İnkretin bazlı ajanların güvenliği...cv death 1.03 (0.87-1.22) 0.52 ci, confidence interval;...
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İnkretin Bazlı Ajanların
güvenliği
Okan BAKINER
Türk Diyabet Kongresi
Antalya - 2016
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Kardiyovasküler Güvenilirlik
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GLP-1
Kardiyomiyosit Endotel Vasküler düz kas hücresi
Miyokardiyal insülin duyarlılığı↑ Apoptosis↓
NO ↑ İnflamasyon↓
Proliferasyon↓
İnfarkt alanında azalma Kardiyak atım hacmi artışı
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GLP-1 RA …KARDİYOVASKÜLER SONLANIMLARI DEĞERLENDİREN ÇALIŞMALAR…
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sitagliptin
alogliptin
saxagliptin
linagliptin
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8
TECOS (n=14,671)
TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin.
Green JB, et al. N Engl J Med. 2015; Jun 8.
Sitagliptin
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Hazard ratio (95% CI) P value
Primary composite 0.96 (≤1.16)* 0.32
Primary endpoint components
CV death 0.79 (0.6-1.04) 0.10
Nonfatal MI 1.08 (0.88-1.33) 0.47
Nonfatal stroke 0.91 (0.55-1.50) 0.71
Primary secondary endpoint† 0.95 (≤1.14)* 0.26
Death from any cause 0.85 (0.66-1.10) 0.21
Alogliptin: KV sonlanımlar
9
0,00 0,50 1,00 1,50 2,00
EXAMINE Safety Endpoints (n=5380)
*Upper boundary of 1-sided repeated CI, alpha level 0.01.
†CV death, nonfatal MI, nonfatal stroke, urgent revascularization for unstable angina.
CI, confidence interval; CV, cardiovascular; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care; MI, myocardial infarction.
White W, et al. N Engl J Med. 2013;369:1327-1335.
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Saxagliptin: KV sonlanımlar
10
0,00 0,50 1,00 1,50
SAVOR-TIMI Prespecified Composite Endpoints and Mortality
(n=16,492)
Hazard ratio (95% CI) P value
Primary composite endpoint* 1.00 (0.89-1.27) 0.99
Secondary composite endpoint† 1.02 (0.94-1.11) 0.66
Death from any cause 1.11 (0.96-1.27) 0.15
CV death 1.03 (0.87-1.22) 0.52
CI, confidence interval; CV, cardiovascular; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction.
Scirica BM, et al. N Engl J Med. 2013;369,1317-1326.
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Kalp yetmezliği kaynaklı hospitalizasyon
Çalışma Ajan Aktif ilaç plasebo
Savor-TIMI Saxagliptin %3.5 %2.8
Examine Alogliptin %3.9 %3.3
FDA Drug Safety Communication: FDA adds warnings
about heart failure risk to labels of type 2 diabetes
medicines containing saxagliptin and alogliptin
[ 5-4-2016 ]
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KY nedeniyle hospitalize olan hastaların ortak özellikleri
• Bilinen KY öyküsü
• Başlangıçta yüksek pro-BNP düzeyleri
• GFR<60 ml/dk
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Neden beklenen etki sağlanamadı?
1. Çok yüksek kardiyovasküler risk barındıran hasta grubu
2. Kısa izlem süresi
(EXAMINE: 18 ay, SAVOR-TIMI: 2.1 yıl, TECOS: 3 yıl)
3.DPP-4 inhibitörleri ile GLP-1 analoglarına göre plazma GLP-1 düzeylerinde daha az yükselme
4.Kardiyoprotektif GLP-1(9-36) inaktif formunun azalması
5.DPP-4 inhibisyonu sonucu, sempatoadrenal hiperaktivite yapan substans P artışı
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Tiroid C hc hiperplazisi ve Medüller Ca
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GLP- RA uygulamasına rodent kalsitonin cevabı
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104 haftalık GLP- RA uygulamasına rodentlerde C hc hiperplazisi ve tümör gelişimi
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GLP- RA uygulamasına maymun kalsitonin cevabı
Liraglutid ile kalsitonin yükselmesi olmamıştır.
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GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin
release from sequential screening in over 5000 subjects with type 2 diabetes or
nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide.
Hegedüs L ve ark. J Clin Endocrinol Metab 2011, 96:853-86
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RODENT İNSAN
GLP-1 vs C- HÜCRE HİPERPLAZİSİ ve MEDÜLLER TR CA MODELLEME
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Sonuç: AACE, FDA
• İnsan tiroid C hücrelerinde GLP-1 reseptör ekspresyonu düşüktür ve GLP-1RA tedavisi kalsitonin yüksekliği yapmaz.
• Tedavi öncesi ve sırasında tiroid görüntüleme, kalsitonin düzeyi takibi gerekli değildir.
• Nodüller geleneksel yolla takip edilir.
• Bilinen tr meduller ca, ailesel tr meduller ca veya MEN-2’li olgulara GLP-1RA verilmemelidir.
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Akut Böbrek Yetmezliği
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Exenatide : 78 vaka Lyraglutide : 3 vaka
Kusma Azalmış sıvı alımı
KKY
PRERENAL AZOTEMİ
Nefrotoksik ilaçlar GLP-1RA ilaç reaksiyonu
Tubulointerstisyel nefrit
ABY
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19 randomize kontrollü çalışmanın metaanalizi
Macconell ve ark, 2012
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PANKREATİT ve PANKREAS CA
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Tarihçe
• Denker ve Dimarco, 2006, ilk exenatide-akut pankreatit vaka bildirimi (diabetes care)
• Ahmad ve ark, 2008, yan etki data sisteminden exenatid-akut pankreatit ilişkisi 30 vaka- ortalama kullanım 34 gün (NEJM)
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Nauck ve Friedrich,2013
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Kuyuya atılan taş: AERS
Advers Etki Exenatid Sitagliptin
Pankreatit 11 kat fazla 7 kat fazla
Pankreas Karsinomu 3 kat fazla 3 kat fazla
Tiroid karsinomu Histolojik tip?
4,7 kat fazla -
Elashoff, 2011
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GLP-1 BAZLI TEDAVİ ALAN 8 OLGUNUN
3 ÜNDE GLUKAGON SALGILAYAN MİKROADENOM ve 1 OLGUDA
NÖROENDOKRİN TÜMÖR!!!
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Incretin based drugs and the risk of pancreatic cancer: international multicentre
cohort study
BMJ 2016; 352
972384 hasta,2024441 hasta yılı,SU vs İnkretinerjik ajanlar
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Ne zaman netlik kazanır?
• GLP-1 RA , DPP-4 İnh ve kontrol gruplarının her biri için en az 89,000 hasta yılını içeren prospektif iyi tasarlanmış bir çalışma yapıldığında (nQuery Advisor, version 6.02; Statistical Solutions,
Cork, Ireland).
• Normal duktal epitel hücresinin tümorogenezi için geçen süre yaklaşık 12 yıl.
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T hücresi
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