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Rev Diabet Stud
. 2015 Feb 10;11(3):202–230. doi: 10.1900/RDS.2014.11.202
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ADVERSE EFFECTS OF GLP-1 RECEPTOR AGONISTS
Theodosios D Filippatos
THEODOSIOS D FILIPPATOS
1Department of Internal Medicine, School of Medicine, University of Ioannina,
45110 Ioannina, Greece
Find articles by Theodosios D Filippatos
1, Thalia V Panagiotopoulou
THALIA V PANAGIOTOPOULOU
1Department of Internal Medicine, School of Medicine, University of Ioannina,
45110 Ioannina, Greece
Find articles by Thalia V Panagiotopoulou
1, Moses S Elisaf
MOSES S ELISAF
1Department of Internal Medicine, School of Medicine, University of Ioannina,
45110 Ioannina, Greece
Find articles by Moses S Elisaf
1,✉
* Author information
* Article notes
* Copyright and License information
1Department of Internal Medicine, School of Medicine, University of Ioannina,
45110 Ioannina, Greece
✉
Address correspondence to: Moses S. Elisaf, e-mail: egepi@cc.uoi.gr
Received 2015 Jan 6; Revised 2015 Jan 23; Accepted 2015 Feb 2; Issue date 2014
Fall-Winter.
Copyright © 2014, SBDR - Society for Biomedical Diabetes Research
PMC Copyright notice
PMCID: PMC5397288 PMID: 26177483
ABSTRACT
Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective
anti-diabetic drugs that improve glycemic control and many other
atherosclerosis-related parameters in patients with type 2 diabetes (T2D).
However, the use of this relatively new class of drugs may be associated with
certain adverse effects. Concerns have been expressed regarding the effects of
these drugs on pancreatic and thyroid tissue, since animal studies and analyses
of drug databases indicate an association of GLP-1 receptor agonists with
pancreatitis, pancreatic cancer, and thyroid cancer. However, several
meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor
agonists and the development of these adverse effects. One benefit of GLP-1
receptor agonists is that they do not cause hypoglycemia when combined with
metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or
insulin may have to be decreased to reduce the risk of hypoglycemic episodes. On
the other hand, several case reports have linked the use of these drugs, mainly
exenatide, with the occurrence of acute kidney injury, primarily through
hemodynamic derangement due to nausea, vomiting, and diarrhea. The most common
symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal
symptoms, mainly nausea. Other common adverse effects include injection site
reactions, headache, and nasopharyngitis, but these effects do not usually
result in discontinuation of the drug. Current evidence shows that GLP-1
receptor agonists have no negative effects on the cardiovascular risk of
patients with T2D. Thus, GLP-1 receptor agonists appear to have a favorable
safety profile, but ongoing trials will further assess their cardiovascular
effects. The aim of this review is to analyze critically the available data
regarding adverse events of GLP-1 receptor agonists in different anatomic
systems published in Pubmed and Scopus. Whenever possible, certain differences
between GLP-1 receptor agonists are described. The review also provides the
reader with structured data that compare the rates of the most common adverse
effects for each of the various GLP-1 receptor agonists.
Keywords: type 2 diabetes, glucagon-like peptide-1, safety, skin, adverse
effects, pancreas, kidney, cardiovascular risk, cancer
--------------------------------------------------------------------------------
Abbreviations: BID – bis in die (twice a day); C-cell – parafollicular cell (in
the thyroid gland); DPP-4 – dipeptidyl peptidase 4; EMA - European Medicines
Agency; FAERS – FDA Adverse Event Reporting System; FDA – Food and Drug
Administration; GLP-1 – glucagon-like peptide-1; Kras – Kirsten rat sarcoma
viral oncogene homolog gene; KrasG12D – G12D mutation of the Kras gene; LEADER –
Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome
Results; MH-OR – Mantel-Haenszel OR; OR – odds ratio; QTc interval – corrected Q
wave / T wave interval; T2D – type 2 diabetes
1. INTRODUCTION
The incidence of carbohydrate metabolism derangements and many cardiovascular
and renal complications is increasing [1-4]. Various classes of drugs have
proved useful in the management of patients with type 2 diabetes (T2D) and its
complications [1, 5-12]. Recent evidence demonstrated the beneficial effects of
incretin-mimetic drugs in the treatment of T2D; these drugs include
glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase 4
(DPP-4) inhibitors [13, 14].
GLP-1 receptor agonists are characterized by increased resistance to enzymatic
degradation by DPP-4 [15]. GLP-1 is secreted by the small intestine in response
to nutrient ingestion. It enhances insulin secretion from pancreatic β-cells,
and decreases glucagon release from pancreatic α-cells [16]. GLP-1 receptor
agonists are useful, injectable drugs for the treatment of T2D as they improve
glycemic control and atherosclerosis-related parameters [17-26]. Short-acting
GLP-1 receptor agonists primarily slow gastric emptying, and thus exert their
main effect on postprandial blood glucose levels. The long-acting compounds have
insulinotropic and glucagonostatic actions, and exert their main effect on
fasting glucose levels [27-29]. However, concerns have been expressed regarding
their safety profile.
This review aims to discuss the available data regarding adverse effects of
currently marketed GLP-1 receptor agonists.
2. METHODS
We searched for eligible trials published in PubMed (last search in February
2015) by using the following search algorithm:
(Glucagon-like peptide-1 receptor agonists OR exenatide OR liraglutide OR
lixisenatide OR albiglutide OR dulaglutide) AND (side effects OR adverse effects
OR safety OR gastrointestinal OR pancreas OR liver OR cardiovascular OR skin OR
allergy OR angioedema OR immune system OR renal OR kidney OR infection OR
central nervous system OR blood OR malignancy OR cancer)
The search was limited by the following criteria:
- Published in the English language.
- Published as clinical trial, meta-analyses, case report, comparative study,
observational study, evaluation study, or validation study.
The initial search identified 503 articles in Pubmed, which were scrutinized for
relevance. After this initial selection, we excluded randomized clinical trials
with <100 participants or with duration <12 months. Data presented in
meta-analyses or large clinical trials were given more weight in the analysis
than those from smaller studies. Observational and animal studies were used
mainly in the sections on pancreas and cancer. Regarding the individual anatomic
systems, further articles were retrieved from Pubmed and Scopus by searching
relevant review articles.
3. ADVERSE EFFECTS OF GLP-1 RECEPTOR AGONISTS (TABLE {T1}, APPENDIX)
3.1 GASTROINTESTINAL SYSTEM (TABLE {T2}, APPEND.)
Gastrointestinal disorders were the most frequently reported adverse effects
during clinical trials of GLP-1 receptor agonists [30]. Among gastrointestinal
symptoms, nausea and diarrhea were very common (≥1/10), whereas vomiting,
constipation, abdominal pain, and dyspepsia were relatively common (≥1/100 to
<1/10) [31-45]. The frequency of these adverse effects was more pronounced at
the beginning of the treatment, but gastrointestinal symptoms decreased
gradually as therapy continued. Nausea is the most common adverse effect
reported with GLP-1 receptor agonists; up to 50% of patients are affected. Most
patients have mild to moderate episodes of nausea, which seem to be
dose-dependent and diminish with ongoing treatment [46, 47]. However, it should
be mentioned that exenatide treatment was discontinued in 4% of patients in
clinical trials because of nausea [48]. Furthermore, dulaglutide, a newer
once-weekly GLP-1 receptor agonist, was associated with increased incidence of
vomiting at the dose of 1.5 mg compared with exenatide (17% vs. 12%, p < 0.05)
[49].
A meta-analysis of 35 studies with exenatide and liraglutide showed that
exenatide 10 µg twice-daily had a significantly higher probability of producing
nausea compared with exenatide 5 µg twice-daily (odds ratio (OR): 2.28) and
exenatide once-weekly (OR: 2.78) [50]. Likewise, exenatide 10 µg twice-daily had
a significantly higher probability of causing nausea compared with liraglutide
1.2 mg/day (OR: 2.16) and 1.8 mg/day (OR: 3.19) [50]. Another trial in patients
with T2D showed that gastric emptying is slowed to a greater degree by exenatide
twice-daily than exenatide once-weekly [51]. The delay in gastric emptying has
been linked to the occurrence of nausea with GLP-1 receptor agonists. More
specifically, GLP-1 receptor agonists with prolonged duration of action may
exert lesser effects on gastric motility, and this could be associated with less
nausea. However, this is merely a hypothesis; more research is needed.
Another possible mechanism is the activation of the centers involved in appetite
regulation, satiety, and nausea during the peak of the GLP-1 effect, which is
evident in parallel with the injection of short-acting preparations. If nausea
occurs at the peak of GLP-1 plasma concentrations, then continuous GLP-1
exposure could result in tachyphylaxis and attenuation of the pharmacological
response, which in turn leads to a lower incidence of nausea and
gastrointestinal symptoms [23, 52].
3.2 PANCREAS
Concerns have been expressed regarding a possible association of GLP-1 receptor
agonist treatment with pancreatic inflammation and pancreatitis [53-61]. In this
regard, evidence from animal studies indicated a potentially harmful effect of
these drugs on pancreatic tissue [62-65]. For example, administration of
exenatide for 10 weeks in male rats resulted in chronic pancreatic damage in 30%
of rats, characterized by pycnosis of acinar cells, increased cytoplasmic
vacuoles, widened cellular gap, and inflammatory cell infiltration in pancreatic
tissue [62].
Moreover, increased myeloperoxidase levels were found in pancreatic tissue of
rats taking exenatide, while animals from the control and inhibitor groups did
not exhibit signs of pancreatic damage [62]. Similarly, liraglutide was only
modestly associated with pancreatitis risk in C57BL6 mice, whereas exendin-4 and
sitagliptin were linked to signs of pancreatitis [66]. These observations point
to a differential effect of incretin-mimetic drugs on the risk of pancreatitis.
It should be mentioned that the findings on pancreatic tissue were mainly
observed in preclinical studies aiming to find evidence of beta-cell
proliferation and other diabetes-related aspects, i.e. it was not the aim of
these studies to identify pancreatic damage, but they did in fact do so.
In the clinical setting, a study of 90 T2D patients taking GLP-1 receptor
agonists or DPP-4 inhibitors showed that 36% of them had elevated serum amylase
or lipase (or both) levels compared with 18% of T2D patients not taking these
agents [67]. However, a recent analysis of the LEADER (Liraglutide Effect and
Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial (n =
9340) showed that amylase and/or lipase were elevated at baseline in 22.7% of
subjects [68]. More specifically, lipase levels were increased in 16.6% (n =
1540) and amylase levels in 11.8% (n = 1094) of patients, without symptoms of
acute pancreatitis [68]. These findings suggest that amylase or lipase levels
are a less sensitive index of pancreatic damage or pancreatitis in T2D patients.
Another study included 1,269 hospitalized cases with acute pancreatitis and
1,269 control subjects matched for age, sex, enrollment pattern, and T2D
complications [69]. It was shown that the use of incretin-mimetic therapies
within 30 days (adjusted OR: 2.24, 95% CI: 1.36-3.68), or their use over a
period ranging from 30 days to 2 years (OR: 2.01, 95% CI: 1.37-3.18) was linked
to increased risk of acute pancreatitis compared with non-users. It should be
mentioned that, although the analysis was adjusted for available confounders and
metformin use, the cases had increased incidence of hypertriglyceridemia,
alcohol use, gallstones, tobacco abuse, obesity, biliary and pancreatic cancer,
or any neoplasm [69]. These factors may lead to an increased risk of
pancreatitis in patients treated with GLP-1-based therapies. A pooled analysis
of phase III clinical trials and two endpoint trials showed a slightly elevated
(but not significant) risk of pancreatitis with GLP-1 receptor agonists (38
events, 17,775 patient-years of exposure) compared with the alternative
treatment (nine events, 5,863 patient-years of exposure; OR: 1.39 (95% CI:
0.67-2.88)) [70]. Based on these observations, the US Food and Drug
Administration (FDA) investigated the risk of pancreatitis associated with the
use of incretin-mimetic drugs [71].
In contrast to the above results, several recent studies and meta-analyses
failed to show increased risk of pancreatitis with the use of GLP-1 receptor
agonists [72-82]. A meta-analysis of 55 randomized controlled trials (n =
33,350) showed no increased risk of pancreatitis with GLP-1 agonists compared
with controls (OR: 1.05, 95% CI: 0.37-2.94) [83]. Moreover, the analysis of
three retrospective cohort studies and two case-control studies (total n =
320,289) did not show an increased risk of pancreatitis with the administration
of exenatide or sitagliptin [83]. Likewise, another recent meta-analysis of nine
observational studies (n = 1,324,515 patients and 5,195 cases of acute
pancreatitis) found no significant association between incretin-based treatment
and acute pancreatitis (OR: 1.03, 95% CI: 0.87-1.20) [84]. Furthermore, FDA and
European Medicines Agency (EMA) recently reevaluated more than 250 toxicology
studies conducted in nearly 18,000 healthy animals and more than 200 trials
involving approximately 28,000 patients taking incretin-based drugs. In a joint
assessment, both agencies concluded that the concerns expressed by many authors
and the media regarding a possible causal association of incretin-mimetic drugs
with acute pancreatitis are inconsistent with the current data [85].
Generally, no direct cause and effect relationship has been shown between GLP-1
receptor agonists and pancreatitis [86]. Moreover, T2D and hypertriglyceridemia
are both independent risk factors for pancreatitis [87, 88]. The presence of
confounding factors should be taken into account when investigating the possible
association between GLP-1 receptor agonists and pancreatitis. However, until
this matter finally resolves, it may be prudent that GLP-1 receptor agonists
should not be given to patients with several risk factors for pancreatitis, such
as severe hypertriglyceridemia or alcohol intake.
3.3 CARDIOVASCULAR SYSTEM
The available data do not indicate any increase in cardiovascular events with
GLP-1 receptor agonists [89-91]. A meta-analysis of 36 trials with a duration
≥12 weeks showed that the Mantel-Haenszel OR (MH-OR) for major cardiovascular
events versus placebo or other comparators was 0.74 for all GLP-1 receptor
agonists (95% CI: 0.50-1.08, p = 0.12), 0.85 for exenatide (95% CI: 0.50-1.45, p
= 0.55) and 0.69 for liraglutide (95% CI: 0.40-1.22, p = 0.20) [92].
Specifically designed long-term trials are currently assessing the
cardiovascular effects of GLP-1 receptor agonists.
GLP-1 receptor agonist treatment has however been associated with a small
increase in heart rate [93] (Table 3, in the Appendix). A meta-analysis of 22
trials showed that GLP-1 agonists overall resulted in a significant increase in
heart rate with a weighted mean difference of 1.86 beats per minute (bpm, 95%
CI: 0.85-2.87) compared with placebo and 1.90 bpm (95% CI: 1.30-2.50) compared
with active control (all p < 0.05) [94]. Exenatide twice-daily increased the
heart rate by 0.82 bpm (95% CI: -0.15 to 1.79) compared with active control and
by 0.88 bpm (95% CI: -0.47 to 2.22) compared with placebo (both p > 0.05). In a
small number of studies with exenatide once-weekly, the drug increased heart
rate by 2.14 bpm (95% CI: 1.11-3.17) compared with active control (p < 0.05).
Liraglutide increased heart rate by 2.71 bpm (95% CI: 1.45-3.97) compared with
placebo and 2.49 (95% CI 1.77-3.21) compared with active control (all p < 0.05)
[94].
TABLE 3. HEART RATE INCREASE WITH GLP-1 RECEPTOR AGONISTS.
Open in a new tab
Dulaglutide, a newer once-weekly GLP-1 receptor agonist, significantly increased
heart rate (2.8 bpm, 95% CI: 1.5-4.2) compared with placebo at the dose of 1.5
mg [95]. Interestingly, a 28-day study showed that lixisenatide significantly
reduced the heart rate by 3.6 bpm, whereas liraglutide increased heart rate by
5.3 bpm (mean difference 8.9 bpm, p < 0.05) [96]. Moreover, in another face to
face 26-week study, dulaglutide 1.5 or 0.75 mg significantly increased heart
rate compared with exenatide 10 µg BID (2.8 vs. 1.2 beats per minute, p < 0.05)
[49]. Generally, the increase in heart rate with GLP-1 receptor agonists is
small but clinically relevant as heart rate is a marker of cardiovascular
disease [97].
Exenatide, liraglutide, and albiglutide do not cause any clinically relevant
increase in the QTc interval [98-101]. Exenatide does not prolong QTc even at
supratherapeutic concentrations [102].
3.4 ALLERGY AND ANGIOEDEMA
GLP-1 receptor agonists are synthetic peptides and, like other subcutaneously
injected peptides, may lead to antibody formation (Table 4, in the Appendix).
The incidence of antibody formation was 44% with exenatide, 8.6% with
liraglutide, 69.8% with lixisenatide, 4% with albiglutide, and 1.6% with
dulaglutide [48, 103-106]. These data show that the various GLP-1 receptor
agonists have different immunogenicity [107]. A multicenter, open-label, 24-week
study assessed the incidence of immune-related and hypersensitivity reactions
after exenatide re-exposure in 58 patients with T2D [108]. Treatment-emergent
adverse events were observed in 40% and 47% of patients with positive and
negative treatment-emergent antibodies, respectively. Immune-related adverse
events, which were not observed previously, appeared in 4 patients with positive
and 2 with negative treatment-emergent antibodies. However, re-exposure to
exenatide was not associated with increased hypersensitivity reactions [108].
TABLE 4. TREATMENT-EMERGENT ANTIBODIES TO GLP-1 RECEPTOR AGONISTS.
Open in a new tab
In an analysis of 12 controlled (n = 2,225; duration 12-52 weeks) and five
uncontrolled (n = 1,538; duration up to 3 years) exenatide twice-daily trials,
and four controlled (n = 653; duration 24-30 weeks) exenatide once-weekly trials
with one uncontrolled period (n = 128), the antibody titers peaked early and
subsequently declined [109]. Specifically, after 30 weeks, 36.7% of patients
receiving exenatide twice-daily were antibody-positive. Most of the
antibody-positive patients (31.7%) had low titers, but 5% had high antibody
titers. After three years, only 16.9% were antibody-positive, with 1.4% having
high titers. Similarly, 56.8% of patients receiving exenatide once-weekly were
antibody-positive (11.8% with high titer) at 24-30 weeks, and this percentage
was reduced to 45.4% (9.2% with high titer) at 52 weeks. Adverse event rates
were similar between antibody-positive and antibody-negative patients, with the
exception of injection site reactions. Importantly, as shown in a subset of
patients, no significant cross-reaction was observed between anti-exenatide
antibodies and human GLP-1 or glucagon. Moreover, efficacy was similar in the
entire cohort of antibody-positive and antibody-negative patients (HbA1c change:
-0.9% and -1.0%, respectively, with exenatide twice-daily; -1.3% and -1.6% with
exenatide once-weekly). However, the reduction in HbA1c was non-significantly
diminished with exenatide twice-daily in the small subset of patients (5%) with
higher titers. Additionally, a significant decrease in efficacy was observed in
the subset of patients who had high antibody titers and who received exenatide
once-weekly (12%) [109]. These results represent a clinically relevant
discovery, pointing to diminishing efficacy of exenatide in patients who develop
high titers of emergent-treatment antibodies.
Severe anaphylactic reactions with GLP-1 receptor agonists have not been
reported in Pubmed. However, post-marketing reports show that anaphylactic
reactions occur rarely with liraglutide (≥1/10,000 to <1/1,000), very rarely
with exenatide (<1/10,000), and uncommonly with lixisenatide (≥1/1,000 to
<1/100) [48, 104, 105, 110]. Moreover, rare post-marketing reports of pruritus,
urticaria, and angioneurotic edema have been described with exenatide,
liraglutide, and lixisenatide [48, 104, 105]. Dulaglutide was linked to systemic
hypersensitivity events in 0.5% of patients in phase II and III trials [103].
3.5 SKIN SIDE EFFECTS
Injection site reactions, such as rash, erythema, or itching at the injection
site, are common with GLP-1 receptor agonists (Table 5, in the Appendix). In
phase II and III trials, 5.1% of the patients receiving exenatide twice-daily,
16% of those receiving exenatide once-weekly, 3.9% of those receiving
lixisenatide, and 15% of those receiving albiglutide experienced injection site
reactions [48, 105, 106, 110]. Injection site reactions are reported more
frequently with long-acting than short-acting GLP-1 receptor agonists [111]. The
predominant injection site reaction is pruritus. These reactions are most often
transient, and generally do not cause discontinuation of the treatment.
Interestingly, patients who receive GLP-1 receptor analogs, and who develop
antibodies against the drug, tend to have more injection site reactions, despite
the fact that they experience similar rates and types of adverse events to those
experienced by patients who do not develop antibodies [48, 105, 106, 109, 110].
TABLE 5. INJECTIONS SITE REACTIONS WITH GLP-1 RECEPTOR AGONISTS.
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Legend: * Injection site nodule.
Many patients receiving exenatide once weekly experience small, raised bumps in
their abdomen, which usually have a diameter of less than 0.75 cm. This reaction
is attributed to the known properties of poly (D,L-lactide co-glycolide) polymer
microsphere formulation of the drug. Generally, despite this reaction, which
typically resolves within 4-8 weeks, patients remain asymptomatic, and do not
discontinue the drug [110].
In some case reports, exenatide administration has been associated with the
development of panniculitis, although a causal association has not been proven
[112-114]. Hyperhidrosis was reported as a common adverse event (≥1/100 to <
1/10), while alopecia and macular/papular rash were found to be rare (≥1/10,000
to < 1/1,000), in phase III trials of exenatide [48].
3.6 ENDOCRINE EFFECTS
The combination of GLP-1 receptor agonists and metformin has not been associated
with an increase in the rate or severity of clinically relevant hypoglycemic
events [32, 34, 45, 46, 115-122]. However, in clinical trials examining GLP-1
receptor agonists in combination with sulphonylurea (with or without metformin)
or insulin, the incidence of hypoglycemia, although low overall, was increased
compared with placebo (Table 6, in the Appendix) [32, 33, 42, 123-135].
Interestingly, the concomitant administration of GLP-1 receptor agonists with a
sulphonylurea in the in situ perfused rat pancreas led to uncoupling of the
insulinotropic effect of GLP-1 from its glucose dependence [136]. Hence, the
increased incidence of hypoglycemia caused by the combination of GLP-1 receptor
agonists and sulphonylureas may be linked to the uncoupling of GLP-1 from its
glucose dependence. Therefore, it is recommendable to decrease the sulphonylurea
or insulin dose in patients on sulphonylurea or insulin therapy who start a
GLP-1 receptor agonist to reduce the risk of hypoglycemic episodes [137].
TABLE 6. INCIDENCE OF HYPOGLYCEMIA IN SELECTED PLACEBO-CONTROLLED STUDIES WITH
GLP-1 RECEPTOR AGONISTS COMBINED WITH SULPHONYLUREAS.
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3.7 MUSCULOSKELETAL DISORDERS
A meta-analysis of 16 randomized controlled trials (n = 11,206) assessed the
risk of bone fractures associated with liraglutide or exenatide, in comparison
to placebo or other active drugs [138]. The administration of liraglutide was
associated with a significantly decreased risk of incident bone fractures
(MH-OR: 0.38, 95% CI: 0.17-0.87), while exenatide administration was linked with
an increased risk (MH-OR: 2.09, 95% CI: 1.03-4.21). These results point to
heterogeneity between liraglutide and exenatide. However, these observations
need to be confirmed by future trials [138].
Despite the negative effects of exenatide on bone fracture risk found in the
above meta-analysis, a study of 69 metformin-treated subjects with T2D
randomized to exenatide twice-daily (n = 36) or insulin glargine once-daily (n =
33) showed that bone mineral density was similar in both groups after the
44-week therapy (between-group difference p = 0.782). Moreover, fasting serum
alkaline phosphatase, calcium, and phosphate levels did not significantly change
during treatment [139].
3.8 INFECTION
GLP-1 receptor agonist trials report upper respiratory and urinary tract
infections (Table 7, in the Appendix). Nasopharyngitis, influenza, cystitis, and
viral infection are also commonly reported with these drugs [48, 104-106, 110].
However, no cause-effect association between the use of GLP-1 receptor agonists
and more serious infections has been observed.
TABLE 7. INCIDENCE OF UPPER RESPIRATORY AND URINARY TRACT INFECTION WITH GLP-1
RECEPTOR AGONISTS.
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3.9 CENTRAL NERVOUS SYSTEM (CNS)
Headache is reported in GLP-1 receptor agonist trials (Table 8, in the
Appendix). However, this adverse effect does not usually lead to
discontinuations.
TABLE 8. INCIDENCE OF HEADACHE WITH GLP-1 RECEPTOR AGONISTS.
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3.10 RENAL EFFECTS
Exenatide has been associated with the development of acute kidney injury in
about 100 case reports [140-146]. In most reports, acute kidney injury was
attributed to pre-renal acute failure due to exenatide-induced nausea and
vomiting, decreased fluid intake, and significant loss of fluids. In this
context, a kidney biopsy was performed and showed ischemic glomeruli with
moderate to severe interstitial fibrosis and early diabetic nephropathy [145].
Other factors that may be associated with the impairment of renal function are
GLP-1-induced natriuresis and reduction in renal perfusion [147, 148].
It should be mentioned that most of the subjects who experienced deterioration
of kidney function with exenatide had at least one risk factor for developing
kidney disease, such as cardiac failure, hypertension, or use of nephrotoxic
drugs [140]. Importantly, most subjects with exenatide-induced volume
contraction were receiving drugs that inhibit the renin-angiotensin system and
aldosterone formation. Activation of the renin-angiotensin system is an
important homeostatic mechanism in states associated with volume depletion, and
the use of inhibitors of these systems contributes to occurrence of acute kidney
injury in subjects with volume depletion [149].
Acute interstitial nephritis has also been demonstrated to be a mechanism of
exenatide-induced acute kidney injury. In a case report on a person with
exenatide-associated acute kidney injury, kidney biopsy showed active,
moderately severe, diffuse tubulointerstitial nephritis with infiltration of
eosinophils [150]. These observations suggested a drug-induced reaction. The
person’s condition was improved with the administration of prednisolone [150].
Another case report showed an improvement in kidney function with prednisolone
in a person with exenatide-induced acute kidney injury [151].
In contrast to the case reports on altered renal function seen with exenatide, a
pooled analysis of 5,594 participants from 19 randomized, controlled clinical
trials of exenatide twice-daily (5 μg and 10 μg) showed that renal
impairment-related adverse events, including acute renal failure, were rare (1.6
per 100 person-years for both groups). Also, no significant difference was seen
between the exenatide and pooled comparator (placebo and insulin) groups (95%
CI: -0.98 to 0.96) [152]. Further analyses have shown that there was no
difference in the adjusted risk for acute kidney injury among T2D patients
taking exenatide compared with patients receiving other drugs (hazard ratio
(HR): 0.77, 95% CI: 0.42-1.41, p = 0.40) [153].
Liraglutide has been associated with acute kidney injury in a few case reports
[140, 154]. The pathological mechanism seems to be based on acute tubular
necrosis due to dehydration and volume contraction resulting from severe and
progressively worsening gastrointestinal symptoms [155]. Liraglutide has been
linked to acute interstitial nephritis in one case report [156]. Despite these
few reports, liraglutide seems to be a safe drug in terms of kidney function.
Clinicians should consider the possible risk of acute renal failure associated
with the administration of GLP-1 receptor agonists. The main mechanism of acute
kidney injury in people receiving GLP-1 receptor agonists is volume contraction
due to gastrointestinal symptoms [140]. Therefore, these drugs should not be
given to people with uncontrolled T2D, polyuria, and polydipsia or people who
develop severe symptoms that predispose to volume depletion (for example
vomiting). Patients should also be advised to discontinue therapy in case of
severe vomiting or diarrhea.
Clinicians should also be cautious in the case of T2D patients receiving drugs
that inhibit the renin-angiotensin system. These patients are more prone to
develop acute kidney injury due to dehydration and volume contraction. GLP-1
receptor agonists should be stopped in patients with acute kidney injury, and
rehydration should be initiated. In severe cases, dialysis may be needed.
Finally, in cases where volume contraction is not the obvious mechanism of acute
kidney injury, the possibility of acute interstitial nephritis should be
considered. In such a case, a kidney biopsy should be performed to establish the
diagnosis and start steroid treatment.
3.11 CANCER
Concerns have been expressed about the effects of incretin-mimetic drugs on
pancreatic tissue [157, 158]. It has been shown that the administration of the
GLP-1 receptor agonist exendin-4 results in the expansion of pancreatic duct
glands in rats, and acceleration of the formation of dysplastic lesions and
chronic pancreatitis in the KrasG12D mouse model [63].
The results of animal studies are difficult to extrapolate to humans. A study by
Butler et al. examined pancreatic tissue from organ donors with T2D taking
sitagliptin (n = 7), exenatide (n = 1), or other medication (n = 12), and from a
group of subjects without diabetes (n = 14). In 40% of patients, treatment with
incretin-mimetic drugs was associated with increased pancreatic mass accompanied
by increased exocrine cell proliferation (p < 0.0001) and increased pancreatic
intraepithelial neoplasia (dysplasia, p < 0.01) [159]. Moreover, patients
receiving incretin-mimetic drugs had α-cell hyperplasia and glucagon-expressing
microadenomas (3 out of 8) and one had a neuroendocrine tumor [159].
Analyses based on the FDA Adverse Event Reporting System (FAERS) showed that
incretin-mimetic drugs are linked with increased incidence of pancreatitis and
pancreatic cancer compared with other anti-diabetic drugs [160-162]. A FAERS
analysis conducted between 2004 and 2009 showed a significant increase in cases
of pancreatitis with exenatide (OR: 10.68, 95% CI: 7.75-15.1, p < 0.0001) and
sitagliptin (OR: 6.74, 95% CI: 4.61-10.0, p < 0.0001), and in cases of
pancreatic cancer (exenatide OR: 2.9, p < 0.0001; sitagliptin OR: 2.7, p =
0.008) and thyroid cancer (exenatide OR: 4.73, p = 0.004) [161]. Based on this
evidence, FDA investigates reports of possible increased risk of pancreatitis
and pre-cancerous findings of the pancreas from incretin-mimetic drugs [71].
However, it should be mentioned that the study by Butler et al. has been accused
of methodological deficiencies including the following issues:
- The age distribution of the three groups was mismatched.
- The increase in pancreatic mass was due to an outlier in the GLP-1 receptor
agonists group.
- The increase in pancreatic mass may also be due to the possible inclusion of
type 1 diabetic patients (who have decreased pancreatic mass) in the type 2
diabetic control group [163].
- The distinction between alpha- and beta-cells was not clear due to variability
in staining intensity [163].
Other long-term animal studies did not find a harmful effect of incretin-mimetic
drugs on pancreatic tissue [164, 165]. Furthermore, analyses from adverse
reporting systems are useful, but are difficult to control for confounding
factors that increase the risk of pancreatitis and cancer, such as obesity,
alcohol consumption, smoking, and the use of other drugs. Recent reports and
meta-analyses did not show an increased risk of pancreatic cancer with
incretin-mimetic drugs [77, 166, 167]. A meta-analysis of 25 studies showed that
the use of exenatide (OR: 0.86, 95% CI: 0.29-2.60) and liraglutide (OR: 1.35,
95% CI: 0.70-2.59) did not significantly increase the risk of pancreatic cancer,
independently of the baseline comparator [78].
Hence, at this point no significant evidence exists linking GLP-1 receptor
agonists with pancreatic cancer. In a recent joint statement, FDA and EMA agree
that concerns regarding a causal association between incretin-mimetic drugs and
pancreatitis or pancreatic cancer are inconsistent with the available evidence
[85]. However, a final all-clear regarding the risk of pancreatitis or
pancreatic cancer caused by incretin-mimetic drugs cannot be given [85]. On the
other hand, there is some evidence of an antitumor effect of GLP-1 receptor
activation in pancreatic cancer cell lines [168].
Concerns have also been expressed regarding a possible link between GLP-1
receptor agonists and medullary thyroid cancer [161]. These concerns are mainly
based on rodent studies. Liraglutide and exenatide have been associated with the
development of thyroid C-cell tumors in rodents after lifetime exposure at
supratherapeutic doses [169]. Furthermore, a 13-week continuous exposure to
GLP-1 receptor agonists induced marked increases in plasma calcitonin and in the
incidence of C-cell hyperplasia in wild-type mice, but not in GLP-1 receptor
knockout mice [170]. In contrast to the results in rodents, in vivo animal
studies with cynomologus monkeys did not show any liraglutide-induced calcitonin
release or any effect on relative C-cell fraction in the thyroid gland after 87
weeks at doses up to 60-fold higher than the highest dose recommended in humans
[169]. Another study in monkeys also showed that dulaglutide at doses amounting
to the 500-fold maximum human plasma exposure for 52 weeks were not associated
with increases in serum calcitonin or alterations in thyroid weight, histology,
C-cell proliferation, or absolute/relative C-cell volume [171].
The harmful effect of GLP-1 receptor agonists in rodents but not in primates
indicates that the proliferative C-cell effects may be rodent-specific [172].
Moreover, an analysis of liraglutide trials (duration 20-104 weeks) did not show
any significant change between treatment groups regarding calcitonin levels or
the proportion of participants with an increase in calcitonin levels above 20
pg/ml [173]. It should be mentioned that in the Liraglutide Effect and Action in
Diabetes (LEAD)-6 trial (duration 26 weeks) no difference was observed in
estimated geometric mean calcitonin levels between liraglutide 1.8 mg once daily
and exenatide 10 μg twice daily [31]. Finally, a meta-analysis of 25 studies
showed that liraglutide was not significantly associated with an increased risk
of thyroid cancer (OR: 1.54, 95% CI: 0.40-6.02), and no thyroid malignancies
were reported with exenatide [78].
3.12 OVERDOSE
Some cases of GLP-1 receptor agonist overdose have been reported [174-178]. For
example, a 49-year-old woman with T2D accidentally injected the whole
liraglutide pen and received a total dose of 18 mg [179]. She developed severe
nausea and vomiting, but no abdominal pain, deterioration of liver function
tests, increase in amylase levels, or hypoglycemia. This patient was treated
with intravenous fluids and intravenous metoclopramide [179].
Generally, severe nausea, vomiting, abdominal pain, and diarrhea were described
in cases of GLP-1 receptor agonist overdose. Hypoglycemia did not develop, even
with doses of 72 mg or in cases where an overdose of liraglutide was continued
for seven months [174, 175]. Moreover, no incident of pancreatitis or other
serious complication has been reported. Therapy in GLP-1 receptor agonist
overdose is mainly supportive.
4. CONCLUSIONS
GLP-1 receptor agonists are useful drugs for the treatment of patients with T2D.
These drugs improve glycemic control and many other atherosclerosis-related
parameters. However, concerns have been expressed regarding the effects of these
drugs on pancreatic and thyroid tissue, but current evidence and meta-analyses
do not show a cause-effect association between GLP-1 receptor agonists and the
development of pancreatitis, pancreatic cancer, or thyroid cancer.
GLP-1 receptor agonists do not generally cause hypoglycemia, but it is
recommendable to decrease the dose of concomitant sulphonylurea or insulin to
reduce the risk of hypoglycemic episodes. In many case reports, the use of these
drugs, mainly exenatide, has been associated with acute kidney injury, in which
hemodynamic factors are predominantly implicated. Other common adverse effects
of these drugs include injection site reactions, headache, and nasopharyngitis,
but these effects do not usually lead to discontinuation of the drug.
Finally, GLP-1 receptor agonists do not seem to affect negatively the
cardiovascular risk in patients with T2D, but an ultimate all-clear regarding
the risk of cardiovascular events, pancreatitis, or pancreatic cancer, which may
be caused by incretin-mimetic drugs, cannot be given as there is scattered
evidence for these side effects. Ongoing and future trials need to assess and
clarify further the cardiovascular and overall safety profile of GLP-1 receptor
agonists.
5. ARTICLE HIGHLIGHTS
- GLP-1 receptor agonists cause gastrointestinal symptoms, but these effects do
not usually cause discontinuation of therapy.
- Nausea appears to be less common with long-acting than short-acting compounds.
- GLP-1 receptor agonists are associated with pre-renal acute kidney injury in
cases of severe gastrointestinal symptoms and dehydration.
- Evidence does not point to an increased risk of pancreatitis with GLP-1
receptor agonists.
- Meta-analyses do not show an increased risk of pancreatic or thyroid cancer
with the use of these drugs.
DISCLOSURES
This work was conducted independently; it was not supported financially.
Professor Moses Elisaf has received speaker honoraria, consulting fees, and
research funding from AstraZeneca, Schering Plough, Merck, Pfizer, Solvay,
Abbott, Boehringer Ingelheim, and Fournier, and has participated in clinical
trials with AstraZeneca, Merck, Sanofi-Synthelabo, Solvay, Glaxo, Novartis,
Pfizer, and Fournier. The authors have given talks and attended conferences
sponsored by various pharmaceutical companies, including Bristol-Myers Squibb,
Pfizer, Lilly, Abbott, Amgen, Astrazeneca, Novartis, Vianex, Teva, and MSD.
APPENDIX
TABLE 1. ADVERSE EFFECTS OF GLP-1 RECEPTOR AGONISTS.
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TABLE 2. INCIDENCE OF NAUSEA, VOMITING, AND DIARRHEA ASSOCIATED WITH GLP-1
RECEPTOR AGONISTS.
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--------------------------------------------------------------------------------
Articles from The Review of Diabetic Studies : RDS are provided here courtesy of
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* Abstract
* 1. Introduction
* 2. Methods
* 3. Adverse effects of GLP-1 receptor agonists (Table {t1}, Appendix)
* 4. Conclusions
* 5. Article highlights
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