Type 2 diabetes is a complex metabolic disorder characterized by hyperglycemia arising
from a combination of insufficient insulin secretion together with resistance to insulin
action. The incidence and prevalence of type 2 diabetes are rising steadily, fuelled
in part by a concomitant increase in the worldwide rates of obesity. As longitudinal
studies of type 2 diabetes provide evidence linking improved glycemic control with
a reduction in the rates of diabetes-associated complications, there is considerable
interest in the therapy of type 2 diabetes (Fig. 1), with a focus on the development
and use of new agents that exhibit improved efficacy and safety relative to current
available medicines.
Figure 1
Relative comparison of properties exhibited by different classes of agents approved
for the treatment of type 2 diabetes. CVD, cardiovascular disease; TG, triglycerides;
CHF, congestive heart failure. A1C reduction depends on starting A1C.
Although the number of patients with type 2 diabetes that successfully achieve target
levels of A1C is steadily improving, a substantial number of subjects continue to
fall short of acceptable treatment goals, leaving them at high risk for development
of diabetes-associated complications (1). More importantly, a large number of subjects
with type 2 diabetes fail to achieve target values for glucose, lipids, and blood
pressure, with only 12.2% of patients meeting target values despite recent improvements
in therapeutic agents targeting hyperglycemia, dyslipidemia, and hypertension (2).
The development of multiple new agents for the treatment of type 2 diabetes has broadened
the options for patient-specific therapy. However, no currently available agents exhibit
the ideal profile of exceptional glucose-lowering efficacy to safely achieve target
levels of glycemia in a broad range of patients. Hence, highly efficacious agents
that exhibit unimpeachable safety, excellent tolerability, and ease of administration
to ensure long-term adherence and that also clearly reduce common comorbidities and
complications of diabetes are clearly needed (Fig. 1). Furthermore, most patients
require combination therapy to achieve effective control of their disease (3). Recommended
initial therapy generally includes comprehensive lifestyle management and patient
education combined with metformin therapy. Although metformin is widely accepted as
the preferred agent for the initial treatment of type 2 diabetes, there remains considerable
uncertainty and lack of consensus in regard to choice of additional agents that need
to be added to metformin to optimize glycemic control.
Recent recommendations have highlighted the use of insulin, sulfonylureas, and thiazolidinediones
as second-line therapies because of their proven efficacy in long-term outcome studies.
Nevertheless, more recent studies involving intensive use of these therapies in patients
with clinical cardiovascular disease or multiple risk factors to achieve lower target
glucose levels were associated with hypoglycemia, bone fractures, hospitalization
for congestive heart failure, weight gain, and, in some analyses, increased mortality
with modest benefit on rates of myocardial infarction. This has led to a re-examination
of treatment recommendations to minimize the risk of cardiovascular morbidity and
mortality (3,4) and specifically an interest in incretin-based therapies in this regard.
Incretin-based therapies: mechanisms of action and benefits
The two most recently approved classes of therapeutic agents for the treatment of
type 2 diabetes, glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists and dipeptidyl
peptidase-4 inhibitors (DPP-4i), exert their actions through potentiation of incretin
receptor signaling. Incretins are gut-derived hormones, principally GLP-1 and glucose-dependent
insulinotropic peptide (GIP), that are secreted at low basal levels in the fasting
state. Circulating levels increase rapidly and transiently following food ingestion.
As native GLP-1 displays a very short circulating half-life due to renal clearance
and NH2-terminal degradation by the enzyme DPP-4, degradation-resistant GLP-1R agonists
have been developed. Exendin-4, a GLP-1R agonist structurally related to the native
gut peptide, was approved for the treatment of type 2 diabetes in the U.S. in April
2005 and is currently administered as a subcutaneous injection (10 μg twice daily)
for use as monotherapy in subjects not achieving adequate glycemic control on lifestyle
modification alone or one or more oral agents. Liraglutide is an investigational human
acylated GLP-1R agonist approved in Europe that binds noncovalently to albumin and
exhibits a more prolonged duration of action suitable for once daily administration.
A longer-acting microsphere preparation of exenatide suitable for once weekly administration,
exenatide (once weekly), has also been studied in controlled clinical trials and appears
to be somewhat more effective compared with exenatide twice daily (5).
Sitagliptin was the first DPP-4i approved in the U.S. in October 2006. It exerts its
glucoregulatory actions through prevention of incretin degradation, leading to potentiation
of GLP-1 and GIP action (6). Sitagliptin is administered as a single 100-mg daily
tablet either as monotherapy or in combination therapy with oral antidiabetic agents.
Sitagliptin is well tolerated and is not associated with nausea or vomiting as the
levels of endogenous intact GLP-1 achieved following DPP-4 inhibition are at the upper
limit of the normal physiological range; hence, it is not sufficient to induce an
aversive response. Conversely, DPP-4i therapy is not associated with inhibition of
gastric emptying or weight loss, and the available data suggest that long-acting GLP-1R
agonists achieve more potent control of glycemia, relative to DPP-4i, due to more
potent and sustained GLP-1R activation. Vildagliptin, a second DPP-4i, is approved
in Europe and other countries, while saxagliptin has recently been approved in the
U.S. and several other DPP-4i are under regulatory review.
GLP-1R agonists control blood glucose through regulation of islet function, principally
with the stimulation of insulin and inhibition of glucagon secretion (7). Notably,
these GLP-1R–dependent actions are glucose dependent, thereby minimizing the risk
of hypoglycemia in the absence of concomitant sulfonylurea therapy. GLP-1R activation
also inhibits gastric emptying and reduces food intake, leading to weight loss in
the majority of treated subjects (8). The GLP-1R is expressed in cardiomyocytes and
endothelial cells, and preclinical studies demonstrate that GLP-1R activation is associated
with substantial cardioprotection and reduced infarct size in experimental models
of coronary artery ischemia (9,10). Limited evidence suggests that GLP-1 may also
preserve ventricular function and improve outcomes in human subjects with heart failure
or myocardial infarction (11,12). Moreover, both exenatide and liraglutide reduce
blood pressure, body weight, and plasma lipid profiles in subjects with type 2 diabetes
(13), raising the hope that long-term treatment with these agents may reduce the incidence
of cardiovascular events. Intriguingly, the GLP-1 metabolite, GLP-1 (9
–36), also exerts cardioprotective actions in preclinical studies through mechanisms
independent of the known GLP-1R (14); hence, ongoing research is directed at understanding
the complexity of incretin biology in the cardiovascular system and the potential
for incretin-based therapies to differentially modulate cardioprotective signals in
the diabetic heart and blood vessel in vivo (15). The principal treatment-related
adverse events associated with exenatide and liraglutide therapy are nausea and vomiting,
which generally diminish over time (13). Analysis of the antidiabetic actions pursuant
to GLP-1 administration has demonstrated that activation of the GLP-1R for 24 h provides
more sustained and potent control of glycemia relative to shorter periods of GLP-1R
agonism (16). In contrast, sustained GLP-1R activation may be associated with a modest
reduction in control of postprandial glycemia (5,13), observations of interest to
scientists studying the link between postprandial glucose and the development of cardiovascular
morbidity and mortality. As exenatide requires twice daily administration and does
not provide 24-h GLP-1R activation, there has been considerable interest in development
of GLP-1R analogues with more prolonged durations of action (Fig. 2) suitable for
once-daily or once-weekly administration (17). Consistent with the notion that continuous
GLP-1R activation is required for optimal glucoregulation, liraglutide administered
once daily and exenatide administered once weekly appear to be more potent glucose-lowering
agents, relative to twice-daily exenatide (5,13). Furthermore, they seem to be associated
with better tolerability and patient-reported outcomes as well as trends toward greater
benefit on cardiovascular disease risk factors (Fig. 2). There are now over a dozen
long-acting investigational GLP-1R agonists being developed for the treatment of type
2 diabetes (8). Several recent reviews have emphasized the mechanisms of action and
clinical results obtained in trials examining the efficacy of incretin-based therapies
(8,17). Herein we examine adverse events and safety concerns associated with these
agents.
Figure 2
Comparison of features associated with exenatide twice daily versus the properties
of the emerging class of long-acting GLP-1R agonists that achieve more prolonged and
sustained GLP-1R activation. CVD, cardiovascular disease.
Adverse events associated with GLP-1R agonists
Acute pancreatitis.
Pancreatitis has been reported as a rare side effect of exenatide therapy principally
through postmarketing surveillance. There are many risk factors and predisposing causes
for acute pancreatitis, as well as over 200 drugs linked to the development of acute
pancreatitis. The incidence of pancreatitis varies considerably among drugs, being
relatively common for individuals taking 6-mercaptopurine and azathioprine (2–5%),
but very uncommon for steroids and thiazide diuretics. The severity of the disease
also varies; pancreatitis induced by 6-mercaptopurine is often quite severe, while
that caused by cholinesterase inhibitors is usually mild. There are only two circumstances
in which the mechanism of drug-induced disease is understood, drugs that cause hypertriglyceridemia
(e.g., some HIV-protease inhibitors, estrogens, isotrentinoin) and drugs that are
mitochondrial toxins. Drugs are not thought to cause chronic pancreatitis (with the
exception of alcohol and smoking), although they have the theoretical potential to
do so. Numerous animal models for pancreatitis have been developed; however, drugs
that are associated with pancreatitis in humans rarely cause disease in rodents. Whether
these species-specific observations reflect differences in drug metabolism, pancreatitis
responses including inflammation, or the fact that some drugs may act as sensitizers
and require other factors to cause disease, remains unclear.
Clinical data relating GLP-1R agonists and DPP-4i to pancreatitis come from a limited
number of case reports, the U.S. Food and Drug Administration's (FDA) adverse event
reporting system, and clinical trial records from pharmaceutical companies. A summary
of initial 30 cases of individuals taking exenatide who developed acute pancreatitis
was published in 2008 (18). The authors noted that in least 90% of these subjects,
there were other factors that could predispose the individuals to pancreatitis. Rechallenge,
a standard measure for assigning causality in drug-induced pancreatitis, was performed
in only three patients but associated with recurrence of symptoms in each. However,
the recurrence of symptoms with rechallenge was reported to occur only after weeks
in some patients. In most patients with drug-induced pancreatitis, rechallenge usually
causes disease within days. Subsequently, hemorrhagic pancreatitis and several deaths
have been reported to the FDA in patients who previously used exenatide and similar
cases but no deaths have been reported in patients treated with sitagliptin (19).
A recent study used insurance records to determine that the risk of pancreatitis for
subjects followed up to a year was 0.12% and 0.13% with sitagliptin and exenatide,
respectively (20). These relative risks did not differ from a control cohort treated
with metformin or glyburide. Data from the manufacturer of liraglutide reported a
low incidence of acute pancreatitis (0.8 cases/1,000 patient-years). Notably, analysis
of pancreatitis in subjects with type 2 diabetes suggests that their risk is increased
threefold over nondiabetic subjects (21). Since only a fraction of this risk could
be attributed to biliary pancreatitis, it seems likely that other factors such as
obesity and hypertriglyceridemia might contribute to the increased risk in this population.
Several experimental studies have examined the effects of incretin-based agents on
the pancreas in animal models. Koehler et al. (22) found no evidence of pancreatitis
in mice treated with the GLP-1R agonist exendin-4 alone and no GLP-1R–dependent enhancement
of pancreatitis responses in the caerulein-hyperstimulation model. In contrast, Nachnani
et al. (23) detected histological evidence for acinar inflammation, cell drop-out
and possible fibrosis and increased levels of serum lipase in Sprague-Dawley rats
treated with exendin-4 for 75 days. A study by Matveyenko et al. (24) examined the
effects of sitagliptin in human islet amyloid polypeptide (HIP) transgenic diabetic
rats. The investigators reported that one of eight HIP rats receiving the drug developed
acute pancreatitis and noted extensive pancreatic ductal proliferation and metaplasia
and accompanying fibrosis in three HIP rats treated with sitagliptin. Some of the
histological findings from the latter two studies were very similar, and reminiscence
of changes was seen with chronic pancreatitis. The animal studies raise several confounding
issues, namely might there be differences in pancreatitis responses between GLP-1R
agonists and DPP-4i in humans versus rodents and in specific diabetic versus nondiabetic
preclinical models? Though the relevance of the HIP transgenic rat model to human
disease remains unclear, that study does suggest that DPP-4i might induce pancreatic
metaplasia under specific experimental conditions. In summary, the clinical and experimental
data linking GLP-1R agonists and DPP-4i to pancreatitis are still incomplete. More
information is required to allow one to determine whether these agents substantially
increase the risk of acute pancreatitis and whether such disease tends to be severe.
However, patients receiving these medications will need to undergo continued surveillance
for pancreatitis and clinicians should carefully exclude other causes of acute pancreatitis
when it occurs in subjects receiving these drugs. Although the diagnosis of drug-induced
pancreatitis would ideally be associated with confirmatory clinical data following
drug rechallenge, physicians should exercise caution before considering a trial of
drug rechallenge. As GLP-1R agonists may also affect smooth muscle responses and may
regulate cholangiocyte function (25), their effects on the biliary tract and gallstone
formation should also be examined.
Issues linking these agents with pancreatic metaplasia and chronic pancreatitis, as
now suggested by two experimental studies, present a different challenge. Longer-term
experimental studies using different GLP-1R agonists and DPP-4i in several species
and experimental models of diabetes need to be undertaken to help clarify the importance
of these findings. Hence, monitoring of pancreatic function and pancreatic disease
in humans treated with GLP-1R agonists and DPP-4i in ongoing long-term prospective
controlled clinical trials seems prudent.
Medullary thyroid cancer.
Medullary thyroid carcinoma (MTC) is an uncommon neuroendocrine malignancy with an
estimated U.S. annual incidence of fewer than 1,000 persons and a lifetime risk of
development of 0.013% (26). When diagnosed early and still confined to the thyroid
gland, the long-term survival of MTC is nearly 100% (27). About 25% of MTCs occur
as part of an inherited autosomal dominant syndrome, either multiple endocrine neoplasia
type II or familial MTC, and virtually all familial tumors are caused by inherited
mutations in the RET proto-oncogene. Of sporadic MTCs, at least 40% are associated
with somatic mutations and RET, and prognosis is worse in those mutated tumors.
The histological precursors to MTC in the inherited syndromes are well described,
beginning with C-cell hyperplasia, leading to nodular C-cell hyperplasia, and then
eventually to MTC. However, among the sporadically occurring MTCs, the role of this
histological sequence is not defined, and the exact distinction between neoplastic
and non-neoplastic C-cell hyperplasia is controversial (28,29). As a tumor derived
from C-cells, MTCs generally secrete calcitonin, and high serum levels of calcitonin
(>100 pg/ml) are nearly 100% specific for the presence of MTC (30,31). Nonetheless,
the specificity of serum calcitonin concentrations between the upper end of the reference
range and 100 pg/ml is considerably more limited. Other etiologies of mild degrees
of hypercalcitoninemia include lymphocytic thyroiditis, chronic renal insufficiency,
pancreatitis, hypercalcemia, hypergastrinemia (of any etiology), and even the postprandial
state (31,32). Stimulation of calcitonin release with pentagastrin infusion has long
been used to distinguish neoplastic from non-neoplastic causes of mild hypercalcitoninemia;
however, pentagastrin is no longer available for human use in the U.S., and the diagnostic
accuracy of testing with alternative stimulants such as calcium infusion remains to
be established (31).
Animal models of MTC have limitations in regard to the biology and epidemiology of
human MTC. Rats develop spontaneous age-related C-cell lesions at remarkably high
frequency, especially nodular C-cell hyperplasia. Sporadic MTC occurs in 0.5–1% of
most rat species evaluated, with increased frequency in males and with advancing age;
spontaneous RET mutations have not been reported, and some typical histological features
of human MTC are generally lacking. Mice develop spontaneous MTC less frequently,
and most animal models in use are either transgenic or xenografts of the well-characterized
TT cell line.
Food intake links incretin secretion with stimulation of calcitonin secretion in rodents,
potentially via GLP-1 receptors expressed on rodent MTC cell lines, and GLP-1 stimulates
calcitonin release in rodents in vivo (33
–35). Analysis of data reported at the 2 April 2009 FDA Advisory Committee review
of liraglutide revealed that preclinical toxicology studies with liraglutide reported
C-cell hyperplasia and MTC with increasing exposure to liraglutide. At the highest
drug exposures, MTC was reported in 14% of male and 6% of female Sprague-Dawley rats,
which was above the rates observed in untreated rat controls. C-cell lesions were
also reported to be more common with liraglutide in CD-1 mice, albeit at much lower
frequencies; no C-cell lesions were described in the cynomologous monkey. In contrast,
once-daily administration of exenatide in rodents is associated with a high frequency
of nodular C-cell lesions but no carcinomas were reported (36). In safety monitoring
of multiple liraglutide clinical trials, many patients with undetectable calcitonin
levels before initiation of investigational (liraglutide, placebo, or active comparator)
therapy were found to have levels that rose into the mid-reference normal range; rare
patients developed mild hypercalcitoninemia during therapy. Across the trials, six
patients were found to have C-cell findings at thyroidectomy following therapy (36).
Of these patients, four were in liraglutide treatment arms, but three of these had
elevated calcitonin levels before initiation of treatment. The remaining two patients
were in the active comparator arms of trials, and one had an elevated calcitonin level
before treatment. This single patient had MTC and was treated with an active non-GLP-1–based
comparator; the patient had a markedly elevated calcitonin level before initiating
non-GLP-1–based comparator therapy. All of the remaining patients who underwent thyroidectomy
for hypercalcitoninemia were reported to have C-cell hyperplasia. According to the
FDA briefing documents, no cases of C-cell lesions have been documented by histology
in patients treated with exenatide. Several cases of papillary thyroid cancer have
also been reported in the liraglutide clinical development program; however, the small
number of cases, the incidental histopathologic identification of the lesions, together
with the lack of biological plausibility, suggest that this is an incidental finding
not directly related to therapy with GLP-1R agonists.
In summary, rodents exposed to liraglutide and exenatide develop C-cell lesions at
relatively high frequency, although the currently available data suggest that rodent
MTC may be specific to long-acting GLP-1R agonists, likely due to sustained GLP-1R
activation. Because of the historic difficulty of distinguishing neoplastic and non-neoplastic
forms of C-cell hyperplasia in both rodents and humans, the diagnostic significance
of C-cell hyperplasia is unclear. Minimal elevations of calcitonin levels are very
nonspecific, and available methods of dynamic testing add little to clarify the etiologies.
Given the extreme rarity of MTC in humans, the numbers of patients who would need
to be treated for 10 years to yield one additional case of MTC may be extremely high
(35–55,000 if risk is doubled; 10–15,000 if risk is quintupled). Moreover, the differences
in rodent versus human C-cell biology with regard to responsivity to GLP-1R activation
raise important questions about the suitability of mice and rats as models for understanding
the effects of GLP-1R agonists on human C-cells.
Summary and conclusions
Incretin-based therapies provide new options for the treatment of type 2 diabetes
and enable intensification of therapy while controlling body weight through mechanisms
associated with a low rate of hypoglycemia. Investigational long-acting GLP-1R agonists
require less frequent administration and appear to be more potent with respect to
A1C reduction than twice-daily exenatide or once-daily sitagliptin with respect to
A1C reduction. These long-acting GLP-1R agonists have considerable potential as antidiabetic
therapies as they not only lower glucose as or more effectively than other noninsulin
antihyperglycemic therapies, they do so in concert with weight loss, improvement in
cardiovascular disease risk factors, and with very low risk of hypoglycemia. However,
two safety issues have been raised—pancreatitis and medullary carcinoma of the thyroid.
The relationship between the use of incretin therapy and the development of pancreatitis
remains unclear. These agents may not substantially increase the risk of acute pancreatitis
in humans and might not affect the risk at all. The relevance to humans of the pancreatic
metaplasia observed with these agents in two of the rodent studies is unknown. Continued
clinical monitoring and more research are required to clarify the actions of GLP-1R
agonists and DPP-4i on the normal and diabetic exocrine pancreas.
GLP-1R activation stimulates calcitonin secretion and promotes the development of
C-cell hyperplasia and medullary thyroid cancer in rodents but not in monkeys, and
the actions of GLP-1R agonists on human C-cells remain uncertain. Because of the rarity
of medullary carcinoma of the thyroid and the lack of specificity of clinical markers,
screening strategies, except in the setting of familial syndromes, almost certainly
would be associated with an increase in morbidity and perhaps mortality as a result
of false positives.
Taken together, the available evidence supports the use of incretin-based therapies
for patients requiring effective control of glycemia and body weight while minimizing
the risk of hypoglycemia. Ongoing scrutiny and further studies are required to clarify
the potential significance of reports of pancreatic injury, including pancreatitis
and metaplasia, and rodent medullary thyroid cancer for human subjects treated with
GLP-1R agonists and DPP-4i.