Οι επιπτώσεις της παχυσαρκίας και τα οφελη της απωλειας βαρους στο Διαβήτη τύπου 2 Γιώργος Βαλσαμάκης Ενδοκρινολόγος Πανεπιστημιακός Υπότροφος Β Μαιευτικής και Γυναικολογικής κλινικής Αρεταίειο Νοσοκομείο Visiting Associate clinical Professor Warwick Medical School
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Energy Expenditure REE)(%) Κατανάλωση ενέργειας και μάζα των ιστών Tissue energy expenditure Tissue weight 80 60 Liver, Brain, Kidneys, Gut, Heart Skeletal Muscle Adipose Tissue, Lean Person Adipose Tissue, Obese Person 40 Weight (% Body Weight) 20 0
Ο λιπώδης ιστός αποτελείται από Α) τα μικρά (καλά) και πρόσφατα δημιουργηθένταδιαφοροποιημενα λιποκύτταρα που εκκρίνουν παράγοντες ινσουλινοευαισθησίας οπως η αντιπονεκτίνη και καθαρίζουν την κυκλοφορία από τα λιπαρά οξέα (fatty acids). B) τα μεγάλα-ώριμα λιποκύτταρα με αποθηκευμένα λιπαρά τα οποία εκκρίνουν αυξητικούς παράγοντες και λιποκυττοκίνες συμμετέχοντας στη διεργασία της ινσουλινοαντοχής, της αθηροσκλήρυνσης, της αρτηριακής υπέρτασης και ορισμένων μορφών καρκίνου. Γ) τα πρόγονα λιποκύτταρα-ινοβλάστες
Obese derived cellular glucose derangement
Χαρακτηριστικά παχύσαρκου με αυξημένο μεταβολικό κίνδυνο Αυξημένο ενδοκοιλιακό λίπος Διαταραγμένη ισσοροπία λιποκυττοκινών ( CRP, MCP-1, αντιπονεκτίνη κλπ) Υπερτροφία στη μορφολογία του λιποκυττάρου Υπερτροφία στην κατανομή του λιπώδους ιστού Αυξημένος αριθμός μακροφάγων στο ενδοκοιλιακό λίπος
Χαρακτηριστικά παχύσαρκου με μειωμένο μεταβολικό κίνδυνο (healthy obese) Μειωμένο ενδοκοιλιακό λίπος Φυσιολογική συγκέντρωση λιποκυττοκινών ορού Μικρό μέγεθος λιποκυττάρου Μικρός αριθμός μακροφάγων πέριξ των λιποκυττάρων Υπερπλασία στην κατανομή του λιπώδους ιστού
Nicklas et al Diab Care 2003
Okauchi et al Diab Care 2007
Orlistat NICE audit Σε παχύσαρκους ασθενείς με σακχαρώδη διαβήτη τύπου 2 η orlistat έδειξε στατιστικά σημαντική μείωση του βάρους στον ένα χρόνο σε σχέση με placebo, στη γλυχαιμική ρύθμιση, στα επίπεδα των λιπιδίων. Οι γαστρεντερικές παρενέργειες ήταν στατιστικά περισσότερες στα γκρουπ της orlistat σε σχέση με το placebo, Η orlistat μετά από 1 χρόνο συνοδεύτηκε με χαμηλότερα επίπεδα στον ορο λιποδιαλυτών βιταμινών (A,D,E,K).
Orlistat: Αποτελεσματικοτητα μετα 1 χρονο (Diab Care 2002)
Naltrexone-bupropion (Mysimba) oral, sustained-release combination consisting of the dopamine and norepinephrine reuptake antagonist bupropion and the opioid antagonist naltrexone. complementary stimulation of central melanocortin pathways, resulting in increased energy expenditure and reduced appetite Initially, was not approved by the FDA, requested a randomized, double-blind, placebo-controlled trial to demonstrate that the risk of major adverse cardiovascular events in obese and overweight subjects treated with naltrexone/bupropion does not adversely affect the drug s benefit-risk profile
Naltrexone/bupropion (2) double- blind, placebo-controlled study of 1496 obese or over- weight subjects with dyslipidemia and/or hypertension naltrexone sustained-release (32 mg per day) plus bupropion sustained-release (360 mg per day) (NB32) or placebo for up to 56 weeks. (NB32) Significantly (P < 0.001) greater weight loss was observed vs. placebo at week 28 ( 6.5% vs. 1.9%) and week 56 ( 6.4% vs. 1.2%). More NB32-treated participants (P < 0.001) experienced 5% weight loss vs. placebo at week 28 (55.6% vs. 17.5%) and week 56 (50.5% vs. 17.1%).
Naltrexone/bupropion (3) greater improvements in cardiometabolic risk markers, weight-related quality of life and control of eating. most common adverse event with NB was nausea, mild to moderate and transient. It was not associated with increased events of depression or suicidality vs. placebo
The reasons naltrexone-bupropion was approved by EMEAS while other FDA approved drugs not supplied interim heart safety data to the panel. The CHMP opinion was based on the results of four Phase 3 clinical trials evaluating Mysimba in more than 4,500 overweight and obese patients including a dedicated clinical trial in obese patients with diabetes.
EMEAS naltrexone bupropion approval The CHMP also reviewed the interim analysis of the Light Study, a cardiovascular outcomes safety trial with more than 8,900 patients evaluating the effects of Mysimba on heart attack, stroke and cardiovascular death
Liraglutide Gut satiation peptides that are secreted by lower-intestine enteroendocrine cells in response to ingested food. GLP-1 is produced primarily by the L cells of the distal small intestine and colon
liraglutide GLP-1 analogues currently used in clinical practice for diabetes control, have demonstrated anorectic effects and significant weight loss properties The GLP-1 receptor R (GLP1R) is the principle mediator of the anorectic effects of GLP-1 expressed mainly in the gut, pancreas, brainstem, hypothalamus and vagal-afferent nerves
Λιραγλουτίδη (ECO 2011)
Liraglutide Astrup A, Lancet 2009; 374: 1606 1616. randomized, double- blind, placebo-controlled 20-week trial, with an 84-week open-label extension. All 564 individuals were randomly assigned, with a telephone or web-based system, to one of four liraglutide doses (1.2, 1.8, 2.4 or 3.0 mg, n = 90 95) or to placebo (n = 98) administered once a day subcutane- ously, or orlistat (120 mg, n = 95) three times a day orally
liraglutide Mean weight loss with liraglutide 1.2 3.0 mg was 4.8, 5.5, 6.3 and 7.2 kg compared with 2.8 kg with placebo and 4.1 kg with orlistat, and was 2.1 kg (95% confidence interval 0.6 3.6) to 4.4 kg (2.9 6.0) greater than that with placebo
Liraglutide More individuals (76%, n = 70) lost more than 5% weight with liraglutide 3.0 mg that with placebo (30%, n = 29) or orlistat (44%, n = 42). Liraglutide reduced blood pressure at all doses, and reduced the prevalence of prediabetes (84 96% reduction) with 1.2 3.0mg per day.
liraglutide Nausea and vomiting occurred more often in individuals on liraglutide than in those on placebo, but adverse events were mainly transient and rarely led to discontinuation of treatment
Liraglutide SCALE study Wadden TA Int J Obes 2013 a randomized phase III trial with obese and overweight participants who lost 5% of weight with a low-calorie diet, assessed the efficacy of liraglutide in maintaining weight loss. liraglutide 3.0 mg per day or placebo (subcutaneous administration) for 56 weeks weight decreased an additional mean 6.2% with liraglutide and 0.2% with placebo together with improvements in some cardiovascular disease-risk factors More participants receiving liraglutide (81.4%) maintained the 5% run-in weight loss, compared with those receiving placebo (48.9%) (odds ratio 4.8 (3.0; 7.7), P < 0.0001), and 50.5% vs. 21.8% of participants lost 5% of randomization weight (odds ratio 3.9
Liraglutide: nausea and vomiting (Lean ME et al Int J Obes 2013) A randomized, placebo-controlled, doubleblind, 20-week study with an 84-week extension evaluated routinely collected data on nausea and vomiting among individuals on liraglutide and their influence on tolerability and body weight
Liraglutide :nausea and vomit In year 1, more participants reported >1 episode of nausea/vomiting on treatment with liraglutide 1.2 3.0 mg (17 38%) than with placebo or orlistat (both 4%, P < 0.001). Most episodes occurred during dose escalation (weeks 1 6), with mild or moderate symptoms. Among participants on liraglutide 3.0 mg, 48% reported some nausea and 13% some vomiting, with considerable variation between countries, but only four out of 93 (4%) reported withdrawals.
Liraglutide The mean 1-year weight loss on treatment with liraglutide 3.0 mg from randomization was 9.2 kg for participants reporting nausea/vomiting episodes, vs. 6.3 kg for those with none (a treatment difference of 2.9 kg, P = 0.02). Both weight losses were significantly greater than the respective weight losses for participants on placebo (P < 0.001) or orlistat (P < 0.05). the most common adverse effects are GI-related, (e.g. nausea, vomiting) and occur early in therapy but usually resolve after 4 8 weeks
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