DISCLOSURE STATEMENT

Transcription

1 Challenging Cases in Obesity Management Jonathan Q. Purnell, MD Knight Cardiovascular Institute Division of Endocrinology Oregon Health & Science University DISCLOSURE STATEMENT Speaker: Jonathan Q. Purnell, MD Novo Nordisk Advisory Board My presentation will likely include discussion of off label use of drugs for treatment of obesity and comorbid conditions. 1

2 Case Presentation 32 yo F presents with a family history of early CAD and dyslipidemia PMH DM2 2 years duration Initially on metformin attempted to control with diet Suboptimal control with A1C 7.5 Morbid obesity, BMI 43 Lost 13 lb with diet and exercise Hyperlipidemia OSA, on CPAP PCOS, recent dx Depression 2

3 Family History Mother Had GDM, later DM2 in late 40. Dx of Dunnigan s at age 51 with genetic testing in CA PCOS, s/p TAH BSO CAD, stent at age 40, 4v GABG at age 56 Father Died in military accident at age 31 Sister PCOS Labs A1C 7.5 TSH 1.68 FSH 5.5 PRL 10.1 Vit D18 CBC normal CMP normal Lipds: TC 159, LDL 91, HDL 26, TG 208 HIV neg, Hep C neg 3

4 Physical exam Vital signs: normal. BMI 43 Gen: morbidly obese Caucasian female HEENT: Excessive amount of subcutaneous fat in lower face, neck and supraclavicular area Heart: unremarkable Lungs: clear Abdomen: obese, NT, ND Extremities: b/l lower extremities with relatively minimal subcutaneous fat Skin: no rashes, some salmon colored stria Lipodystrophy Heterogeneous group of adipose tissue disorders characterized by selective loss of fat from various parts of body Limited Well demarcated subcutaneous depressed areas or indentations Usually only cosmetic problems Extensive Sometimes nearly compete absence of body fat (congenital generalized lipodystrophy) Metabolic abnormalities Garg A. Lipodystrophies. Am J Med Feb;108(2):

5 Familial Classification Acquired Generalized Partial Generalized Partial Dunnigan s Kobberling Mandibuloacral dysplasion Garg A. Lipodystrophies. Am J Med Feb;108(2): HIVassociated Protease inhibitor Localized Drugs Pressure Centrifugal Panniculitis Idiopathic Total Congenital Generalized Lipodystrophy Andreelli, et al. JCEM , MJ Elders. Lipodystrophies. MBID. Autosomal dominant Absence of fat in limbs, trunk, viscera Easily visible veins Defined musculature Normal fat in face, palms, soles +++ insulin resistance and DM2 +++ hypertriglyceridemia 5

6 Ectopic Fat in Lipodystrophy Liver HGO Glucose VLDL TG Muscle Intrahepatic fat IMCL glucose IAF MRI: NEJM 346: 570 8, 2002 Diabetes 52: , 2003 Leptin Treatment for Lipodystrophies Oral et al. 346 (8): 570, Figure 1,

7 Familial Partial Lipodystrophy Dunnigan Köbberling 7

8 Partial Lipodystrophy Clinical features Childhood: Normal adipose tissue Puberty: Loss of fat from extremities increased muscularity Loss of fat from trunk (variable) Later: Double chin Excess supraclavicular fat Round face Increased fat in genital area Partial lipodystrophy Men vs Women Men difficult to recognize increased muscularity phenotype Probably underreported Men carrying the same mutation as their affected female relatives have normal body fat distribution Men may not be as severely affected with metabolic complications Le Monument à Balzac by Auguste Rodin 8

9 Genetics of Dunnigan s lipodystrophy Previously thought to be x linked dominant, now pedigrees show autosomal dominant Chromosome 1q21 22 Several mutations identified R482W encoding Laminin A/C (structural protein of nuclear membraine) most common mutation Dunnigan s = laminopathy Laminopathies Striated muscle (e.g. Emery Dreifuss Muscular Dystrophy, Dilated Cardiomyopathy) Adipose tissue (e.g. Dunnigan type familial partiallipodystrophy) Abnormal senescence and growth deformities (e.g. Progeria syndrome) Recent Pat Endocr Metab Immune Drug Discov. 2015;9(2): Biology and Regulatory Roles of Nuclear Lamins in Cellular Function and Dysfunction. Khadija SG, Chen F, Hadden T, Commissaris RL, Kowluru A1. 9

10 Management of Lipodystrophies General Lifestyle Weight loss meds/surgery Metformin for DM Lipid meds (usually includes TG lowering medication: fibrate) Specific Thiazolidinediones Leptin other Case Presentation 54 yo M follow up after hospitalization for non STelevation MI Stent placed Started on: ASA Beta blocker 80 mg atorvastatin 10

11 PMH Type 2 DM 5 years duration Initially on metformin Past year: A1c % Central Obesity, BMI 38.7 kg/m2 Waist circumference 44 inches Hyperlipidemia: Pre MI Post MI TC TG LDL HDL What About Meds for Obesity? $225 / month $800 / month Currently FDA Approved phentermine (Fastin, Ionamin, Adipex) phentermine + topiramate (Qsymia) lorcasarin (Belviq) buproprion + naltrexone (Contrave) liraglutide 3.0 mg (Saxenda) 11

12 Case Presentation 54 yo M follow up after hospitalization for non STelevation MI Stent placed Started on: ASA Beta blocker 80 mg atorvastatin Lantus (insulin) 24 units Case Presentation A1c now 7.7% Weight up 8 lbs. What do you recommend? a) Focus on diet and exercise? b) Increase insulin? c) Begin thiozolindinedione (pioglitazone)? d) Add in GLP 1agonist? e) Add in SGLT 2 inhibitor? f) Other? 12

13 Case Presentation What do you recommend? a) Focus on diet and exercise? b) Increase insulin? c) Begin thiozolindinedione (pioglitazone)? d) Add in GLP 1agonist? e) Add in SGLT 2 inhibitor? f) Other? LOOK AHEAD Cardiovometabolic Risk Factors in T2DM: Changes in Weight, Physical Fitness, Waist Circumference and HgA1C over 10 years Look AHEAD Research Group. NEJM. 2013;369:

14 LOOK AHEAD: Effect of Lifestyle on Cardiovascular Outcomes in T2DM Look AHEAD Research Group. NEJM. 2013;369: Case Presentation What do you recommend? a) Focus on diet and exercise? b) Increase insulin? c) Begin thiozolindinedione (pioglitazone)? d) Add in GLP 1agonist? e) Add in SGLT 2 inhibitor? f) Other? 14

15 ACCORD: Median Glycated Hemoglobin Levels at Each Study Visit The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358: ACCORD: Increased All-Cause Mortality with Diabetes Intensification The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:

16 Case Presentation What do you recommend? a) Focus on diet and exercise? b) Increase insulin? c) Begin thiozolindinedione (pioglitazone)? d) Add in GLP 1agonist? e) Add in SGLT 2 inhibitor? f) Other? Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Trials JAMA. 2007;298(10):

17 Case Presentation What do you recommend? a) Focus on diet and exercise? b) Increase insulin? c) Begin thiozolindinedione (pioglitazone)? d) Add in GLP 1agonist? e) Add in SGLT 2 inhibitor? f) Other? LEADER: Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes Marso SP et al. N Engl J Med 2016;375:

18 SGLT2 Inhibitor (Empaglifozin): CVD Outcomes and Death from Any Cause Zinman B et al. N Engl J Med 2015;373: Case Presentation A1c now 7.7% Weight up 8 lbs. What do you recommend? a) Focus on diet and exercise? b) Increase insulin? c) Begin thiozolindinedione (pioglitazone)? d) Add in GLP 1agonist? e) Add in SGLT 2 inhibitor? f) Other? 18

19 Weight loss/bariatric/metabolic Surgery Surgery alters how food/nutrients pass through the gut. Gastric Band (Lap Band) Gastric Bypass (Roux en Y Gastric Bypass) Nearly all are key hole laparoscopic Sleeve Gastrectomy Type 2 Diabetes Mellitus Remission Rates: 3 years after bariatric surgery in the Longitudinal Assessment of Bariatric Surgery (LABS) 2 study All Surgeries (n=627) RYGBP (n=466) LAGB (n=140) Year 1 Year 2 Year 3 Purnell, et al. Diabetes Care Jul;39(7): Courcoulas, et al. JAMA. 2013;310:

20 Type 2 Diabetes Mellitus Incidence Rates: 3 years after bariatric surgery in the Longitudinal Assessment of Bariatric Surgery (LABS) 2 study 4 All Surgeries (n=1241) RYGBP (n=838) LAGB (n=338) Year 1 Year 2 Year 3 Purnell, et al. Diabetes Care Jul;39(7): Courcoulas, et al. JAMA. 2013;310: Baseline Characteristics of Subjects Achieving Type 2 DM Remission Over 3 years in LABS 2 Purnell, et al. Diabetes Care Jul;39(7): Younger age Increased BMI and % fat Increased waist circumference Shorter diabetes duration Not insulin use or fewer non insulin diabetes meds Lower HbA1c Higher fasting insulin, C peptide RYGBP vs. LAGB 20

21 RCT: STAMPEDE 3 yr Outcomes HbA1c BMI RCT: STAMPEDE 3 yr Outcomes Diabetes medications 21

22 Microvascular Complications Macrovascular Complications 22

23 Macrovascular Complications Obesity Treatment: Bariatric Surgery Cardiovascular Disease and Mortality 23

24 SOS: Cardiovascular Events Meta-analyses of adverse CVD events risk after bariatric surgery as compared to no surgery Int J Cardiol 173 (2014)

25 Retrospective Study : Impact of RYGB on Survival obese patients from Washington state (3328 had bariatric surgery) 33% lower all cause mortality at 15 years of follow up SOS: Mortality 30% reduction in mortality 25

26 Association Between Bariatric Surgery and Long term Survival Deaths 263 vs % reduction in mortality Arteburn D et al., Hazards Ratios for Death: Surgery (n=7000) vs. Control Group (n=7000) Adams, et al. N Engl J Med (8):753-61, % reduction All Cause Death CVD Death Cancer Death Diabetes Death 26

27 Obesity Treatment of T2DM Metformin GLP-1 agonist SGLT2 inhibitor DPP IV inhibitor RYGBP or Sleeve Gastrectomy 27