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Program Editors Ralph Anthony DeFronzo, MD Professor of Medicine and Chief of the Diabetes Division University of Texas Health Science Center Audie L.

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Presentation on theme: "Program Editors Ralph Anthony DeFronzo, MD Professor of Medicine and Chief of the Diabetes Division University of Texas Health Science Center Audie L."— Presentation transcript:

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2 Program Editors Ralph Anthony DeFronzo, MD Professor of Medicine and Chief of the Diabetes Division University of Texas Health Science Center Audie L. Murphy Memorial Veterans Hospital San Antonio, Texas, USA Jaime A. Davidson, MD President, Worldwide Initiative for Diabetes Education Clinical Professor of Internal Medicine Division of Endocrinology University of Texas Southwestern Medical School Dallas, Texas, USA

3 Faculty Professor Rury Holman Professor of Diabetic Medicine Honorary Consultant Physician Diabetes Trials Unit University of Oxford Oxford, United Kingdom Professor Stefano Del Prato Professor of Endocrinology and Metabolism School of Medicine University of Pisa Pisa, Italy Professor Allan Vaag Chief Physician Steno Diabetes Center Gentofte, Denmark

4 Educational Objectives Upon completion of this activity, participants will be able to Name 5 current challenges for glycemic control in individuals with type 2 diabetes List the key physiologic, biochemical, and molecular events involved in the renal regulation of glucose metabolism Understand the effects of inhibiting glucose reuptake by the kidney in individuals with type 2 diabetes

5 Magnitude of the Diabetes Epidemic

6 28.3 M 40.5 M 43.0% 16.2 M 32.7 M 102% 53.2 M 64.1 64.1 M 20% 67.0 M 99.4 M 48% 10.4 M 18.7 M 80% 46.5 M 80.3 M 73% M=million; AFR=Africa; EMME=Eastern Mediterranean and Middle East; EUR=Europe; NA=North America; SACA=South and Central America; SEA=South-East Asia; WP=Western Pacific. International Diabetes Federation. Diabetes Atlas. 3rd ed. Available at: http://www.eatlas.idf.org/index.asp. World 2007=246 M 2025=380 M 54% AFR NA SACA EUR SEA WP 24.5 M 44.5 M 82% EMME 2007 2025 Global Projections for the Diabetes Epidemic: 2007-2025

7 Global Increase in Obesity Overweight, BMI 25 kg/m 2 ; obese, BMI >28 kg/m 2 (Asian) or >30 kg/m 2. James WP. J Intern Med. 2008;263:336-352. USA UK Australia Finland Sweden Norway Brazil Cuba Japan 19701975198019851990199520002005 Prevalence of Obesity (%) 35 30 25 20 15 10 5 0200220072015 Obese356 million523 million704 million Overweight1.4 billion1.5 billion2.3 billion

8 Increasing Problem of Obesity and Diabetes: United States *BMI 30 kg/m 2. Centers for Disease Control and Prevention. National diabetes fact sheet. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2008; Mokdad AH, et al. JAMA. 1999;282:1519-1522; Mokdad AH, et al. Diabetes Care. 2000;23:1278-1283; Ogden CL, et al. NCHS data brief no 1. Hyattsville, MD: National Center for Health Statistics, 2007. Obesity* Diabetes US Population (%) 20% increase 19982007 92% increase 19982006 40 20 0

9 Increasing Problem of Obesity and Diabetes: Mexico ObesityDiabetes Mexican Population (%) Aguilar-Salinas CA, et al. Am J Med. 2002;113:569-574; Aguilar-Salinas CA, et al. Diabetes Care. 2003;26:2021-2026; Sánchez-Castillo CP, et al. Public Health Nutr. 2005;8:53-60. 19932000 Men Women 40 20 0 21% increase 17% increase 19932000

10 19911999-2000 Men Women 10 5 0 169% increase Increasing Problem of Obesity and Diabetes: China Obesity*Diabetes Chinese Population (%) *Asian-specific obesity cut-point: BMI 28 kg/m 2. Gu D, et al. Diabetologia. 2003;46:1190-1198; Wildman RP, et al. Obesity (Silver Spring). 2008;16:1448-1453. 19942000-2001 120% increase

11 Increasing Problem of Weight Gain and Diabetes: India Rural Indian Population (%) *BMI 25 kg/m 2. Ramachandran A, et al. Diabetologia. 2004;47:860-865. Overweight*Diabetes 191% increase 19892003 750% increase 19892003 20 10 0

12 Hyperglycemia Biochemical marker by which the diagnosis of diabetes is made –Assessed with HbA 1c, daily SMBG, and eAG Major and treatable risk factor for microvascular disease (DCCT, UKPDS 33 and 35) Independent and treatable risk factor for macrovascular disease (DCCT-EDIC, UKPDS 35 and 80) Self-perpetuating cause of diabetes –Glucotoxicity insulin resistance and impaired insulin secretion eAG=estimated average glucose. SMBG=self-monitoring of blood glucose.

13 HbA 1c Is Correlated With Average Glucose AG=average glucose. Nathan DM, et al. Diabetes Care. 2008;31:1473-1478. 450 400 350 300 250 200 150 100 50 0 357 9 1113 15 AG (mg/dL) HbA 1c (%)

14 Diabetes Report Card: HbA 1c Levels in the United States Hoerger TJ, et al. Diabetes Care. 2008;31:81-86. Patients (%) HbA 1c (%) <6.0 6.0-6.9 7.0-7.9 8.0-8.9 9.0-9.9 >10.0 0 20 40 60 80 100 22% 35% 20% 11% 6%

15 NHANES1988-1994 Advances in Therapy, but Falling Short of Goals 5 6 7 8 9 10 1980s 1980s1990s 2000s 2000s HbA 1c (%) SU / Insulin Metformin (1995) TZDs (1998) Incretins (2004) Pre-DCCT9.0% 7.7NHANES 1999- 2000 7.8 NHANES2001-2002 7.5 NHANES2003-2004 7.2 Future 6.0% ? 1997: ADA lowered T2DM diagnosis from FPG 7.8 mmol/L to 7.0 mmol/L 2003: ADA eliminated HbA 1c action point of <8% from guidelines SU=sulfonylurea; TZDs=thiazolidinediones; T2DM=type 2 diabetes. Koro CE, et al. Diabetes Care. 2004;27:17-20; Hoerger TJ, et al. Diabetes Care. 2008;31:81-86. 2005: ADA added HbA 1c goal of <6% for individual patients to guidelines General ADA Target: <7% 1998: UKPDS results published 2008: ACCORD, ADVANCE, VADT, and UKPDS 80 published 2009: ADA added less stringent HbA 1c goal for patients with significant comorbidities or risk of hypoglycemia, or short life expectancy

16 CVD=cardiovascular disease. Adapted from © 2005 International Diabetes Center, Minneapolis, MN. All rights reserved. Weight Management Type 2 Diabetes Multiple Defects in Type 2 Diabetes Adverse Effects of Therapy Hyperglycemia Unmet Needs in Diabetes Care CVD Risk (Lipid and Hypertension Control)

17 Relationship Between Hyperglycemia and Microvascular and Macrovascular Complications

18 IGT (HbA 1c =5.9%) IGT………..…7.9% IGT (HbA 1c =6.1%) T2DM………12.6% Neuropathy (%) IGT………..…13%* *Prevalence. Diabetes Prevention Program Research Group. Diabet Med. 2007;24:137-144; Singleton JR, et al. Diabetes Care. 2001;24:1448-1453; Ziegler D, et al. Diabetes Care. 2008;31:464-469. Diabetic Retinopathy (%) Incidence of Microvascular Complications in IGT

19 Diabetes Is a Cardiovascular Disease Risk Equivalent DM=diabetes mellitus; MI=myocardial infarction. Haffner SM, et al. N Engl J Med. 1998;339:229-234. 0 10 20 30 40 50 7-Year Incidence Rate of MI (%) Diabeticn=1059 P<0.001 3.5 18.8 20.2 45.0 DM MI DM No MI No DM MI No DM No MI Nondiabeticn=1373

20 Microvascular Disease 0 10 20 30 40 50 60 70 80 567891011 Mean HbA 1c (%) Stratton IM, et al. BMJ. 2000;321:405-412. Estimated 37% decrease in microvascular risk for each 1% decrement in HbA 1c (P<0.0001) Historic Rationale for Improving Glycemia: Microvascular Risk Reduction Incidence per 1000 Person- Years (%)

21 Microvascular Disease Stratton IM, et al. BMJ. 2000;321:405-412. Macrovascular Disease Estimated 14% decrease in myocardial infarction risk for each 1% decrement in HbA 1c (P<0.0001) Less Strong Association Between Hyperglycemia and Macrovascular Risk in Type 2 Diabetes Estimated 37% decrease in microvascular risk for each 1% decrement in HbA 1c (P<0.0001) 0 10 20 30 40 50 60 70 80 567891011 Mean HbA 1c (%) Incidence per 1000 Person- Years (%)

22 Optimizing Glycemia in Advanced Type 2 Diabetes Exerts Unclear Macrovascular Benefit ACCORD Study Group. N Engl J Med. 2008;358:2545-2559; ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572; Duckworth W, et al. N Engl J Med. 2009;360:129-139. Endpoint HbA 1c (%) 6 7 8 9 Primary Endpoint Macro 6% P=0.37 Macro 10% P=0.16 Intensive therapy Conventional therapy ADVANCEN=11,140 ACCOR D N=10,251VADTN=1791 Macro 13% P=0.12

23 Lasting Benefits of Early, Intensive Intervention: UKPDS Legacy Effect P=0.029 P=0.040 P=0.0099 P=0.001 P=0.052 P=0.014 P=0.44 P=0.007 Any Diabetes Endpoint Microvascular Disease Myocardial Infarction All-cause Mortality Relative Risk Reduction (%) Intervention Post-trial Monitoring Holman RR, et al. N Engl J Med. 2008;359:1577-1589; UKPDS Study Group. Lancet. 1998;352:837-853.

24 ACCORD Study Group. N Engl J Med. 2008;358:2545-2559; ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572; Duckworth W, et al. N Engl J Med. 2009;360:129-139; Holman RR, et al. N Engl J Med. 2008;359:1577-1589. Early vs Late Intervention in Type 2 DiabetesTrial Intensive Arm HbA 1c Reduction No Patients / Trial Duration Disease Severity Macrovascular Benefit ACCORD Goal: <6.0% Endpoint: 6.4% 1.4% from BL in 4 months N=10,251 3.4 yr CVD or 2 risk factors 10 yr from T2DM diagnosis No ADVANCE Goal: <6.5% Endpoint: 6.5% 0.6% from BL in 12 months N=11,140 5.0 yr Vascular disease or 1 risk factor 8 yr from T2DM diagnosis VADT Goal: 1.5% vs standard Endpoint: 6.9% 2.5% from BL in 3 months N=1791 5.6 yr 12 yr from T2DM diagnosis UKPDS 80 Goal: FPG <6.0 mmol/L (108 mg/dL) Intervention endpoint: 7.0% Follow-up: 7.7% N=4209 17 yr Newly diagnosed with T2DM Yes

25 Steno-2: Time to Cardiovascular Events Gaede P, et al. N Engl J Med. 2008;358:580-591. 20 40 60 80 0 024681012 Cumulative Incidence of Any CV Event (%) Years No. at Risk Conventional8070604638292514 Intensive8072656156504731 P<0.001 Conventional Treatment Intensive Treatment InterventionFollow-up

26 Steno-2: Goal Attainment BP=blood pressure. Gaede P, et al. N Engl J Med. 2008;358:580-591. HbA 1c <6.5% Cholesterol <175 mg/dL Triglycerides <150 mg/dL Systolic BP <130 mm Hg Diastolic BP <80 mm Hg P=0.31 P=0.35 P=0.005 P=0.27 P=0.14 Patients (%) Intensive therapyConventional therapy P=0.06 P<0.001 P=0.005 P=0.001 P=0.21 0 20 40 60 80 100 Intervention Follow-up 0 20 40 60 80 100

27 Etiology of Type 2 Diabetes Insulin Resistance and -Cell Dysfunction

28 Etiology of Type 2 Diabetes Primary Predisposing Factors Genes Adverse intrauterine environment Tertiary Accelerating Factors Glucose and lipid toxicity Secondary Precipitating Factors Obesity Low physical activity Age Smoking Sleep disturbance Other

29 Metabolic syndromeHyperglycemia Failing -cell Functional -cell Heine RJ, Spijkerman AM. 2006. Insulin resistance Type 2 Diabetes: A Heterogeneous Disorder

30 Type 2 Diabetes: Insulin Resistance Plus Impaired -Cell Function Normal -cell function Compensatory hyperinsulinemia Normoglycemia (Metabolic syndrome) Abnormal -cell function Relative insulin deficiency Hyperglycemia Type 2 diabetes Both insulin resistance and -cell dysfunction are present at the time of diagnosis of type 2 diabetes Insulin resistance

31 DM=diabetes mellitus; IGT=impaired glucose tolerance; INS=insulin; NGT=normal glucose tolerance; OB=obesity. DeFronzo RA. Diabetes. 1988;37:667-687; Jallut D, et al. Metabolism. 1990;39:1068-1075. Natural History of Type 2 Diabetes Insulin- Mediated Glucose Uptake (mg/m 2 min) 300 250 200 150 100 Mean Plasma Insulin During OGTT (µU/mL) Mean Plasma Glucose During OGTT (mg/dL) 140 100 60 20 400 300 200 100 OB- DM Lo INS Lean NGT OB- DM Hi INS OB- IGT OB NGT

32 Etiology of -Cell Dysfunction in Type 2 Diabetes Insulin Resistance Age -Cell Dysfunction -Cell DysfunctionGenetics (TCF 7L2) Lipotoxicity Free Fatty Acids Glucose Toxicity Amyloid (Islet Amyloid Polypeptide) Deposition Incretin IncretinEffect

33 β-Cell failure occurs much earlier in the natural history of type 2 diabetes and is more severe than previously appreciated Natural History of -Cell Dysfunction in Type 2 Diabetes

34 San Antonio Metabolism and VAGES Studies Normal glucose tolerance318 Impaired glucose tolerance259 Type 2 diabetes201 Subjects were classified as NonobeseifBMI <30 kg/m 2 ObeseifBMI 30 kg/m 2 VAGES=Veterans Administration Genetic Epidemiology Study. Abdul-Ghani MA, et al. Diabetes. 2006;55:1430-1435; Ferrannini E, et al. J Endocrinol Metab. 2005;90:493-500; Gastaldelli A, et al. Diabetologia. 2004;47:31-39. Methods: OGTT and insulin clamp SubjectsNumber

35 NGT <160 <180 <200 IGTIGT <160 <180<200 Q1 T2DM Q2 Q3Q4 Q1 Q2 Q3Q4 T2DM 0 4 8 12 Glucose AUC (mmol/L 120 min) 0 4 8 12 Insulin AUC (pmol/L 120 min) Plasma Glucose and Insulin AUC Gastaldelli A, et al. Diabetologia. 2004;47:31-39.

36 I / G ÷IR 2-Hour Plasma Glucose (mg/dL) Insulin Secretion / Insulin Resistance (Disposition) Index During OGTT G=glucose; I=insulin; IR=insulin resistance. Gastaldelli A, et al. Diabetologia. 2004;47:31-39. 30 20 10 0 40 NGT Lean <100 <120 <140 Obese <180 IGT <200 <160 <240 <280 <360 <320 >400 <400 T2DM

37 6 -4 0 -2 2 4 6.54.04.55.05.56.0 Ln I / G ÷ IR (mL/min kg FFM ) Ln 2-Hour Plasma Glucose (mg/dL) r=0.91 P<0.00001 T2DM IGT NGT Log Normalization of the Relationship Between 2-Hour Plasma Glucose and Insulin Secretion / Insulin Resistance Index Ln=log normalization. Gastaldelli A, et al. Diabetologia. 2004;47:31-39.

38 GENFIEV: Insulin Secretion as a Function of Insulin Sensitivity HOMA-R=homeostasis model assessment index ratio. Diabetes. 2006;55(suppl 2):A322. Δ AUC C-peptide / Δ AUC Glucose ÷ HOMA-R 2-Hour Plasma Glucose (mg/dL) Trend test P<0.001

39 § # * Plasma Glucose (mmol/L) Insulin Secretion Rate (pmol. min -1. m -2 ) *P<0.01 vs NFG/NGT; § P<0.05 vs NFG/IGT and IFG/NGT; # P<0.05 vs IFG/IGT and NFG/DGT. Diabetes. 2006;55(suppl 2):A2472. GeNFIEV: Stimulus-response Curve (Proportional Control) of Insulin Secretion GENFIEV: Stimulus-Response Curve (Proportional Control) of Insulin Secretion

40 Insulin Secretion and Insulin Resistance in Different Ethnic Populations With IGT AIR=acute insulin response to glucose. Abdul-Ghani MA, et al. Diabetes Care. 2006;29:1130-1139. Latino/Hispanic Pima Indian White Δ AIR (%) Insulin resistance Decrease in AIR Necessary to Convert From NGT to IGT

41 Insulin Resistance and -Cell Dysfunction: Summary Individuals with impaired glucose tolerance –Are maximally or near-maximally insulin resistant –Have lost ~80% of their -cell function –Have an incidence of diabetic retinopathy of ~10%

42 Pathogenesis of Diabetes Evolving Concepts

43 Pathogenesis of Type 2 Diabetes HGP=hepatic glucose production. Islet -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake

44 Pathogenesis of Type 2 Diabetes HGP=hepatic glucose production. Islet -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake Time (minutes) 1st Phase2nd Phase i.v. Glucose Diabetes Normal glucose tolerance -5-5 -10-10 051010 1515 2020 2525 3030 3535 4040 4545 50505 6060 6565 7070 7575 8080 8585 9090 100100 9595 Insulin Secretion Time (minutes) 1st Phase2nd Phase i.v. Glucose Diabetes Normal glucose tolerance -5-1005101520253035404550556065707580859010095 Insulin Secretion Adapted from Weyer C, et al. J Clin Invest. 1999;104:784-789; Ward WK, et al. Diabetes Care. 1984;7:491-502.

45 Pathogenesis of Type 2 Diabetes Islet -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake

46 DeFronzo RA, et al. Metabolism. 1989;38:387-395. Pathogenesis of Type 2 Diabetes Islet -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake Basal HGP (mg/kg min) FPG (mg/dL) 2.0 2.5 3.0 3.5 4.0 100200300 r = 0.85 P<0.001 Control T2DM

47 Pathogenesis of Type 2 Diabetes Islet -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake

48 Pathogenesis of Type 2 Diabetes Islet -cell Impaired Insulin Secretion DeFronzo RA, et al. J Clin Invest. 1979;63:939-946; DeFronzo RA, et al. J Clin Invest. 1985;76:149-155. IncreasedHGP Decreased Glucose Uptake

49 The Disharmonious Quartet Islet -cell Impaired Insulin Secretion IncreasedHGP Decreased Glucose Uptake FFA IncreasedLipolysis FFA=free fatty acids.

50 FACoA Gluconeogenesis Glucose Utilization Lipolysis Plasma FFA HGP Role of Free Fatty Acids Hyperglycemia HGP Muscle Liver FACoA=FFA-derived long-chain acyl-CoA esters. Boden G. Proc Assoc Am Physicians. 1999;111:241-248. IncreasedLipolysis

51 Free Fatty Acids Impair -Cell Function *Percent difference between lipid infusion and saline infusion in subjects with family history of T2DM. Kashyap S, et al. Diabetes. 2003;52:2461-2474. Δ C-peptide Concentration (%)* First PhaseSecond Phase Hyperglycemic Clamp Procedure in NGT Individuals With Positive Family History of T2DM P<0.001 P<0.04

52 The Quintessential Quintet Islet -cell Impaired Insulin Secretion Decreased Glucose Uptake IncreasedLipolysis Decreased Incretin Effect IncreasedHGP

53 *P<0.05. GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide. Jones IR, et al. Diabetologia. 1989;32:668-677; Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86:3717-3723. 20 15 10 5 0 060120180 240 Time (min) GLP-1 (pmol/L) * * * * * * * * Meal P<0.01 GIP Levels Are Increased in T2DM GIP (pmol/L) Time (min) Postprandial GLP-1 Levels Are Decreased in Patients with IGT and T2DM GLP-1 and GIP Responses in Type 2 Diabetes NGTIGTT2DM 210060 * * * 40 0 80 -30120180 20 60 100

54 GLP-1, GIP, and Insulin AUC Across the Spectrum of Glucose Tolerance Vaag AA, et al. Eur J Endocrinol. 1996;135:425-432. AUC 1 Insulin (mU/mL · min) 12 10 8 6 4 2 0 -2 P<0.00005 P<0.005 AUC 1 GLP-1 (nmol/L · min) 0 1 2 3 4 P<0.05 AUC 1 GIP (nmol/L · min) 0 2 4 6 8 10 12 14 16 ControlsNGTIGTT2DM ControlsNGTIGTT2DM ControlsNGTIGTT2DM

55 The Setaceous Sextet Decreased Glucose Uptake IncreasedLipolysis IncreasedHGP Islet -cell Increased Glucagon Secretion Decreased Incretin Effect Islet -cell Impaired Insulin Secretion

56 Pancreatic -Cells and -Cells in Normal Individuals Cabrera O, et al. PNAS. 2006;103:2334-2339; Cleaver O, et al. In: Joslins Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21-39. -Cells -Cells Endocrine mass ~50%~35% RoleProduce insulin and amylinProduce glucagon Mechanism of action Secrete insulin in response to blood glucose elevations Secrete glucagon in response to blood glucose decreases Metabolic effect Permit glucose uptake by peripheral tissues Suppress glucagon and HGP Stimulate HGP to meet energy needs between meals

57 P<0.05 Clark A, et al. Diabetes Res. 1988;9:151-159. Area of -Cells Is Increased in Type 2 Diabetes -Cell Islet Area (%) (n=10)(n=15)

58 SRIF=somatostatin infusion. Baron A, et al. Diabetes. 1987;36:274-283. 0 50 100 150 200 250 Plasma Glucagon (pg/mL) Basal HGP (mg/m 2 min) 0 40 80 120 160 P<0.001 T2DM + SRIF T2DM + SRIF 44% 58% NGTT2DMNGTT2DM Basal Glucagon Levels and Basal Hepatic Glucose Production in Type 2 Diabetes

59 Plasma Glucose (mmol/L)Plasma Insulin (mU/L)Plasma Glucagon (mU/L) 02448 hr Plasma FFA ( mol/l) 02448 hr Del Prato S, et al. J Clin Invest. 1987;79:547-556. Hyperglucagonemia and Insulin- Mediated Glucose Metabolism

60 Inverse Relationship Between Insulin:Glucagon Ratio and Plasma Glucose in IGT Yellow symbols=NGT; green symbols=IGT; circles=nonobese; squares=obese. Mitrakou A, et al. N Engl J Med. 1992;326:22-29. 40 12 86 50 60 70 80 90 100 Glucose Appearance (mmol/5 hr) Peak Postprandial Plasma Glucose Level (mmol/L) Plasma Insulin:Glucagon Ratio r=0.72 P<0.0001 1014 15 501020 r=-0.62 P<0.001

61 Abnormal Meal-Related Insulin and Glucagon Dynamics in Type 2 Diabetes Glucose (mg %) Insulin (µU/mL) Glucagon (pg/mL) Time (min) Type 2 diabetes (n=12) Normal subjects (n-=11) -60060120180240 360 330 300 270 240 110 80 140 130 120 110 100 90 120 90 60 30 0 Meal Delayed/depressed insulin response Nonsuppressed glucagon Müller WA, et al. N Engl J Med. 1970;283:109-115.

62 The Septicidal Septet IncreasedLipolysis Increased Glucose Reabsorption Decreased Glucose Uptake IncreasedHGP Islet -cell Increased Glucagon Secretion Islet -cell Impaired Insulin Secretion Decreased Incretin Effect

63 Renal Glucose Reabsorption in Type 2 Diabetes Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule Renal glucose reabsorption is increased in type 2 diabetes Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose Wright EM, et al. J Intern Med. 2007;261:32-43.

64 SGLT1 (180 L/day) (900 mg/L)=162 g/day 10% Glucose No Glucose S1 S3 Renal Handling of Glucose SGLT2 90%

65 GLUT2 AMG Uptake NGTT2DMNGTT2DM AMG=methyl- -D-[U 14 C]-glucopyranoside; CPM=counts per minute. Rahmoune H, et al. Diabetes. 2005;54:3427-3434. SGLT2 NGTT2DM 0 2 6 8 0 500 1000 1500 2000 Normalized Glucose Transporter Levels CPM Increased Glucose Transporter Proteins and Activity in Type 2 Diabetes P<0.05 4

66 The Ominous Octet Islet -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect

67 Lower Posterior Hypothalamus Magnitude of Inhibitory Response (%) 0 4 8 ObeseLean P<0.01 Time to Max Inhibitory Response (min) 0 4 8 Obese Lean P<0.01 12 Matsuda M, et al. Diabetes. 1999;48:1801-1806. Altered Hypothalamic Function in Response to Glucose Ingestion in Obese Humans

68 1.Should be based upon known pathogenic abnormalities, and NOT simply on the reduction in HbA 1c 2.Will require multiple drugs in combination to correct multiple pathophysiologic defects 3.Must be started early in the natural history of T2DM, if progressive -cell dysfunction is to be prevented Treatment of Type 2 Diabetes

69 DPP-4 Inhibitors Sulfonylureas/ Meglitinides Treatment of Type 2 Diabetes: A Sound Approach Based Upon Its Pathophysiology Metformin TZDs Metformin GLP-1 analogues Islet -cell Impaired Insulin Secretion IncreasedLipolysis Decreased Glucose Uptake IncreasedHGP DPP-4=dipeptidyl peptidase-4.

70 Years 8 7 6 0 9 036 9 1215 UKPDS Group. Lancet. 1998;352:854-865. Median HbA 1c (%) UKPDS: Effect of Glibenclamide and Metformin Therapy on HbA 1c IDF Treatment Goal: <6.5% ConventionalGlibenclamideMetformin

71 Kahn SE, et al. N Engl J Med. 2006;355:2427-2443. ADOPT: Effect of Glyburide, Metformin, and Rosiglitazone on HbA 1c HbA 1c (%) Years IDF Treatment Goal: <6.5% 7.6 7.2 6.8 6.4 0 012345 -0.13% (P=0.002) -0.42% (P<0.001) GlyburideMetforminRosiglitazone

72 Adapted from © 2005 International Diabetes Center, Minneapolis, MN. All rights reserved. Weight Management Type 2 Diabetes Multiple Defects in Type 2 Diabetes Adverse Effects of Therapy Hyperglycemia Unmet Needs in Diabetes Care CVD Risk (Lipid and Hypertension Control)

73 SGLT2 Inhibition A Novel Treatment Strategy for Type 2 Diabetes

74 5 mmol/L Fasting Plasma Glucose Muscle Normal Glucose Homeostasis Fat Liver Pancreas

75 Fasting Plasma Glucose Pathophysiology of Type 2 Diabetes 10 mmol/L Islet -cell Impaired Insulin Secretion Insulin Resistance Increased HGP 5 mmol/L

76 Rationale for SGLT2 Inhibitors Inhibit glucose reabsorption in the renal proximal tubule Resultant glucosuria leads to a decline in plasma glucose and reversal of glucotoxicity This therapy is simple and nonspecific Even patients with refractory type 2 diabetes are likely to respond

77 Fasting Plasma Glucose Pathophysiology of Type 2 Diabetes 10 mmol/L Islet -cell Impaired Insulin Secretion Insulin Resistance Increased HGP Glucosuria

78 Fasting Plasma Glucose Pathophysiology of Type 2 Diabetes 10 mmol/L Islet -cell Impaired Insulin Secretion Insulin Resistance Increased HGP 5 mmol/L Glucosuria

79 SGLT1 (180 L/day) (900 mg/L)=162 g/day 10% Glucose No Glucose S1 S3 Renal Handling of Glucose SGLT2 90%

80 Sodium-Glucose Cotransporters SGLT1SGLT2SiteIntestine, kidneyKidney Sugar specificity Glucose or galactoseGlucose Glucose affinity High K m =0.4 mM Low K m =2 mM Glucose transport capacity LowHigh Role Dietary absorption of glucose and galactose Renal glucose reabsorption

81 Major transporter of glucose in the kidney Low affinity, high capacity for glucose Nearly exclusively expressed in the kidney Responsible for ~90% of renal glucose reabsorption in the proximal tubule Hediger MA, Rhoads DB. Physiol. Rev. 1994;74:993-1026. S1 Proximal Tubule Na + K+K+ ATPase Glucose GLUT2 Glucose SGLT2 BloodLumen Na + SGLT2 Mediates Glucose Reabsorption in the Kidney

82 Plasma Glucose Concentration (mmol/L) 155 Glucose Reabsorption and Excretion Splay Excretion Tm G 10 Actual Threshold Reabsorption Theoretical threshold Renal Glucose Handling

83 Rossetti L, et al. J Clin Invest. 1987;79:1510-1515. Effect of Phlorizin on Insulin Sensitivity in Diabetic Rats: Study Design Rat Group Pancreatectomy / Diabetic Status Phlorizin Meal Tolerance Test I (n=14) Sham Control –+ II (n=19) 90% Diabetes –+ III (n=10) 90% Diabetes ++ IV (n=4) 90% Diabetes + / – 10-12 days after discontinuation of phlorizin Phlorizin treatment period: 4-5 weeks Diet was same for all groups; body weight was similar across groups at end of study

84 Fasting Glucose (mmol/L) Diabetes +/- Phlorizin Diabetes + Phlorizin Diabetes Control * Fed Glucose (mmol/L) Diabetes +/- Phlorizin Diabetes + Phlorizin Diabetes Control *P<0.05 vs control and phlorizin. P<0.001 vs control and phlorizin. Rossetti L, et al. J Clin Invest. 1987;79:1510-1515. Effect of Phlorizin on Fed and Fasting Plasma Glucose in Diabetic Rats 0 5 10 15 20 0 2 4 6 8

85 Glucose Uptake (mg/kg min) *P<0.001 vs control and phlorizin. Rossetti L, et al. J Clin Invest. 1987;79:1510-1515. Insulin-Mediated Glucose Uptake in Diabetic Rats Following Phlorizin Treatment Diabetes +/- Phlorizin Diabetes + Phlorizin DiabetesControl 20 25 30 35 40 * *

86 Mechanism of Action of SGLT2 Inhibitors Inhibition of SGLT2Reversal of glucotoxicity Insulin sensitivity in muscle GLUT4 translocation Insulin signaling Other Insulin sensitivity in liver Glucose- 6-phosphatase Gluconeogenesis Decreased Cori cycle PEP carboxykinase -Cell function

87 Effect of Phlorizin on -Cell Function in Diabetic Rats: Study Design Rat Group Pancreactomy / Diabetic Status Phlorizin I Sham Control – II 90% Diabetes – III 90% Diabetes 0.4 g/kg/day Sprague-Dawley male rats weighing 80-100 g Phlorizin treatment period: 3 weeks Arginine clamp (2 mM); hyperglycemic clamp (5.5 mmol/L) Rossetti L, et al. J Clin Invest. 1987;80:1037-1044.

88 First Phase Second Phase Control Diabetes + Phlorizin Diabetes 6 0 4 * * 2 Plasma Insulin (ng/mL min / g Pancreas) Plasma Insulin Response to Glucose *P<0.001 vs control. Rossetti L, et al. J Clin Invest. 1987;80:1037-1044.

89 Starke A, et al. Proc Natl Acad Sci. 1985;82:1544-1546. Glucagon (pg/mL) Glucose Infusion Rate (mg/kg min) Diabetic + Phlorizin Diabetic -400 -200 0 241612862 Plasma Glucagon Concentration in Diabetic Dogs Before and After Phlorizin

90 Familial Renal Glucosuria: A Genetic Model of SGLT2 Inhibition

91 Familial Renal Glucosuria Presentation Glucosuria: 1-170 g/dayGlucosuria: 1-170 g/day AsymptomaticAsymptomaticBlood Normal glucose concentration No hypoglycemia or hypovolemiaNo hypoglycemia or hypovolemia Kidney / bladder No tubular dysfunction Normal histology and function Complications No increased incidence of –Chronic kidney disease –Diabetes –Urinary tract infection Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882; Wright EM, et al. J Intern Med. 2007;261:32-43.

92 Familial Renal Glucosuria Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882. Plasma Glucose Concentration (mmol/L) 155 Glucose Reabsorption 10 Type A Type B Normal Theoretical Observe d

93 Analysis of SGLT2 Gene in Patients With Renal Glucosuria Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882. 23 families analyzed for mutations In 23 families, 21 different mutations were detected in SGLT2 Cause of glucosuria in other 2 families remains unknown

94 GLUT2 AMG Uptake NGTT2DMNGTT2DM Rahmoune H, et al. Diabetes. 2005;54:3427-3434. SGLT2 NGTT2DM 0 2 6 8 0 500 1000 1500 2000 Normalized Glucose Transporter Levels CPM Increased Glucose Transporter Proteins and Activity in Type 2 Diabetes P<0.05 4

95 An adaptive response to conserve glucose (ie, for energy needs) becomes maladaptive in diabetes Moreover, the ability of the diabetic kidney to conserve glucose may be augmented in absolute terms by an increase in the renal reabsorption of glucoseImplications

96 SGLT2 Inhibitors for the Treatment of Type 2 Diabetes

97 Effect of SGLT2 Inhibition on Renal Glucose Handling Plasma Glucose Concentration (mmol/L) 155 Glucose Reabsorption and Excretion Splay Excretion Tm G 10 Actual Threshold Reabsorption Theoretical threshold

98 FPG (mg/dL) BaselineDay 8Day 15 Vehicle (n=6) 0.01 mg/kg (n=6) 0.1 mg/kg (n=6) 1 mg/kg (n=6) 10 mg/kg (n=6) 0 100 200 300 400 *P<0.05; P<0.0001 vs vehicle. ZDF=Zucker diabetic fatty. Han S, et al. Diabetes. 2008;57:1723-1729; Whaley J, et al. Diabetes. 2007;56(suppl 2). Abstract 0559-P. Effects of Dapagliflozin on Fasting Plasma Glucose in ZDF Rats * * * *

99 Hepatic Glucose Production (mg/kg min) Glucose Infusion Rate (mg/kg min) 0 1.0 2.0 3.0 4.0 0 2.0 4.0 6.0 8.0 CONDAPACONDAPA P<0.01 CON=controls; DAPA=dapagliflozin. Han S, et al. Diabetes. 2008;57:1723-1729. Effect of Dapagliflozin on Insulin-Stimulated Glucose Disposal and Hepatic Glucose Production in ZDF Rats

100 Dapagliflozin-Induced Glucosuria Reduces HbA 1c : A Dose-Ranging Trial Study design 12 week, double-blind, placebo-controlled12 week, double-blind, placebo-controlled –Dapagliflozin: 2.5, 5, 10, 50 mg/day –Metformin XR: 1500 mg/day –Placebo Patients 389 drug-naive T2DM patients HbA 1c >7.0% MeasurementsFPG, PPG, HbA 1c List JF, et al. Diabetes Care. 2009;32:650-657.

101 Baseline HbA 1c (%)7.78.08.07.87.97.7 All comparisons vs placebo; no statistical comparisons with metformin were made. List JF, et al. Diabetes Care. 2008;2009;32:650-657. P<0.01 Effect of Dapagliflozin on HbA 1c Δ HbA 1c (%) P<0.01 -0.8 -0.6 -0.4 -0.2 0 DAPA 2.5 DAPA 5 DAPA 10 DAPA 50 PBO MET XR 1500

102 Dapagliflozin: Glucosuric and Metabolic Effects Glucosuria 52-85 g/day FPG 16-30 mg/dL PPG 23-29 mg/dL Body weight 2.2-3.2 kg ( 2.5%-3.4%) Urine volume 107-470 mL/day List JF, et al. Diabetes Care. 2009;32:650-657.

103 Adverse Events With Dapagliflozin PBO (n=54) Met 1500 mg QD (n=56) Dapa 2.5 mg QD (n=59) Dapa 5 mg QD (n=58) Dapa 10 mg QD (n=47) Dapa 20 mg QD (n=59) Dapa 50 mg QD (n=56) Hypoglycemia, n (%) 2 (4)5 (9)4 (7)6 (10)3 (6)4 (7) UTIs, n (%)3 (6)5 (9)3 (5)5 (9)5 (11)7 (12)5 (9) Genital infection, n (%) 0 (0)1 (2)2 (3)1 (2) 4 (7) Hypotensive event, n (%) 1 (2)2 (4)0 (0) 1 (2) UTI=urinary tract infection. List JF, et al. Diabetes Care. 2009;32:650-657.

104 Investigational SGLT2 Inhibitors AgentManufacturer Phase III DapagliflozinAstraZeneca/Bristol-Myers Squibb Phase II AVE-2268 sanofi-aventis BI 10773 Boehringer Ingelheim JNJ-28431754 Johnson & Johnson Remogliflozin Sergliflozin GSK/Kissei TS-033 Taisho YM-543 Astellas/Kotobuki Pharmaceuticals Phase I CSG-452A Chugai/Roche SAR-7226 sanofi-aventis TA-7284 Mitsubishi Tanabe/Johnson & Johnson

105 Highly specific for the kidney and SGLT2 transporter ~80% reduction in SGLT2 mRNA/protein in Sprague- Dawley rats, ZDF rats, and dogs without any effect on SGLT1 Marked reduction in FPG, PPG, and HbA 1c in all three species No changes in plasma or urine electrolytes Wancewicz EV, et al. Diabetes. 2008;57(suppl 2). Abstract 334-OR. ISIS 388626 – A Specific SGLT2 Antisense Oligonucleotide

106 Unanswered Questions About SGLT2 Inhibition Durability The efficacy of SGLT2 inhibition may wane once blood glucose falls into the normal range Safety and tolerability The long-term safety of this class remains to be proven Risk of nocturia and genitourinary infections may limit use in some patients Renal impairment SGLT2 inhibition may not be effective in patients with renal impairment

107 SGLT2 Inhibition: Meeting Unmet Needs in Diabetes Care Weight Management Type 2 Diabetes Multiple Defects in Type 2 Diabetes Adverse Effects of Therapy Hyperglycemia CVD Risk (Lipid and Hypertension Control) Improvements in Glucose and Weight Support Other CVD Interventions Complements Action of Other Antidiabetic Agents Promotes Weight Loss Corrects a Novel Pathophysiologic Defect No Hypoglycemia Improves Glycemic Control

108 Conclusions SGLT2 inhibition represents a novel approach to the treatment of type 2 diabetes Studies in experimental models of diabetes have demonstrated that induction of glucosuria reverses glucotoxicity –Restores normoglycemia –Improves -cell function and insulin sensitivity

109 Conclusions Genetic mutations leading to renal glucosuria support the long-term safety of SGLT2 inhibition in humans Early results with dapagliflozin provide proof of concept of the efficacy of SGLT2 inhibition in reducing both fasting and postprandial plasma glucose concentrations in type 2 diabetes

110 Overall Conclusions Understanding of the pathophysiology of type 2 diabetes is an evolving process As new concepts emerge, there is potential for new treatment modalities Optimal management of type 2 diabetes requires a multifaceted approach that targets multiple defects in glucose homeostasis


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