Ινκρετινικζς αγωγζς, οξεία

παγκρεατίτιδα και Ca παγκρζατος.

Τελικά τι;
Αναςταςία Θανοποφλου
Επίκουρη Καθηγήτρια Παθολογίασ – Σακχαρώδη Διαβήτη
Ιατρικήσ Σχολήσ, Ε.Κ.Π.Α.

A critical analysis of the clinical use of incretinbased therapies: Are the GLP-1 therapies safe?
• The story is familiar.
• A new class of agents is rushed to market and widely promoted in
the absence of any evidence of long-term beneficial outcomes.
• Evidence of harm accumulates, but is vigorously discounted. The
regulators allow years to pass before they act.
• The manufacturers are expected— quite unrealistically—to monitor
the safety of their own product.
• We should be thankful that those responsible for aircraft safety do
not operate on the assumption that the absence of evidence is
evidence of absence. Drug safety can never be assumed, and the
legal principle of “innocent until proved guilty” does not apply.
• The case presented here does not prove that these agents are
unsafe, but it does suggest that the burden of proof now rests with
those who wish to convince us of their safety.

Diabetes Care. 2013 Jul;36(7):2118-25. doi: 10.2337/dc12-2713. Epub 2013 May 3.

Patients with type 2 diabetes may have an
increased risk of acute pancreatitis.

Diabetes Care 2009; 32:834–838
Eur J Gastroenterol Hepatol 2012;24:1092-8

Marked Expansion of Exocrine and Endocrine Pancreas
With Incretin Therapy in Humans With Increased
Exocrine Pancreas Dysplasia and the Potential for
Glucagon-Producing Neuroendocrine Tumors
• Examination of pancreata from age-matched organ donors with T2
DM treated by incretin therapy (n = 8, sitagliptin=7, exenatide=1)
or other therapy (n = 12) and non-DM controls (n = 14)
• Pancreata in DM treated with incretin therapy :
• 40% increased pancreatic mass, with both increased exocrine cell
proliferation (P , 0.0001) and dysplasia (increased pancreatic
intraepithelial neoplasia, P , 0.01)
• a-cell hyperplasia and glucagon-expressing microadenomas (3 of
8) and a neuroendocrine tumor
• b-Cell mass was reduced by 60% in those with DM, yet a sixfold
increase was observed in incretin-treated subjects, although DM
persisted.
Diabetes 62:2595–2604, 2013

Marked Expansion of Exocrine and Endocrine Pancreas
With Incretin Therapy in Humans With Increased
Exocrine Pancreas Dysplasia and the Potential for
Glucagon-Producing Neuroendocrine Tumors

Diabetes 62:2595–2604, 2013

Dore D, et al. Current Medical Research and Opinion. 2009;25(4):1019-1027.

FDA’s database 2004-2009

Use of sitagliptin
or exenatide
compared with
other therapies
increased the OR
for pancreatitis
and pancreatic
cancer

GASTROENTEROLOGY 2011;141:150–156

Relative risk of acute pancreatitis in initiators of
exenatide twice daily compared with other antidiabetic medication: a follow-up study
• US health insurance claims database 2005 - 2009
• Initiators of exenatide had more severe diabetes
compared with initiators of other anti–diabetic
medications.
• After adjustments for propensity score, insulin and
use of medication potentially associated with acute
pancreatitis, the odds ratio with exenatide twice
daily exposure was 0.95 (95% CI 0.65–1.38).
Diabet Med 2012;29(11):1412-8.

Sitagliptin: review of preclinical and clinical data
regarding incidence of pancreatitis

Preclinical and clinical trial data do not indicate
an increased risk of pancreatitis in patients with
T2DM treated with sitagliptin.

Int J Clin Pract 2010; 64: 984–990

• ABCD nationwide liraglutide audit (2009–2013;
6010 patients)
• routine clinical practice in the UK
• monitored 3720 years of exposure to liraglutide
• 4 cases of possible pancreatitis and only 1 with
no aetiological cause.
• This sole case represents an incidence of
0.027/100 patient-years of exposure to
liraglutide.

British Journal of Diabetes and Vascular Disease. 2013;13(5-6):253-259.

GLP-1–based therapies and pancreatitis
• US 2005 - 2008.
• Patients aged 18 to 64 years
• 1269 hospitalized cases with acute pancreatitis and 1269
control subjects matched for age category, sex,
enrollment pattern, and diabetes complications.
• After adjustment for confounders and metformin use,
current use of GLP-1–based therapies within 30 days
(adjusted OR, 2.24; 95% CI, 1.36 – 3.68) and recent use
past 30 days and less than two years (adjusted OR, 2.01;
95% CI, 1.37 – 3.18) were associated with significantly
increased odds of acute pancreatitis relative to the odds
in nonusers.
JAMA Intern Med 2013; 25:1-6

Incretin-based therapies and pancreatitis, pancreatic
cancer, thyroid cancer and other neoplasms
• Available data indicate that there may be a connection between GLP-1
agonist and DPPIV inhibitor administration and pancreatitis or
pancreatic cancer.
• Increased risk of pancreatitis or pancreatic cancer may be explained by
the pro-proliferative properties of incretin-based therapies —upregulation of pancreatic ductal cell turnover has been reported.
• Therefore whenever such therapy is started it would be wise to
proceed with caution, especially if personal history of neoplasms is
present
• Until more data is available on the subject, it may be wise to use
incretins always in addition to metformin and keep in mind the possible
occurrence of the potential side effects mentioned above — therefore it
would be clinically responsible to regularly evaluate the condition of the
pancreas and the thyroid.
Eur J Intern Med. 2013 Apr;24(3):207-12

GLP1 and cancer
• Considering the relatively short duration of these studies, it is more
likely that premalignant lesions are stimulated in presence of GLP1,
rather than new neoplasms induced.
• Interpreting results of animal studies is difficult because of speciesspecific differences in presence and density of GLP1 receptors.
• Data are emerging suggesting beneficial effects of GLP1 on colon
and breast cancer.
• In conclusion, presently, the benefits of using DPP4 inhibitors or
GLP1 receptor agonists for treatment of type 2 diabetes outweight
the risks. Nonetheless, their safety profile should be monitored and
their indications should be widened cautiously.

Endocrine-Related Cancer (2012) 19 F77–F88

DIABETES AND CANCER
AN AACE/ACE CONSENSUS STATEMENT

Endocr Pract. 2013;19(No. 4): 675 – 693

2014

• database from Piedmont, Italy
• 282,429 patients receiving treatment for T2
• 1003 cases admitted to hospital for acute
pancreatitis (2008 – 2012), and 4012 controls
who were matched for sex, age, and time of start
of antidiabetic therapy. Mean age = 72·2
• After adjustment for available confounders, use
of incretins in the 6 months before hospital
admission was not associated with increased risk
of acute pancreatitis (OR 0·98, 95% CI 0·69-1·38;
p=0·8958).
Lancet Diabetes Endocrinol 2014;2(2):111-5.

Incretin based drugs and risk of acute pancreatitis in
patients with type 2 diabetes: cohort study

• 680 general practices in the UK, 2007-2012
• 20.748 new users of incretin based drugs were
compared with 51.712 users of sulfonylureas
• The rate of acute pancreatitis associated with
the use of incretin based drugs was not
increased
BMJ 2014;348:g2780 doi: 10.1136/bmj.g2780 (Published 24 April 2014)

A prospective, claims-based assessment of the risk of
pancreatitis and pancreatic cancer with liraglutide compared
to other antidiabetic drugs

Liraglutide vs non GLP-1-based therapies:
adjusted RR 1.10; CI 0.81–1.49 for pancreatitis
adjusted RR 0.65; 95% CI 0.26–1.60 for pancreatic Ca
no excess risk of either outcome associated with
liraglutide relative to individual or pooled comparator
drugs.
Diabetes, Obesity and Metabolism 16: 273–275, 2014.

DPP-4is and pancreatitis risk:
a meta-analysis of randomized clinical trials

• 134 trials
• The overall risk of pancreatitis and pancreatic
cancer was not different between DPP4is and
comparators (MH-OR: 0.93[0.51–1.69];
p=0.82)
• The number of observed cases of incident
pancreatitis is small and the CI are wide.

Diabetes, Obesity and Metabolism 16: 48–56, 2014.

Incretin treatment and risk of pancreatitis in patients
with T2 DM: systematic review and
meta-analysis of RCT’s and non- RCT’s
• 60 studies (n=353 639), consisting of 55 RCT’s (n=33
350) and 5 observational studies (3 retrospective
cohort studies and 2 case-control studies; n=320 289)
• The incidence of pancreatitis among patients using
incretins is low and that the drugs do not increase the
risk of pancreatitis.
• Estimates by type of incretin suggested similar results
• Current evidence, however, is not definitive, and more
carefully designed and conducted observational studies
are warranted to definitively establish the extent, if
any, of increased risk.
BMJ 2014;348:g2366 doi: 10.1136/bmj.g2366 (Published 15 April 2014)

• a clear-cut odds ratio for an association
between acute pancreatitis and incretins, has
been reported in only one of eight
pharmacoepidemiological studies.
• none of the intervention trials investigating
these compounds, including two large
randomized controlled trials with
cardiovascular endpoints, confirmed the
purportedly increased risk of acute
pancreatitis with incretin use.
Diabetes Obes Metab 2014. doi: 10.1111/dom.12297.

• Pooled analysis of phase III clinical trials and two
endpoint trials
• a trend towards a slightly elevated risk of
pancreatitis with GLP-1 receptor agonists
• no consistent trend was found with DPP-4
inhibitors
• the incidence numbers of cases of pancreatitis
were still very small, and the statistical power
was limited. Future endpoint trials may help to provide a
better estimate of the true risk of pancreatitis with incretin-based
therapies.
Diabetologia 2014; DOI 10.1007/S00125-014-3231-y

Pancreatic Safety of Incretin-Based Drugs
FDA and EMA Assessment
A pooled analysis of data from 14.611 patients
with T2, from 25 clinical trials in the sitagliptin
database provided no compelling evidence of an
increased risk of pancreatitis or pancreatic
cancer

N Engl J Med 2014; 370:794-797

Pancreatic Safety of Incretin-Based Drugs
FDA and EMA Assessment
Both agencies agree that assertions concerning
a causal association between incretin-based
drugs and pancreatitis or pancreatic cancer, as
expressed recently in the scientific literature and
in the media, are inconsistent with the current
data.

N Engl J Med 2014; 370:794-797

• In patients with risk factors for pancreatitis,
including gallstones, high triglycerides, or
excessive alcohol intake, incretins should be used
with caution.
• incretins are not recommended in patients with a
history of pancreatitis
• the totality of clinical, preclinical, and
postmarketing evidence does not clearly
substantiate an association between incretin
therapies and acute pancreatitis
Adv Ther (2014) 31:289–317

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