 21.1h (25mg) 2.2 to 3.8h 40 h DPP-4 inhibition at 24h ~80% at 24h ~78% at 24h (25 mg) 5 mg: ~55% at 24h 75% at 24 h Elimination Kidney (mostly unchanged) Kidney (mostly unchanged) Liver and kidney Active metabolite Bile (mostly unchanged) Renal Dose Adjustments Required Yes Yes Yes No Selectivity for DPP-4 >2600 fold vs DPP-8 >10,000 fold vs DPP-9 >10,000 fold vs DPP- 8/9 >400 fold vs DPP-8 >100 vs DPP-9 >10,000 fold vs DPP-8/9 Potential for DDI Low Low Strong CYP3A4/5 inhibitors d Strong CYP3A4/5 inhibitors d Food effect No No No No Efficacy of DPP-4 Inhibitor Therapy Added to Metformin Sitagliptin Saxagliptin Linagliptin Alogliptin BL A1C (%) n=273 n=743 n=701 n=701 n=273 n=273 n=743 n=743 n=743 n=701 n=527 n=190 Sitagliptin 100 mg Rosiglitazone Saxagliptin 2.5 mg Saxagliptin 5 mg Saxagliptin 10 mg Linagliptin 5 mg Alogliptin mg 1. Charbonnel. Diabetes Care. 2006;29: Raz et al. Curr Med Res Opin. 2008;24: Scott et al. Diabetes Obes Metab. 2008;10: DeFronzo et al. Diabetes Care. 2009;32: Taskinen et al. Diabetes Obes Metab. 2011;13: Nauck et al. Int J Clin Pract. 2009;63: MSB 16

17 DPP-4 Inhibitors vs Sulfonylureas Added to Metformin 2-Year Results ALO (25 mg) 1,a LINA (5 mg) 2,b SAXA (5 mg) 3,c SITA (100 mg) 4,d GLIP 1,3,4 GLIM 2 P =.01 Noninferiority vs SU Agent Weight, kg Hypoglycemia, % 1. Del Prato et al. Diabetes Obes Metab. 2014;16: Gallwitz et al. Lancet. 2012;380: Göke et al. Int J Clin Pract. 2013;67: Seck et al. Int J Clin Pract. 2010;64: Nauck et al. Diabetes Obes Metab. 2007;9: DPP-4i SU DPP-4i SU ALO 1,a 0.9 e LINA 2,b 1.4 e e 36 SAXA 3,c SITA 4,d Cardiovascular Outcomes Trials for DPP-4 Inhibitors SAVOR-TIMI 53 1 CVD or CRFs A1c % n=16,492 Saxagliptin Median follow-up 2.1 years Primary Endpoint CV death, nonfatal MI, or nonfatal stroke Hazard Ratio 1.00 (95% CI 0.89, 1.12) p=0.99 EXAMINE 2 ACS A1c % n=5,380 Alogliptin Median follow-up 1.5 years CV death, nonfatal MI, or nonfatal stroke 0.96 (upper boundary of 1-sided repeated CI 1.16) p=0.315 TECOS 3 CVD A1c % n=14,735 Sitagliptin Randomization Year 1 Year 2 Year 3 Median Duration of Follow-up Median follow-up 3 years CV death, nonfatal MI, or nonfatal stroke, or UA requiring hospitalization CV death, nonfatal MI, or nonfatal stroke 0.98 (95% CI 0.88, 1.09) p=0.645 (superiority) 0.99 (95% CI 0.89, 1.10) p=0.84 (superiority) EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction; TECOS = Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin 1. Scirica BM, et a. NEJM. 2013;369: ; 2. White W, et al. NEJM. 2013;369: ; 3. Green JB, et al. NEJM, 2015 in press MSB 17

18 Cardiovascular Outcomes Trials in Patients with T2DM with or at risk for CV Events Patients, % Saxagliptin (SAVOR-TIMI 53 Trial 1 ) 2 0 N=16,492 Saxagliptin Hazard ratio: (95% CI: ) P < (noninferiority) Days Composite of CV death, MI, or ischemic stroke Scirica, BM, et al. New Eng J Med Oct 3;369(14): White WB, et al. N Engl J Med Oct 3;369(14): Green JB, et al. N Engl J Med Jul 16;373(3): Alogliptin (EXAMINE Trial 2 ) N=5380 Months Alogliptin Hazard ratio: 0.96 (upper boundary of onesided repeated 95% CI: ) Composite of CV death, nonfatal MI, or nonfatal stroke. Sitagliptin (TECOS Trial 3 ) N=14,671 Months Sitagliptin 5 Hazard ratio: 0.98 (95% CI: 0.89, 1.08) P= Composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina DPP-4 Inhibitors: Dosing in Renal Disease Moderate impairment CrCl: ml/min or Serum Cr (mg/dl): Men > Women > Severe impairment/ ESRD CrCl <30 ml/min or Serum Cr (mg/dl): Men >3.0 Women >2.5 or dialysis Linagliptin 1 Sitagliptin 2 Saxagliptin 3 Alogliptin 4 No dose adjustment No dose adjustment 50 mg once daily 25 mg once daily 1. Linagliptin full prescribing information Sitagliptin full prescribing information. 3 S li ti f ll ibi i f ti 2.5 mg once daily 2.5 mg once daily 12.5 mg once daily 6.25 mg once daily MSB 18

19 Advantages and Disadvantages of DPP-4 Inhibitors Advantages Enhance insulin secretion Decrease glucagon Glucose dependent Physiologic route Oral, once daily Superior tolerability Disadvantages Cost Efficacy Unknown long term safety Pancreatitis warning Durability? Heart failure (saxagliptin) Weight neutral No apparent CV risk (saxagliptin, alogliptin, sitagliptin) GLP-1 Receptor Agonists His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Phe Leu Arg Val Ala Glu Glu Glu Met Gln GLP-1 RA Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Ser Pro Pro Pro Exendin-4 analogues Human GLP-1 Analogues [4] His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Lys Ala Ala Gln Gly Glu Leu Tyr Ser Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Lixisenatide Exenatide BID Exenatide QW Liraglutide Albiglutide Dulaglutide Semaglutide* *Not approved Structural modifications confer albumin (liraglutide, albiglutide) or IgG Fc fraction (dulaglutide) binding 1. Christensen M, et al. Idrugs. 2009;12: Ratner RE, et al. Diabet Med. 2010;27: Stewart M, et al. ADA 2008, poster 522-p. 4. Glaesner, et al. Diabetes Metab Res Rev. 2010;26: Meier JJ. Nat Rev Endocrinol. 2012;8: MSB 19

20 GLP-1 RA Administration and Devices * *Not FDA approved 1. BYETTA Prescribing Information. 2. Victoza Summary of Product Characteristics. 3. Eperzan Summary of Product Characteristics. 4. Lyxumia Summary of Product Characteristics. 5. BYDUREON Prescribing Information. Dulaglutide Automatic Injection Hidden needle Short-Acting vs. Long-acting GLP-1 RAs: Pharmacokinetic Differences Category Agent Half-life T max Increasing protraction Short-acting GLP-1 RAs Long-acting GLP-1 RAs Exenatide BID h 2 h Lixisenatide h h Liraglutide 3 13 h 8 12 h Dulaglutide 4 90 h h Albiglutide 5 5 days 3 5 days Semaglutide 6 ~7 days days Exenatide OW days 6 7 weeks OD, once daily; T max, time to reach maximum concentration 1. Byetta. Summary of Product Characteristics; 2. Lyxumia. Summary of Product Characteristics; 3. Victoza. Summary of Product Characteristics; 4. Barrington et al. Diabetes Obes Metab 2011;13:434 8; 5. Eperzan. Summary of Product Characteristics; 6. Novo Nordisk data on file; 7. Fineman et al. Clin Pharmacokinet 2011;50:65 74 MSB 20

21 Exenatide BID vs Exenatide QW: Effect on Fasting and Post-Prandial Glucose Exenatide QW (n = 129) Exenatide BID (n = 130) PPG (mmol/l) Baseline Week 30 Pre Post Pre Post Pre Post 03:00 Breakfast Lunch Dinner Data presented are means ± SE PPG taken from SMBG profile Drucker DJ, et al. Lancet. 2008;372: GLP-1RA Duration Influences FPG, PPG and A1c Short-acting Long-acting FPG PPG FPG PPG FPG, fasting plasma glucose; PPG, postprandial plasma glucose Fineman MS et al. Diabetes Obes Metab 2012;14: MSB 21

22 Head-to-Head Trials Comparing Efficacy of GLP-1 RAs EXN BID 10 mcg LIRA 1.8 mg EXN QW 2.0 mg ALBI 50 mg DULA 1.5 mg LEAD-6 1 DURATION-5 2 DURATION-6 3 HARMONY-7 4 AWARD-1 5 AWARD-6 6 a b a a,b a c Added to MET ± SU Added to Drug-naïve or MET ± SU ± TZD Added to Drug-naïve or MET ± SU ± TZD Added to MET ± SU ± TZD 1. Buse JB, et al. Lancet. 2009;374:39-47; 2. Blevins T, et al. J Clin Endocrinol Metab. 2011;96: ; 3. Buse JB, et al. Lancet. 2013;381: ; 4. Pratley R, et al. Lancet Diabetes Endocrinol. 2014;2: ; 5. Wysham C, et al. Diabetes Care. 2014;37: ; 6. Dungan K, et al. Lancet. 2014; 384(9951): Added to MET ± TZD Added to MET a P <.05 between groups. b Noninferiority vs LIRA not met. c DULA noninferior to LIRA, P < GLP-1 RAs vs DPP-4 Inhibitors Added to Metformin A1c From Baseline, % P<0.001 P< P<0.001 P< P<0.001 Agent Weight, kg GLP-1 DPP-4i RA Hypoglycemia, % of patients GLP-1 RA DPP-4i DULA (1.5 mg) 4,h EXEN BID 1,d 2.8 NA 5 NA EXEN QW 2,e 2.3 b d 3 LIRA 3,f 3.4 a d 5 DULA 4,g 3.0 b d 5 ALBI 5,h 0.8 c d,j 16 j EXEN BID (10 μg) 1,e EXEN QW (2 mg) 2,f ALBI (30 or 50 mg) 5,i LIRA (1.8 mg) 3,g SITA a P< vs DPP-4 inhibitor; b P<0.001 vs DPP-4 inhibitor; c P<0.05 vs DPP-4 inhibitor; d No statistical analysis performed; e EXEN BID: 30-week study of exenatide twice daily; baseline A1C, 8.2%; f EXEN QW: 26-week trial of exenatide once weekly; baseline A1c, 8.4%; g LIRA: 26-week trial with liraglutide; baseline A1c, 8.5%; h DULA: 52-week trial; baseline A1c, 8.1%; i ALBI: 26-week trial of albiglutide; baseline A1c, 8.2%; j Almost all patients experiencing hypoglycemia were also taking a sulfonylurea. 1. DeFronzo RA, et al. Diabetes Care. 2005;28: ; 2. Bergenstal RM, et al. Lancet. 2010;376: ; 3. Pratley RE, et al. Lancet. 2010;375(9724): ; 4. Nauck M, et al. Diabetes Care. 2014;37(8): ; 5. Leiter LA, et al. Diabetes Care. 2014;37(10): MSB 22

23 Efficacy of GLP-1 RAs Versus Insulin EXN BID 1-5 LIRA 6 EXN QW 7 (4-Trial Analysis) a (LEAD-5) b (DURATION-3) b ALBI 8 (HARMONY-4) P =.09 (noninferior) P =.0015 P =.017 P =.009 (noninferior) INS EXN BID LIRA EXN ER ALBI a EXN BID vs insulin glargine (3 trials, weeks) or biphasic insulin aspart 70/30 (1 trial, 16 weeks); mean insulin dose = U/day. b Versus insulin glargine, 26-week outcomes; mean insulin doses = 24 (LEAD-5) and 31 (DURATION-3) U/day. 1. Blevins T et al. Postgrad Med. 2010;122: Heine R et al. Ann Intern Med. 2005;143: Nauck M et al. Diabetologia. 2007;50: Barnett A et al. Clin Ther. 2007;29: Davies M et al. Diabetes Obes Metab. 2009;11: Russell-Jones D et al. Diabetologia. 2009;52: Diamant M et al. Lancet. 2010;375: Weissman PN et al. Diabetologia. Published online 11 Sept DOI /s Head-to-Head Trials Comparing Weight Effects of GLP-1 RAs EXN BID 10 mcg LIRA 1.8 mg EXN QW 2.0 mg ALBI 50 mg DULA 1.5 mg LEAD-6 1 DURATION-5 2 DURATION-6 3 HARMONY-7 4 AWARD-1 5 AWARD-6 6 Weight Change, kg Added to MET ± SU a Added to Drug-naïve or MET ± SU ± TZD 1. Buse JB, et al. Lancet. 2009;374:39-47; 2. Blevins T, et al. J Clin Endocrinol Metab. 2011;96: ; 3. Buse JB, et al. Lancet. 2013;381: ; 4. Pratley R, et al. Lancet Diabetes Endocrinol. 2014;2: ; 5. Wysham C, et al. Diabetes Care. 2014;37: ; 6. Dungan K, et al. Lancet. 2014; 384(9951): a Added to Drug-naïve or MET ± SU ± TZD a a Added to MET ± SU ± TZD Added to MET ± TZD a P <.05 between groups. a Added to MET MSB 23

24 Hypoglycemia With GLP-1 RAs: Head-to-Head Clinical Trial Results LIRA (1.8 mg QD) EXN (10 mcg BID) EXN (2.0 mg ER) Albiglutide With Sulfonylurea Without Sulfonylurea Significantly lower minor hypoglycemia with LIRA vs EXN BID; 1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; P = Only 2 cases of major hypoglycemia (EXN BID + SU in LEAD-6) 1-3 Most hypoglycemia events (albiglutide >90%, liraglutide >85%) occurred with sulfonylurea 4 1. Buse J et al. Lancet. 2009;374: Drucker DJ et al. Lancet. 2008;372: NCT Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: a Minor hypoglycemia = self-treatable, with plasma glucose < 55 mg/dl; major hypoglycemia = requiring third party assistance. Nausea with GLP-1 RAs * EXN QW EXN BID LIRA ALBI ** 1. Drucker D, et al. Lancet. 2008;372: Blevins T, et al. J Clin Endocrinol Metab. 2011;96: Buse J, et al. EASD 47th Annual Meeting. 2011;75 4. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: * Significantly lower vs EXN BID ** Significantly lower vs LIRA MSB 24

25 Blood Pressure and Lipid Changes With GLP-1 RAs: Meta-Analysis of RCTs 1,a Parameter Change 95% Confidence Interval Systolic blood pressure 3.57 mm Hg 5.49 to 1.66 Diastolic blood pressure 1.38 mm Hg 2.02 to 0.73 Total cholesterol 3.9 mg/dl 6.19 to 1.55 In head-to-head trials BP changes were similar for individual GLP-1 RAs 2-4 Total cholesterol changes ranged from 3 to 12 mg/dl 2-4 LDL-cholesterol changes ranged from 17 mg/dl to 1 mg/dl 2,3 Triglyceride changes ranged from 8 mg/dl to 36 mg/dl 2-4 a Includes overweight and obese individuals without T2DM; treatments include exenatide and liraglutide. 1.Vilsbøll T, et al. BMJ. 2012;344:d Drucker D, et al. DURATION-1 Study Group. Lancet. 2008;372: Buse J, et al. LEAD-6 Study Group. Lancet. 2009;374: Buse J, et al. Lancet Nov 6. [Epub ahead of print]. ELIXA Study: Lixisenatide vs. Run-in 1 week Lixisenatide 10 μg Titration 2 weeks Lixisenatide, 20 μg maximum dose 203±1 weeks Trial information Multi-centre Double-blind Parallel-group Event-driven Randomised Randomisation (1:1) End of treatment Run-in period Patients were trained in selfadministration of daily subcutaneous volume-matched placebo Titration Lixisenatide or matching placebo (1:1) Initial dose 10 μg/day Down- or up-titration permitted to maximum of 20 μg/day Glucose control was managed by site investigators judgement Bentley-Lewis R et al. AHJ 2015; 169: e7; Results of ELIXA, oral presentation 3-CT-SY28. Presented at the American Diabetes Association 75 th annual scientific sessions, Boston, 8 June 2015 MSB 25

26 ELIXA Study: Primary Composite Endpoint Time to first occurrence of the primary CV event: CV death, non-fatal MI, non-fatal stroke or hospitalisation for unstable angina Patients with event (%) 10 5 HR=1.02 (0.89, 1.17) Lixisenatide: 406/3034 = 13.4% : 399/3034 = 13.2% 0 Number at risk Lixisenatide Months CV, cardiovascular; MI, myocardial infarction 1. Clinicaltrials.gov. Available at Accessed May 2015 Results of ELIXA, oral presentation 3-CT-SY28. Presented at the American Diabetes Association 75 th annual scientific sessions, Boston, 8 June 2015 LEADER: Liraglutide vs. Cardiovascular Outcomes Trial Key inclusion criteria Adult T2D patients: HbA 1c 7.0% Antidiabetic drug naïve; or Treated with one or more OADs; or Treated with basal or premix insulin (alone or in combination with OADs) High-risk CV profile * runin period of 2 weeks Patients demonstrating 50% adherence to regimen and willingness to continue with injection protocol for duration of trial proceeded to randomisation R A N D O M I S A T I O N (1:1) N=9340 Standard of care + liraglutide ( mg once daily) year follow-up Standard of care + placebo * *Daily single-blind subcutaneous injection of placebo CV, cardiovascular; OAD, oral antidiabetic drug; T2D, type 2 diabetes Marso et al. Am Heart J 2013;166: e5 MSB 26

27 LEADER: Primary and Secondary Outcomes with Liraglutide Patients With Event, % Primary Outcome a Hazard ratio, 0.87 (95% CI, ) P<0.001 for noninferiority P=0.01 for superiority Liraglutide Cardiovascular- Related Death Hazard ratio, 0.78 (95% CI, ) P=0.007 Liraglutide Months Since Randomization 5 Death From Any Cause Hazard ratio, 0.85 (95% CI, ) P=0.02 Liraglutide a Composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. N=9340 patients with T2DM and high cardiovascular risk. Marso SP, et al. N Engl J Med June 13 [Epub ahead of print]. SUSTAIN: Primary and Secondary Outcomes With Semaglutide Marso et al. NEJM, Oct 2016 MSB 27

28 CV Effects of GLP-1 GLP-1 Heart Kidney Natriuresis Diuresis Blood vessels BP Body weight Brain Cardioprotection GLP -1 Inflammation Fat and other tissues Drucker DJ. Cell Metab. 2016;24: Platelets Coagulation Intestine Postprandial lipids Glucose & hypoglycemia Alpha cell: Glucagon Beta cell: secretion Insulin secretion & biosynthesis Apoptosis GLP-1R Inflammation Glucose uptake Ischemic injury LV function Heart rate GLP-1R Inflammation Endothelial function Vasodilation Plaque stability Blood flow Smooth muscle proliferation Platelet aggregation Recommendations for GLP-1 RA Use in CKD Precautions 1-4 Albiglutide Exenatide BID Liraglutide Exenatide QW Renal impairment Use with caution Use with caution Should not be used with severe renal impairment (CrCl <30 ml/min) or ESRD Use with caution Use with caution Should not be used with severe renal impairment (CrCl <30 ml/min) or ESRD Recommendations Use with caution in patients with renal impairment or renal transplantation, especially when initiating or escalating doses Hypovolemia due to nausea/vomiting may worsen renal function ESRD, end-stage renal disease. 1. Traynor K. Am J Health Syst Pharm. 2014;71(11):888; 2. See Drugs@FDA ( 3. See Drugs@FDA ( 4. See Drugs@FDA ( MSB 28

29 Advantages and Disadvantages of GLP-1 Receptor Agonists Advantages Enhance insulin secretion Decrease glucagon Glucose dependent Low risk of hypoglycemia Quick onset Superior efficacy Weight loss Disadvantages Cost Injection Nausea Pancreatitis warning MTC warning Unknown long term safety Durability? CVD safety / benefit Approach To Starting and Adjusting Insulin in T2DM American Diabetes Association Standards of Medical Care in Diabetes. Approaches to Glycemic Treatment. Diabetes Care 2016; 39 (Suppl. 1): SX MSB 29

30 Insulin Developments: Basal Insulins Degludec U-100 Fixed Dose LA Insulins/ GLP-1 Agonists Degludec U-200 Degludec/ Aspart 70/ Upcoming Glargine U st Follow-on Biologic Insulin Glargine Additional Follow-on Biologic Insulins Biosimilars (Follow-on Biologics): Potential Place in Therapy Patients where cost a major concern &/or required by formulary Issues when working with patients As a substitution for the branded product, with appropriate cautions when switching from one type of insulin to another Monitor glucose levels more often to assess any difference of effects Different administrative device may require brief education MSB 30

31 Basal Insulins Intermediate-acting insulin: NPH Long-acting insulin: - Detemir, Glargine - Glargine U Degludec U-100 or U Time (hours) Insulin Type Product Onset Peak Duration Human NPH insulin Humulin / Novolin N 90-4 hours 4-12 hours up to 24 hours Insulin detemir Levemir 45 min - 4 hrs up to 22 hours Lantus /Basaglar Insulin glargine Minimal peak (depending on Insulin glargine Toujeo ~ 6 hrs dose) > 24 hours U-300 Insulin degludec U-100 or U-200 Tresiba 1 hrs > 42 hours Adapted from Hirsch I. N Engl J Med. 2005;352: Variability of Effect Variability in effects of an insulin can cause 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 *Area under curve, glucose infusion rate Adapted from: Rossetti P, et al. Diabetes Obes Metab, 2014;16: ; Becker RHA, et al. Diabetes Obes Metab, 2015;17:261-7 MSB 31

32 U-300 Glargine vs U-100 Glargine in T2DM: Meta-Analysis of Phase III Trials EDITION 1, 2, & 3 Baseline to Month 6 Glargine U- 300 (N=1247) Glargine U- 100 (N=1249) RR (95% CI) A1C (%), LS mean NS Weight (kg), LS mean P = Any hypo in 24 hr* ( ) Any nocturnal hypo* ( ) Confirmed BG <54 mg/dl or severe hypo* ( ) Confirmed nocturnal BG <54 mg/dl or severe hypo* ( ) *% people 1 event. LS = least squares; RR = relative risk; BG = blood glucose; CI = confidence interval. Ritzel RA, et al. Presentation 963, EASD 2014, Diabetologia, 2014 Degludec (U-100) vs Glargine (U-100) Noninferior A1C & FPG Zinman et al BEGIN Once Long Diabetes Care 2012 MSB 32

33 Degludec (U-100) vs Glargine (U-100) Significantly Nocturnal Hypoglycemia Zinman et al BEGIN Once Long Diabetes Care 2012 Newer Basal Insulins: Place in Therapy Patients who need a better basal insulin Often this includes people with: Nocturnal hypoglycemia Shift work Complaints of variability of fasting glucose levels Adherence issues MSB 33

34 GLP-1 + Basal Insulin: Change in HbA 1c Buse et al At 30 weeks GetGoal-L At 24 weeks GetGoal-Duo At 24 weeks HARMONY-6 At 26 weeks n=137 BL: 8.3 n=122 BL: 8.5 n=327 BL: 8.4 n=166 BL: 8.4 n=223 BL: 7.6 n=223 BL: 7.6 n=282 BL: 8.5 n=281 BL: Exenatide Lixisenatide Albiglutide Lispro Difference for GLP-1 vs. comparator: *p<0.001; **p=0.0002; p=ns Buse et al. Ann Intern Med 2011;154: ; Riddle et al. Diabetes Care 2013;36: ; Riddle et al. Diabetes Care 2013;36: ; Rosenstock et al. Diabetes Care 2014; 37(8): GLP-1 + Basal Insulin: Change in Body Weight Buse et al At 30 weeks GetGoal-L At 24 weeks GetGoal-Duo At 24 weeks HARMONY-6 At 26 weeks n=137 BL: 95.4 n=122 BL: 93.4 n=327 BL: 87.4 n=166 BL: 89.1 n=223 BL: 87.5 n=223 BL: 86.7 n=282 BL: 92.5 n=281 BL: 91.6 Exenatide Lixisenatide Albiglutide Lispro Difference for GLP-1 vs. comparator: *p<0.001; **p=0.0012; p< Buse et al. Ann Intern Med 2011;154: ; Riddle et al. Diabetes Care 2013;36: ; Riddle et al. Diabetes Care 2013;36: ; Rosenstock et al. Diabetes Care 2014; 37(8): MSB 34

35 Basal Insulin-GLP-1 RA Fixed-Ratio Coformulations DEG-LIRA 1,a DEG 1,a LIRA 1,a GLAR-LIXI 2,b GLAR 2,b A1C < 7%, % 81% 60% c 65% c 84% 80% Noninferior to DEG Superior to LIRA Superior to GLAR 3 severe hypoglycemic episodes per group Lower rate of hypoglycemia for LIRA vs DEG or DEG-LIRA (overall and nocturnal) 1 Lower rate of hypoglycemia for GLAR-LIXI than for GLAR (overall) 2,d a 26-wk open-label, treat-to-target, RCT; N = 1663 (insulin naïve); BL A1C, 8.3%; BL wt, 87.2 kg to 87.4 kg; b 24-wk open-label, treat-to-target, RCT; N = 323 (insulin naïve); BL A1C, 8.01% to 8.06%; BL wt, kg to kg; c P <.001 vs DEG-LIRA; d P <.001 vs GLAR-LIXI. 1. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2: Rosenstock J, et al. Diabetologia. 2014;57(suppl 1) [abstract 241]. Important Features of Type 2 Diabetes Multiple metabolic abnormalities Primary - precede and predict DM Insulin resistance and -cell dysfunction Secondary - to worsening metabolic milieu Hepatic glucose overproduction and glucagon Incretin defect Renal glucose reabsorption Dynamic process progressing over years Observed abnormalities depend on stage MSB 35

36 Individualizing Glycemic Targets According to Patient Characteristics More Stringent A1C < 7% Less Stringent Risks associated with hypoglycemia or other drug adverse effects Low High Disease duration Newly diagnosed Long-standing Usually not modifiable Life expectancy Long Short Important comorbidities Absent Few/mild Severe Established vascular complications Absent Few/mild Severe Patient attitude and expected treatment efforts Highly motivated, adherent, excellent self-care capabilities Frequent Less motivated, nonadherent, poor self-care capabilities Potentially modifiable Resources and support system Inzucchi SE, et al. Diabetes Care. 2015;38: Readily available Limited Choice of Therapy After Metformin SU TZD DPP-4i GLP-1RA SGLT-2i Basal insulin Efficacy ( HbA 1c ) Hypo risk Weight effect Major side effects Hypo Edema, Heart failure, Bone Rare DPP-4i, dipeptidyl peptidase-4 inhibitor; fracturesgi, gastrointestinal; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA 1c, glycosylated haemoglobin; SU, sulphonylurea; TZD, thiazolidinedione; SGLT-2i, sodium glucose co-transporter 2 inhibitors;, weight gain;, weight loss;, weight neutral; +, low; ++, moderate/intermediate; +++, high; ++++, highest GI Urinary and genital infections Hypo Based on Inzucchi et al. Diabetologia 2012;55: ; SGLT 2i: Bailey et al. Lancet 2010;375: MSB 36

37 Considerations for Selecting Therapies Current HbA1c and magnitude of reduction needed to reach goal Potential effects on body weight and BMI Potential for hypoglycemia age, lack of awareness of hypoglycemia, disordered eating habits Effects on CVD risk factors blood pressure and blood lipids Comorbidities CAD, heart failure, CKD, liver dysfunction Patient factors adherence to medications and lifestyle changes, preference for oral vs injected therapy, economic considerations Inzucchi et al. Diabetes Care 2012; 35: How Do Comorbidities Affect Anti-Hyperglycemic Therapy in T2DM? Coronary Disease Metformin: CVD benefit (UKPDS) Avoid hypoglycemia? SUs & ischemic preconditioning? Pioglitazone & CVD events? Effects of incretin based therapies Heart Failure Metformin: May use unless condition is unstable or severe Avoid TZDs? Effects of incretinbased therapies SCr = serum creatinine; GFR = glomerular filtration rate Renal Disease risk of hypoglycemia Metformin & lactic acidosis US: 1.5 (1.4 women) UK: half < 45 < 30 Caution with SUs (esp. glyburide) DPP4 Is dose adjust for most Avoid exenatide if GFR < 30 Liver Dysfunction Most drugs not tested in advanced liver disease Pioglitazone may help steatosis Insulin best option if disease severe Hypoglycemia Emerging concerns regarding association with increased morbidity / mortality Proper drug selection is key in hypoglycemia prone MSB 37

38 Physicians Delay Intensifying Therapy for Months, Especially Initiating Insulin Insulin 9.5% A1C >8% (mon) A1C >7% (mon) Brown, et al. Diabetes Care. 2004;27: N= N= N= N= Summary (1) Diet, exercise, & education are the foundation of therapy Diabetes therapy should be personalized Patient factors and preferences Comorbid conditions and life expectancy Metformin usually first-line therapy for T2DM Multiple options for improving glycemic control after monotherapy failure Ultimately, many patients will require insulin therapy alone or in combination with other agents to maintain control. MSB 38

39 Summary (2) Selection of 2nd / 3rd line therapy depends on goals: Glycemic efficacy: GLP-1 agonists SGLT-2i > TZDs > SUs DPP4i Weight loss: SGLT-2i, GLP-1 agonists > DPP4i > AGI > SUs > TZDs Hypoglycemia: Insulin > SUs > SGLT-2i, GLP-1 agonists, DPP4i, TZDs Blood Pressure Reductions: SGLT-2i, GLP-1 agonists > TZDs > SUs, DPP4i All treatment decisions should be made in conjunction with the patient (focus on preferences, needs, & values.) CV risk reduction should be major focus of therapy. Diabetes Care 2012;35: Improvements in Diabetes Treatment Have Lowered Rates of Complications ESRD, end-stage renal disease. Gregg E, et al. N Engl J Med 2014;370: MSB 39

40 MSB 40