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Targeting Abdominal Obesity in Diabetology What can we do about it?

Targeting Abdominal Obesity in Diabetology What can we do about it?. Luc Van Gaal, MD, PhD Department of Endocrinology, Diabetology & Metabolism Antwerp University Hospital Antwerp, Belgium. Targeting Abdominal Obesity in Diabetology What can we do about it?. Luc Van Gaal, MD, PhD

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Targeting Abdominal Obesity in Diabetology What can we do about it?

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  1. Targeting Abdominal Obesity in DiabetologyWhat can we do about it? Luc Van Gaal, MD, PhD Department of Endocrinology, Diabetology & Metabolism Antwerp University Hospital Antwerp, Belgium

  2. Targeting Abdominal Obesity in DiabetologyWhat can we do about it? Luc Van Gaal, MD, PhD Department of Endocrinology, Diabetology & Metabolism Antwerp University Hospital Antwerp, Belgium

  3. Key Challenges of Type 2 Diabetes Diabetes is a progressive disease characterized by: • Declining β-cell function • Insulin resistance • Deterioration of glycemic control • Obesity, mainly abdominal fat accumulation • Increased prevalence of cardiovascular disease • Hypoglycemia risk • Complex treatment regimens

  4. Weight Increase With Conventional Approach UKPDS: up to 8 kg in 12 years ADOPT: up to 4.8 kg in 5 years 100 8 7 Insulin(n=409) Rosiglitazone 6 96 5 Glibenclamide Weight (kg) Change in weight (kg) Glibenclamide (n=277) 4 92 3 Metformin 2 88 1 Metformin (n=342) 0 0 0 3 6 9 12 0 1 2 3 4 5 Yearsfromrandomization Years Conventionaltreatment (n=411); dietinitiallythensulphonylureas, insulin and/or metformin if fasting plasma glucose >15 mmol/l. UKPDS: United Kingdom Prospective DiabetesStudy ADOPT: A DiabetesOutcome Progression Trial Adapted from Lancet 1998;352:854-65 and Kahn SE et al. N Engl J Med 2006;355:2427-43

  5. Nurses’ Health Study: Risk for Type 2 Diabetes Relative risk* of type 2 diabetes Waist circumference (inches) * Controlled for age, family history of diabetes, exercise, smoking, saturated fat intake, calcium, potassium, magnesium and glycemic index. Adapted from Carey VJ et al. Am J Epidemiol 1997;145:614-9

  6. Not all Fat Is the Same… Maria Age: 58 years Weight: 92 kg BMI: 35.4 kg/m2 Intra-abdominal(visceral) adiposity Subcutaneousfat • Maria'smetaboliccardiovascular profile: • Cholesterol 188 mg/dl (4.87 mmol/l) • LDL cholesterol 106 mg/dl (2.75 mmol/l) • HDL cholesterol 56 mg/dl (1.45 mmol/l) • Glucose 84 mg/dl (4.7 mmol/l) • Blood pressure 125/78 mm Hg Adapted from Van Gaal LF Eur Neuropsychopharmacol 2006;16:S142-8

  7. Not all Fat Is the Same… Claudine Age: 58 years Weight: 92 kg BMI: 35.4 kg/m2 Intra-abdominal (visceral) adiposity Subcutaneousfat • Claudine'smetaboliccardiovascular profile: • Cholesterol 241 mg/dl (6.24 mmol/l) • LDL cholesterol 185 mg/dl (4.79 mmol/l) • HDL cholesterol 38 mg/dl (0.98 mmol/l) • Glucose 132 mg/dl (7.3 mmol/l) • Blood pressure 140/85 mm Hg Adapted from Van Gaal LF Eur Neuropsychopharmacol 2006;16:S142-8

  8. Intra-Abdominal (Visceral) Adiposity Promotes Insulin Resistance and β-Cell Dysfunction Hepatic insulin resistance Small, dense LDL   Hepatic glucose output  Lipolysis Intra-abdominal adiposity Low HDL cholesterol  TG-rich VLDL cholesterol  FFA CETP,Lipolysis Portal circulation Glucose utilization Insulin resistance   Systemic circulation Long-term damageto b-cells by FFA Insulin secretion  Splanchnic& systemic circulation CETP: cholesteryl ester transfer protein FFA: free fatty acids TG: triglycerides Adapted from Lam TK et al. Am J Physiol Endocrinol Metab 2003;284:E281-90: Carr MC et al. J Clin Endocrinol Metab 2004;89:2601-7: Eckel RH et al. Lancet 2005;365:1415-28.

  9. Intra-Abdominal (Visceral) Fat or Just Ectopic Tissue Fat? Reproduced with permission from Van Gaal LF et al. Nature 2006;444:875-80

  10. Intra-Abdominal (Visceral) Fat Excess – What Can We Do? • Assessment of problem and risk • Reduction of total and visceralfat by: • Lifestyleintervention • Pharmacotherapy • Bariatricsurgery • Prevention • Otherapproaches

  11. Vascular Disease and Hypertension According to Fat Distribution in Type 2 Diabetes Vascular disease CIHD Hypertension Subjects with disease (%) Nonobese WHR<1 Nonobese WHR>1 Obese WHR>1 CHID: coronaryheartischemicdisease WHR: waist-to-hip ratio Adapted from Van Gaal LF et al. Diabetes Care 1988;11:103-6.

  12. Intra-Abdominal (Visceral) Fat in Obese Diabetic Patients Women *p≤0.01 From Van Gaal LF et al. unpublished data

  13. Abdominal Obesity – What to do About it? Metabolic syndrome Visceralobesity Insulinresistance • Glucose intolerance • Dyslipidemia • Hypertension • Microalbuminuria Additionalriskfactors • Low-grade inflammation • Disturbedadipokinesecretion • Disturbances in hemostasis and fibrinolysis (PAI-1) Cardiovasculardisease Type 2 diabetes Adapted from Van Gaal LF et al. Nature 2006;444:875-80

  14. Intra-Abdominal (Visceral) Fat and the Risk of Mortality Reproduced with permission from Kuk JL et al. Obesity (Silver Spring) 2006;14:336-41

  15. Intra-Abdominal (Visceral) Fat Excess – What Can We Do? • Assessment of problem and risk • Reduction of total and visceralfat by: • Lifestyleintervention • Pharmacotherapy • Bariatricsurgery • Prevention • Otherapproaches

  16. Effect of Aerobic Exercise on Total and Intra-Abdominal (Visceral) Fat 60 r=0.70 p<0.01 40 20 Changes in visceral fat area (cm2) 0 -20 -40 -15 -10 -5 0 5 10 Changes in fat mass (kg) Adapted from Després JP et al. Am J Physiol 1991;261:E159-67

  17. Health Effects: Reduction in Subcutaneous and Intra-Abdominal (Visceral) Fat During a 3-Month Treatment Period Subcutaneous adipose tissue Visceral adipose tissue Exercise without weight loss Exercise-induced weight loss Diet-induced weight loss Control Adipose tissue (kg) Adapted from Ross R et al. Ann Intern Med 2000;133:92-103

  18. Changes in Intra-Abdominal (Visceral) Fat and Fat Mass After a Diet-Induced Weight Loss With or Without Aerobic Exercise in Obese Subjects: a 12-Week Randomized Intervention Study EXO DIO DEX Δvisceral adipose tissue/Δ fat mass * * * DIO: VLED-hypocaloricdiet DEX: VLED-hypocaloricdiet and exercise EXO: exerciseonly VLED: verylowenergydiet * p<0.01 – the relative reduction in visceral adipose tissue as compared with the relative reduction in fat mass. Adapted from Christiansen T et al. Eur J Endocrinol 2009;160:759-67

  19. Predictors of Intra-Abdominal (Visceral) Fat Loss With Lifestyle 0.7 EXO DIO 0.6 DEX 0.5 R2=0.72 p<0.01 0.4 Δvisceral adipose tissue/Δ fat mass 0.3 0.2 DIO: VLED-hypocaloricdiet DEX: VLED-hypocaloricdiet and exercise EXO: exerciseonly VLED: verylowenergydiet 0.1 0.0 0.0 0.1 0.2 0.3 0.4 0.5 Baseline visceral adipose tissue/fat mass Adapted from Christiansen T et al. Eur J Endocrinol 2009;160:759-67

  20. Correlations Between Changes in Anthropometric Measurements and Changes in Metabolic Variables Related to the Metabolic Syndrome * p<0.05 by Pearson’s correlation coefficient HOMA: homeostasis model of assessment DBP: diastolicblood pressure FPG: fasting plasma glucose SAT: subcutaneous adipose tissue SBP: systolicblood pressure TG: triglycerides VAT: visceral adipose tissue Adapted from Park HS and Lee K Diabet Med 2005;22:266-72

  21. Twice-Weekly Progressive Resistance Training Decreases Abdominal Fat and Improves Insulin Sensitivity in Older Men With Type 2 Diabetes 1200 5.5 ** 5.0 1100 * 4.5 1000 4.0 900 3.5 800 Insulinsensitivity index (10-4xmin-1xμUxml-1) 3.0 Total abominal fat (cm3) 700 2.5 600 2.0 500 1.5 400 1.0 300 0.5 0 0.0 Pretraining 16-week Pretraining 16-week * p<0.001vs. the pretraining value ** p<0.01 vs. the pretraining value Adapted from Ibañez J et al. Diabetes Care 2005;28:662-7

  22. Ectopic Fat Change vs. Metabolic Indices 0.6 1.25 0.4 0.75 0.2 0.25 HDL particle size change (nm) LDL particle size change (nm) 0.0 -0.25 -0.2 -0.75 r=-0.423 p=0.0065 r=-0.521 p=0.0006 -0.4 -1.25 -6 -5 -4 -3 -2 -1 0 1 2 -6 -5 -4 -3 -2 -1 0 1 2 Intermuscular adipose tissue changes (cm2) Intermuscular adipose tissue changes (cm2) Adapted from Durheim MT et al. Am J Physiol Endocrinol Metab;295:E407-12

  23. Intra-Abdominal (Visceral) Fat Excess – What Can We Do? • Assessment of problem and risk • Reduction of total and visceralfat by: • Lifestyleintervention • Pharmacotherapy • Bariatricsurgery • Prevention • Otherapproaches

  24. Recent Experience on Weight and Abdominal Fat With Anti-Obesity Drugs • Central active drugs • Sibutramine • Topiramate/phentermin combo • Pre-absorptive nutrient partitioning • Orlistat • Blockade of endocannabinoid system • Rimonabant

  25. SCOUT: Trial Population Previous cardiovascular event: • Myocardial infarction • Coronary artery bypass graft • Percutaneoustransluminal coronary angioplasty • Coronary artery disease • Type 2 diabetes with cardiovascular risk: • Controlled hypertension (≤160/≤90 mmHg) • Dyslipidemia • Current smoker • Diabetic nephropathy AdaptedfromJames WPT Eur Heart J; 2005;7:L44-8

  26. Lipase Inhibition: Mechanism of Action Intestinal lumen Mucosal cell Lymphatics TG GI lipase + Xenical FFA FA MG MG Bile acids Micelle 30% GI: gastrointestinal FA: fattyacids FFA: free fattyacids MG: monoglyceride TG: triglycerides

  27. Δ 2.15* Δ1.20 Improvement in Glucose Utilization With Orlistat Compared With Placebo at 6 Months Intervention + orlistat baseline Intervention + orlistat 6 months 8 7 6 5 4 3 2 1 0 Intervention + placebo baseline Intervention + placebo 6 months Glucose utilization (mg·min-1·kg-1 fat free mass) * p<0.05 vs. intervention + placebo -60 -30 0 30 60 90 120 150 180 210 240 Time (minutes) Adapted from Kelley DE et al. Diabetes Care 2004;27:33-40

  28. Effect of Lipase Inhibition on Fat Distribution ** * ** * Intra-abdominal (visceral) fat (cm3) Subcutaneous fat (cm3) Before After Before After Before After Before After Orlistat Placebo Orlistat Placebo ‡ † Intra-abdominal (visceral) fat/total fat (%) * p<0.0001 ** p<0.001 † p<0.01 ‡ p<0.05 Before After Before After Orlistat Placebo Adapted from Tiikkainen et al. Am J Clin Nutr 2004;79:22-30

  29. Recent Experience on Weight and Abdominal Fat With Anti-Obesity Drugs • Central active drugs • Sibutramine • Pre-absorptivenutrientpartitioning • Orlistat • Blockade of endocannabinoid system • Rimonabant

  30. Changes in Intra-Abdominal (Visceral) and Ectopic Fat in ADAGIO-Lipids Placebo n=87 Rimonabant 20 mg n=92 Placebo n=72 Rimonabant 20 mg n=68 Chhangefrombaseline in subcutaneous adipose tissue (%) Change frombaseline in visceral adipose tissue (%) p=0.0003 p=0.0043 p=0.0017 * Fatty liver index: liver/spleen attenuation ratio Change frombaseline in fattyliver index* Placebo n=59 Rimonabant 20 mg n=51 Adaptedfrom Després JP et al. ArteriosclerThrombVascBiol 2009;29:416-23

  31. (1) (1) (2) (2) (3) (3) Endocannabinoids vs. Changes in Intra-Abdominal (Visceral) Adipose Tissue Visceral adipose tissue variation (cm2) Anandamide concentrations (pmol/ml) * * After 1 year intervention Baseline Tertiles of changes in visceral adipose tissue 2-AG concentrations (pmol/ml) Triglyceride variation (mmol/l) † After 1 year intervention Baseline Tertiles of changes in 2-AG AG: arachidonoylglycerol Adapted from Di Marzo V. et al. Diabetologia 2009;51:1356-67 *Different from tertile 1, p<0.05 †Different from tertile 1 and 2, p<0.05

  32. Future – What Is Lacking? • Long-term trial with anti-obesity drugs in patients with early onset diabetes. • Maintenance studies in patients with metabolic syndrome and type 2 diabetes. • Safe combination studies. • Outcome trials with hard cardiovascular endpoints.

  33. Future Drug Options: A Search to Break the 10% Weight Loss Target • Second generation peripheral CB1 antagonists • 11 β-hydroxysteroid dehydrogenase inhibitor • Growth hormone in lipodystrophy? • GLP-1 analogues/mimetics • Leptin – Pramlintide combination

  34. Effect of Inhibition of 11 b-Hydroxysteroid Dehydrogenase Type 1 Mesenteric adipose depot SCD1 FAS DGAT1 ATGL mRNA (cprx10-3) * mRNA (cprx10-3) mRNA (cprx10-3) mRNA (cprx10-3) * * * CPT1 PEPCK Control Compound A ATGL: adipose triglyceride lipase CPT1: carnitinepalmitoyltransferase 1 DGAT1: diacylglycerolacyltransferase 1 FAS: fattyacidsynthase mRNA: messenger of ribonucleicacid PEPCK: phosphoenolpyruvatecarboxykinase SCD1:stearoyl-CoAdesaturase * mRNA (cprx10-3) Activity (nkat/g) * * p<0.05 vs. control Adapted from Berthiaume M et al. Endocrinology 2007;148:2391-7

  35. Effect of Growth Hormone on Intra-Abdominal (Visceral) Fat Change in visceral adipose tissue (%) Change in body fat (%) * * Growth hormone Growth hormone Placebo Placebo * Change in waist-to-hip ratio (%) Change in restingenergyexpenditure (%) * Growth hormone Growth hormone Placebo Placebo Adapted from Beauregard C et al. J Clin Endocrinol Metab 2008;93:2063-71 * p<0.05

  36. Human Glucagon-Like Peptide-1 (GLP-1) Effects: the Glucoregulatory Role of Incretins ↓ b-cell workload GLP-1 secreted upon the ingestion of food Promotes satiety and reduces appetite ɑ-cells: ↓ Postprandialglucagon secretion ↑ b-cell response Liver: ↓ Glucagon reduces hepatic glucose output b-cells:Enhances glucose-dependent insulin secretion Stomach: Helps regulate gastric emptying Adapted from Nauck MA et al. Diabetologia 1996;39:1546-53 and Drucker DJ Diabetes1998;47:159-69

  37. Liraglutide Lowers Weight in Subjects With Type 2 Diabetes Liraglutide 0.65 mg/day Liraglutide 1.25 mg/day Liraglutide 1.9 mg/day Placebo Weight change frombaseline (kg) Data are mean ±SEM Adapted from Vilsbøll et al. Diabet Med 2008;25:152-6

  38. Liraglutide Reduces Intra-Abdominal (Visceral) Body Fat: Results From the LEAD-2 Substudy Change in body fat DEXA scan Visceral vs. subcutaneous fat CT scan Visceral Subcutaneous 3 10 +1.1 kg (+0.4%) +3.4 2 5 1 0 0 5 Change in body fat (kg, (%)) Change in percentage fat (%) -1 -10 -7.8* -4.8 -8.5* -15 -2 -1.6* (-1.1%*) -3 -20 -2.4* (-1.2%*) -16.4 -17.1 -25 -4 Liraglutide 1.2 mg + metformin Liraglutide 1.8 mg + metformin Two thirds of weight lost was fat tissue (liraglutide 1.8 mg). * p<0.05 vs. glimepiride + metformin. Glimepiride + metformin Adapted from Jendle J et al. Diabetes Obes Metab 2009;11:1163-72

  39. Intra-Abdominal (Visceral) Fat Excess – What Can We Do? • Assessment of problem and risk • Reduction of total and visceralfat by: • Lifestyleintervention • Pharmacotherapy • Bariatricsurgery • Prevention • Otherapproaches

  40. Diabetes 2006;55:2025-31 Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery. Guidone C, Manco M, Valera-Mora E, laconelli, A Gniuli D, Mari A, Nanni G, Castagneto M, Calvani M, Mingrone G Reproduced with permission from DeMaria EJ N Engl J Med 2007;356:2176-83

  41. Intra-Abdominal Obesity or Fat Mass? Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease Beforeliposuction Afterliposuction Photographs and abdominal magnetic resonance images obtained before and after liposuction. The photographs of one study subject and images of another show the large amount of subcutaneous abdominal fat removed by liposuction. Reproduced with permission from Klein S et al. N Engl J Med 2004;350:2549-57

  42. Reduction of Subcutaneous Fat Mass Does not Improve Inflammatory Status Effects of liposuction on mediators of inflammation in obese women with normal glucose tolerance or type 2 diabetes* * Plus–minus values are means ±SD. The measurements were made within 9 days before liposuction and again 10 to 12 weeks after liposuction. † Values were obtained from six subjects in each group. Adapted from Klein S et al. N Engl J Med 2004;350:2549-57

  43. Effect of Additional Omentectomy on Metabolic Features 5 Control 0 Omentectomy Body mass index (kg/m2) -5 -10 5 p=0.18 0 -15 0 5 10 15 20 25 -5 Time (months) Insulin (mU/l) -10 p=0.04 -15 0.5 -20 0.0 0 5 10 15 20 25 -0.5 Time (months) Glucose (mmol/l) -1.0 -1.5 p=0.03 -2.0 -2.5 0 5 10 15 20 25 Time (months) Adapted from Thörne A et al. Int J Obes Relat Metab Disord 2002;26:193-9

  44. Surgical Removal of Omental Fat Does Not Improve Insulin Sensitivity and Cardiovascular Risk Factors in Obese Adults Fabbrini E, Tamboli RA, Magkos F, Marks-Shulman PA, Eckhauser AW, Richards WO, Klein S, Abumrad NN PotentialAdditionalEffect of Omentectomy on Metabolic Syndrome, Acute-Phase Reactants, and InflammatoryMediators in Grade III Obese Patients UndergoingLaparoscopic Roux-en-Y GastricBypass: A Randomized Trial Herrera MF, Pantoja JP, Velázquez-Fernández D, Cabiedes J, Aguilar-Salinas C, García-García E, Rivas A, Villeda C, Hernández-Ramírez DF, Dávila A, Zaraín A Adapted from Fabbrini E et al. Gastroenterology 2010;139:448-55 and Herrera MF et al. Diabetes Care 2010;33:1413-8

  45. Effect of Additional Omentectomy on Metabolic Features(1 of 2) LRYGB: laparoscopic Roux-en-Y gastricbypass Data after surgery are means ± SD or percent of change from basal (95% CI). Minus signs denote decreases and plus signs increases. All comparisons p=ns. Adapted from Herrera MF et al. Diabetes Care 2010;33:1413-8

  46. Effect of Additional Omentectomy on Metabolic Features(2 of 2) LRYGB: laparoscopic Roux-en-Y gastric bypass  Data after surgery are means ± SD or percent of change from basal (95% CI). Minus signs denote decreases and plus signs increases. All comparisons p=ns. Adapted from Herrera MF et al. Diabetes Care 2010;33:1413-8

  47. Effect of Additional Omentectomy on Metabolic Features 1200 LRYGB alone 900 * LRYGB + omentectomy * * * Insulin-mediatedincrease in glucose disposal (% above basal) 600 300 0 Before surgery 6 months after surgery 12 months after surgery 3 * * * 2 Hepaticinsulinsensitivity index (103·min·l/mg·mU) * 1 LRYGB: laparoscopic Roux-en-Y gastric bypass 0 Before surgery 6 months after surgery 12 months after surgery * p<0.00002 vs. value before surgery Adapted from Fabbrini E et al. Gastroenterology 2010;139:448-55

  48. Type of Surgery vs. Effect on Intra-Abdominal (Visceral) Adipose Tissue Band Bypass 3 3 r=0.81 p=0.005 r=0.36 p=0.43 2 2 Visceral adipose tissue (kg) Visceral adipose tissue (kg) 1 1 0 0 20 30 40 50 60 20 25 30 35 40 45 Total adipose tissue (kg) Total adipose tissue (kg) 3 r=-0.28 p=0.53 3 r=-0.73 p=0.016 2 Visceral adipose tissue (kg) 2 Visceral adipose tissue (kg) 1 1 0 0 20 30 40 50 -1 10 20 30 40 50 Weightloss (%) Weightloss (%) Adapted from Korner J et al. Int J Body Compos Res 2008;6:93-9

  49. Percentage of Patients With Resolution or Improvement of Major Comorbidities* * The table shows the mean percentage of patients (with number of studies; and 95% CI). Data were compiled by Buchwald et al. JAMA 2004;292:1724-37 from separate studies. Adapted from Kral JG and Näslund E Nat Clin Pract Endocrinol Metab 2007;3:574-83

  50. Intra-Abdominal (Visceral) Fat Excess – What Can We Do? • Assessment of problem and risk • Reduction of total and visceralfat by: • Lifestyleintervention • Pharmacotherapy • Bariatricsurgery • Prevention • Otherapproaches

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