Achttiende diabetessymposium Bariatrische heelkunde pros en cons. B.J. Van der Schueren

Transcription

1 Achttiende diabetessymposium Bariatrische heelkunde pros en cons B.J. Van der Schueren

2 Disclaimer No Conflicts of Interest Member of the Committee for Medicinal Products for Human Use at EMA Subject famhp/entity/division-unit-cell Date 2

3 Disclaimer Disclaimer: The views expressed in this presentation are the personal views of the speaker and may not be understood or quoted as being made on behalf of or reflecting the position of EMA or one of its committees or working parties. Subject famhp/entity/division-unit-cell Date 3

4 Obesitaskliniek UZLeuven Artsen Matthias Lannoo Bart Van der Schueren Ann Mertens Katrien Laga Roman Vangoitsenhoven Psychologen Amber Van den Eynde Wout Van der Borght Coördinatoren Ann Desmet (obesitaskliniek) Mieke De Vadder (bariatrische chirurgie) Apotheker Ina Gesquière Diëtisten Liesbeth Renaerts Evy Weynants Mieke Roelants Laura Celis Kine Ilse Muylaert Ben Matters Wetenschappelijke Coördinatoren Christophe Matthys Ann Meulemans Studenten Brecht Gijbels Miranda van der Ende Nele Steenackers

5 Gastric Bypass

6 Gastroplasty (Sleeve)

7 Gastric Banding

8 malabsortive surgical procedure Bilio-pancreatic diversion

9

10 Bariatric Surgery Sjöström L et al., Journal of Internal Medicine, 2013, 273;

11 Bariatric Surgery Mortality Sjöström L et al., Journal of Internal Medicine, 2013, 273;

12 Bariatric surgery cures diabetes Sjöström L et al., Journal of Internal Medicine, 2013, 273;

13 Bariatric surgery cures diabetes Schauer et al., N Engl J Med. 2014

14 Bariatric surgery cures diabetes Schauer et al., N Engl J Med. 2014

15 Bariatric surgery cures diabetes? Arterburn et al. OBES SURG (2013) 23:

16 Bariatric surgery PREVENTS diabetes Sjöström L et al., Journal of Internal Medicine, 2013, 273;

17 Key challenges of type 2 diabetes Unhealthy lifestyle and environmental factors Genes Environment Inflammation + Free fatty acid Glucose Hyperglycaemia Failing beta-cells Type 2 diabetes

18 Decline of -Cell Function in UKPDS Illustrates Progressive Nature of Diabetes ? Time of diagnosis -cell function (% of normal by HOMA) Pancreatic function = 50% of normal Years HOMA=homeostasis model assessment Adapted from Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21-S25; UKPDS. Diabetes. 1995;44:

19 Modest Weight Loss Prevents Diabetes in Overweight and Obese Persons with Impaired Glucose Tolerance Diabetes Prevention Program Research Group. N Eng J Med 2002;346:393. Copyright Massachusetts Medical Society. All rights reserved.

20 Bariatric Surgery Mortality Sjöström L et al., Journal of Internal Medicine, 2013, 273;

21 Bariatric Surgery Mortality Sjöström L et al., Journal of Internal Medicine, 2013, 273;

22 Bariatric Surgery Mortality Sjöström L et al., Journal of Internal Medicine, 2013, 273;

23 The nature of the internist

24 Bariatric Surgery Mortality Sjöström L et al., Journal of Internal Medicine, 2013, 273;

25 Bariatric Surgery Mortality Sjöström L et al., Journal of Internal Medicine, 2013, 273;

26 Major CV outcome studies in T2D Baseline Patient Age (yrs) Severity/ Duration of Disease Mean Followup Inclusion Criteria: CV Risk Outcome UKPDS 2 53 T2D: Newly diagnosed 10 yrs No Risk of MVD Risk of CVD RECORD 7 57 T2D: Without history of HF 5.5 yrs No Risk of CVD* PROACTIVE 8 62 T2D: History of macrovascular disease 34 mos Yes Risk of CVD* ORIGIN 9 64 T2D or CV risk factors and impaired fasting glucose, impaired glucose tolerance 6.2 yrs Yes Risk of MVD Risk of CVD VADT 3 60 T2D: Substandard response to therapy 5.6 yrs No Risk of MVD Risk of CVD ADVANCE 4 67 T2D: History of vascular disease or risk for vascular disease 5 yrs Yes Risk of MVD Risk of CVD ACCORD 5, 6 62 T2D: CVD or CV risk 5 yrs Yes Risk of MVD Risk of CVD 1. Nathan DM, et al. N Engl J Med. 2005;353: ; 2. Stratton IM, et al. BMJ. 2000;321: ; 3. Duckworth W, et al. VADT Investigators. N Engl J Med. 2009;360: ; 4. The ADVANCE Collaborative Group, et al. N Engl J Med. 2008;358: ; 5. The ACCORD Study Group, et al. N Engl J Med. 2011;364: ; 6. Ismail-Beigi F, et al. Lancet. 2010;376: ; 7. Home PD, et al. RECORD Study Team. Lancet. 2009; 373: ; 8. Dormandy JA, et al; PROactive investigators. Lancet. 2005;366: ; 9. The ORIGIN Trial Investigators, et al. N Engl J Med. 2012;367:

27 Legacy Effect of Earlier Glucose Control UKPDS After median 8.5 years post-trial follow-up Aggregate Endpoint Any diabetes related endpoint RRR: 12% 9% P: Microvascular disease RRR: 25% 24% P: Myocardial infarction RRR: 16% 15% P: All-cause mortality RRR: 6% 13% P: RRR = Relative Risk Reduction, P = Log Rank

28 CV death Empagliflozin Cumulative incidence function. Treated set. CV, cardiovascular; HR, hazard ratio. 28

29 All-cause mortality Empagliflozin Kaplan-Meier estimate. Treated set. HR, hazard ratio. 29

30 3-point MACE 3-point MACE n event/n analysed HR (95% CI) p-value Empagliflozin Placebo Intention-to-treat analysis Treated set 490/ / (0.74, 0.99)* (one-sided)* On-treatment analysis Treated set + 30 days 412/ / (0.74, 1.02) On-treatment set 407/ / (0.74, 1.02) Per-protocol analysis Per-protocol set 487/ / (0.75, 1.00) ,5 1,0 2,0 Favours empagliflozin Favours placebo Cox regression analysis. Treated set: patients who received 1 dose of study drug. On-treatment set: patients who received study drug for 30 days (cumulative) including only events that occurred 30 days after a patient s last intake of trial medication. Per-protocol set: patients who received 1 dose of study drug and did not have important protocol violations affecting the primary endpoint. *95.02% CI; owing to the initial test for non-inferiority, one-sided tests for superiority were conducted (statistical significance was indicated if p< Events observed from randomisation to the end of the study. Only events observed 30 days after a patient s last intake of trial medication. 30

31 Conclusion in terms of type 2 diabetes - Bariatric surgery is no cure for type 2 diabetes - Bariatric surgery does lower the incidence of type 2 diabetes (prevents) (which is also possible with lifestyle interventions) - Medical treatment has more robustly shown to prevent both co-morbidities and mortality due to type 2 diabetes

32 Bariatric Surgery Sjöström L et al., Journal of Internal Medicine, 2013, 273;

33 The answer to obesity is obvious Eat Less and Exercise More

34 Medical Interventions Xenical (mean 5,9 kg)

35 Medical Interventions Liraglutide (Saxenda) Manning et al. Ther Adv Chronic Dis May;5(3):135-48

36 Medical Interventions Mysimba (Naloxone/bupropion) Manning et al. Ther Adv Chronic Dis May;5(3):135-48

37 Modest Weight Loss Prevents Diabetes in Overweight and Obese Persons with Impaired Glucose Tolerance Diabetes Prevention Program Research Group. N Eng J Med 2002;346:393. Copyright Massachusetts Medical Society. All rights reserved.

38 Conclusion in terms of weight, risk for diabetes - There is no alternative for the sustained weight loss observed after bariatric surgery % weight loss seems to be sufficient to prevent both morbidity and mortality caused by obesity - Medical treatment has shown to prevent type 2 diabetes as well

39 Has the surgeon forgotten a patient population? Very few reports on bariatric surgery in type 1 diabetes despite the increase of obesity, also in this patient population Czupryniak et al. (Lodz Poland) reported RYGBP in 2 young women with Type 1 diabetes in 2004 (Diabetes Care) 23 yo woman: Baseline HbA1c 9,5 %, Total insulin 68 U, BMI 38,8 kg/m 2 Post-surgery HbA1c 5,7 %, Total insulin 45 U, BMI 29,1 kg/m 2 Uneventful perioperative and postoperative period 28 yo Woman: Baseline HbA1c 10,4 11,8 %, Total insulin 120 U, BMI 46,3 kg/m 2 Post-surgery HbA1c 7,3 %, Total insulin 70 U, BMI 32,9 kg/m 2 Bilateral Pneumonia in perioperative period

40 Bariatric surgery in T1D A few cases Mendez et al Diabetes Metab Syndr Obes Aug 10;3:281-3.

41 Bariatric surgery in T1D A few cases Mendez et al Diabetes Metab Syndr Obes Aug 10;3:281-3.

42 Bariatric surgery in T1D A few cases Brethauer et al Diabetes Care 2014 (7 RYGBP, 2GB, 1 Sleeve)

43 Bariatric surgery in T1D Effect of Duodeno-jejunal bypass Breen et al. Nature Medicine

44 Bariatric surgery in T1D A well known GLP-1 increase Bose et al. Obesity 2010

45 Surgical procedures Physiology: entero-insular axis Ingestion of food Glucose dependent GI tract Release of incretin gut hormones Active GLP-1 and GIP Pancreas Beta cells Alpha cells Insulin from beta cells (GLP-1 and GIP) Insulin increases peripheral glucose uptake Blood glucose control Glucagon from alpha cells (GLP-1) Glucose dependent Increased insulin and decreased glucagon reduce hepatic glucose output Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145: ; Zander M et al Lancet 2002;359: ; Ahrén B Curr Diab Rep 2003;3: ; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:

46 Rationale for a study in type 1 diabetes Time courses of plasma glucose (A and B), C-peptide (C and D), and glucagon (E and F) during 50-g oral glucose tolerance test (OGTT; filled symbols) and isoglycemic iv glucose infusion (IIGI; open symbols) in patients with type 1 diabetes and no residual β-cell function (circles, left) and healthy control subjects (triangles, right). Hare et al. American Journal of Physiology - Endocrinology and Metabolism

47 Type 1 Diabetes and Bariatric Surgery Gains Insulin therapy induces weight gain Insulin therapy impairs weight loss therapy Glycemic control impaired by insulin resistance Possible improvement of glucose control by suppression of glucagon 47

48 Type 1 Diabetes and Bariatric Surgery Risks Increased perioperative risk Impaired weight loss Worse glycemic control due to variable absorption after bariatric surgery 48

49 Type 1 Diabetes and Bariatric Surgery Effect on carbohydrate absorption Wang et al. OBES SURG

50 Study Lannoo et al. Diabetes Care 2014 Retrospective analysis 3 Belgian centers (AZ Sint-Jan Brugge, UZ Gent, UZ Leuven) Data were collected from before and after bariatric surgery N=21 patients included (4SG & 17 RYGB) Statistics Data are presented in a descriptive plot The values compared before and after the intervention corrected for N of values /patient Intra subject variability is compared before and after in a 50 regression model assuming a linear relation

51 Safety EVENT N PATIENTS N EVENTS KETO ACIDOTIC COMA 2 2 SEVERE HYPOGLYCEMIA 1 1 HOSPITALIZATION DM1 4 6 GASTRIC FISTULA 1 1 MARGINAL ULCER 1 1 INCISIONAL HERNIA 1 1 DYSPHAGIA

52 Lannoo et al. Diabetes Care 2014 Results

53 BMI 95% CI Estimate LL UL Before intervention After intervention LL, UL: lower and upper limit of 95%confidence interval (CI) Difference in level before and after intervention? F Value Pr > F <

54 Insulin need: bolus 95% CI Estimate LL UL Before intervention After intervention LL, UL: lower and upper limit of 95%confidence interval (CI) Difference in level before and after intervention? F Value Pr > F

55 Insulin need: basal 95% CI Estimate LL UL Before intervention After intervention LL, UL: lower and upper limit of 95%confidence interval (CI) Difference in level before and after intervention? F Value Pr > F

56 HBA1c 95% CI Estimate LL UL Before intervention After intervention LL, UL: lower and upper limit of 95%confidence interval (CI) P=0,5695 Estimate Within-subject variability Before intervention SE After intervention SE=standard error Within-subject variability, i.e. the variability of values around the patientspecific linear evolutions 56

57 Secondary prevention SYSTOLIC BP 95% CI Estimate LL UL Before intervention After intervention LL, UL: lower and upper limit of 95%confidence interval (CI) P= DIASTOLIC BP 95% CI Estimate LL UL Before intervention P= After intervention LL, UL: lower 57 and upper limit of 95%confidence interval (CI)

58 Secondary prevention LDL 95% CI Estimate LL UL Before intervention After intervention LL, UL: lower and upper limit of 95%confidence interval (CI) P= HDL 95% CI Estimate LL UL Before intervention After intervention P= LL, UL: lower and 58 upper limit of 95%confidence interval (CI)

59 Conclusion in terms of treating type 1 diabetes - No improvement of glycemic control - Safe

60 Average price per patient (euros) Bariatric surgery is cost effective? * *** ** *** ** Price NIHDI Patient's price M0 M1 M3 M6 M12 Time after RYGB in months

61 Long-term safety of bariatric surgery has many unknowns

62 Long-term safety of bariatric surgery has many unknowns 6.6 completed suicides/10,000 person-years in surgery group 5,2/10,000 for female participants (0.7/10,000) 13.7/10,000 for male participants (2.4/10,000) Ref: Tindle et al. Am J Med 2010

63 Long-term safety of bariatric surgery has many unknowns Substance Use following Bariatric Weight loss Surgery Significant increase of composite substance use from baseline to 24 months after surgery (P = 0.02) Ref: Conason et al. JAMA SURG FEB 2013

64 Overall conclusions - In my opinion the data supporting bariatric surgery are derived from sloppy underpowered trials, though the majority of evidence does support advising patients to undergo surgery when morbidly obese (with the right expectations)