Malabsorption of thyroxine or non-compliance?Subject
• No Conflicts of Interest
• Member of the Committee for Medicinal Products for Human Use at EMA
Subject
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.
Obesitaskliniek UZLeuven
• Apotheker
Bilio-pancreatic diversion
Bariatric Surgery
Sjöström L et al., Journal of Internal Medicine, 2013, 273; 219–234
Bariatric Surgery
Mortality
Sjöström L et al., Journal of Internal Medicine, 2013, 273; 219–234
Bariatric surgery cures diabetes
Sjöström L et al., Journal of Internal Medicine, 2013, 273; 219–234
Bariatric surgery cures diabetes
Bariatric surgery PREVENTS diabetes
Sjöström L et al., Journal of Internal Medicine, 2013, 273; 219–234
Unhealthy lifestyle and
+
UKPDS. Diabetes. 1995;44:1249-1258
Years
0
20
40
60
80
100
10 9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6
Time of diagnosis
Progressive Nature of Diabetes
Glucose Tolerance
Diabetes Prevention Program Research Group. N Eng J Med 2002;346:393. Copyright © 2002. Massachusetts Medical Society. All rights reserved.
Bariatric Surgery
Mortality
Sjöström L et al., Journal of Internal Medicine, 2013, 273; 219–234
Bariatric Surgery
Mortality
Sjöström L et al., Journal of Internal Medicine, 2013, 273; 219–234
Bariatric Surgery
Mortality
Sjöström L et al., Journal of Internal Medicine, 2013, 273; 219–234
The nature of the internist
Bariatric Surgery
Mortality
Sjöström L et al., Journal of Internal Medicine, 2013, 273; 219–234
Bariatric Surgery
Mortality
Sjöström L et al., Journal of Internal Medicine, 2013, 273; 219–234
Baseline Patient
Age (yrs)
up
Outcome
UKPDS2 53 T2D: Newly diagnosed 10 yrs No ↓ Risk of MVD ↓ Risk of CVD
RECORD7 57 T2D: Without history of HF 5.5 yrs No ↔ Risk of CVD*
PROACTIVE8 62 T2D: History of macrovascular disease 34 mos Yes ↓ Risk of CVD*
ORIGIN9 64 T2D or CV risk factors and impaired fasting glucose, impaired glucose tolerance
6.2 yrs Yes ↓ Risk of MVD ↔ Risk of CVD
VADT3 60 T2D: Substandard response to therapy 5.6 yrs No ↔ Risk of MVD ↔ Risk of CVD
ADVANCE4 67 T2D: History of vascular disease or risk for vascular disease
5 yrs Yes ↓ Risk of MVD ↔ Risk of CVD
ACCORD5, 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;353:2643-2653; 2. Stratton IM, et al. BMJ. 2000;321:405-412; 3. Duckworth W, et al. VADT Investigators. N Engl J Med. 2009;360:129-139; 4. The ADVANCE Collaborative Group, et al. N Engl J Med. 2008;358:2560-2572; 5. The ACCORD Study Group, et al.
N Engl J Med. 2011;364:818-828; 6. Ismail-Beigi F, et al. Lancet. 2010;376:419-430; 7. Home PD, et al. RECORD Study Team. Lancet. 2009; 373:2125-2135; 8. Dormandy JA, et al; PROactive investigators. Lancet. 2005;366:1279-1289; 9. The ORIGIN Trial Investigators, et al. N Engl J Med.
2012;367:319-328.
Aggregate Endpoint 1997 2007
P: 0.029 0.040
P: 0.0099 0.001
P: 0.052 0.014
P: 0.44 0.007
CV death Empagliflozin
All-cause mortality Empagliflozin
Empagliflozin Placebo
3-point MACE
Intention-to-treat analysis†
On-treatment analysis
Treated set + 30 days‡ 412/4687 229/2333 0.87 (0.74, 1.02) 0.0903
On-treatment set 407/4607 227/2308 0.87 (0.74, 1.02) 0.0839
Per-protocol analysis
3-point MACE
(one-sided)*
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<0.0249. †Events observed from randomisation to the end of the study. ‡Only events observed ≤30 days after a patient’s last intake of trial medication.
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
Bariatric Surgery
Sjöström L et al., Journal of Internal Medicine, 2013, 273; 219–234
The answer to obesity is obvious
Eat Less and Exercise More
Medical Interventions
Glucose Tolerance
Diabetes Prevention Program Research Group. N Eng J Med 2002;346:393. Copyright © 2002. Massachusetts Medical Society. All rights reserved.
Conclusion in terms of weight, risk
for diabetes
loss observed after bariatric surgery
- 5-10 % weight loss seems to be sufficient to
prevent both morbidity and mortality caused by
obesity
diabetes as well
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/m2
Post-surgery HbA1c 5,7 %, Total insulin 45 U, BMI 29,1 kg/m2
Uneventful perioperative and postoperative period
28 yo Woman: Baseline HbA1c 10,4 – 11,8 %, Total insulin 120 U, BMI 46,3 kg/m2
Post-surgery HbA1c 7,3 %, Total insulin 70 U, BMI 32,9 kg/m2
Bilateral Pneumonia in perioperative period
Bariatric surgery in T1D
Mendez et al Diabetes Metab Syndr Obes. 2010 Aug 10;3:281-3.
Mendez et al Diabetes Metab Syndr Obes. 2010 Aug 10;3:281-3.
(7 RYGBP, 2GB, 1 Sleeve)
Bariatric surgery in T1D
Effect of Duodeno-jejunal bypass
Bariatric surgery in T1D
A well known GLP-1 increase
Bose et al. Obesity 2010
Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr Diab Rep
2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.
Surgical procedures
Hare et al . American Journal of Physiology - Endocrinology and Metabolism
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
diabetes and no residual β-cell
function (circles, left) and healthy
control subjects (triangles, right).
Insulin therapy impairs weight loss therapy
Glycemic control impaired by insulin
resistance
by suppression of glucagon
Gains
47
absorption after bariatric surgery
Risks
48
Effect on carbohydrate absorption
Retrospective analysis
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 regression model assuming a linear relation
Study
50
SEVERE HYPOGLYCEMIA 1 1
HOSPITALIZATION DM1 4 6
GASTRIC FISTULA 1 1
MARGINAL ULCER 1 1
INCISIONAL HERNIA 1 1
BMI
LL, UL: lower and upper limit of 95%confidence interval
(CI)
53
LL, UL: lower and upper limit of 95%confidence interval
(CI)
LL, UL: lower and upper limit of 95%confidence interval
(CI)
LL, UL: lower and upper limit of 95%confidence interval
(CI)
After intervention 0.532 0.077
Within-subject variability, i.e. the variability of values around the patient-
specific linear evolutions
LL, UL: lower and upper limit of 95%confidence interval
(CI)
LL, UL: lower and upper limit of 95%confidence interval
(CI)
LL, UL: lower and upper limit of 95%confidence interval
(CI)
LL, UL: lower and upper limit of 95%confidence interval
(CI)
LDL
HDL
1 diabetes
- Safe
48.11 52.08 53.61
A v
e ra
Price NIHDI
Patient's price
Long-term safety of bariatric surgery
has many unknowns”
surgery group
Ref: Tindle et al. Am J Med 2010
Long-term safety of bariatric surgery
has many unknowns
Surgery
from baseline to 24 months after surgery (P =
0.02)
Overall conclusions
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)