SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
VOLUME 11 NUMBER 1 • MARCH 2014
29
was smaller in the exenatide group, when compared with placebo
(0.30 ± 0.15 versus 0.39 ± 0.15;
p
= 0.003); however, there was no
difference in left ventricular function nor 30-day clinical events.
30
A
study in rats shows regulation of the GLP-1 receptor in the heart
within a few hours of experimental ischaemia, that persisted for up
to three days.
31
Sokos
et al
. investigated the efficacy of a five-week continuous
infusion of GLP-1, in addition to standard therapy, in 12 patients
with New York Heart Association class 3 and class 4 heart failure,
when compared with nine control subjects. It was noted that GLP-1
infusion significantly improved left ventricular ejection fraction,
maximal oxygen uptake (VO
2
max) and the 6-minute walk distance,
when compared with placebo.
32
An experimental human study shows impaired responsiveness
of the myocardium to GLP-1 in patients with type 2 diabetes and
obesity, compared to control subjects; however, there was no
difference in myocardial nor coronary GLP-1 receptor expression
between the groups of subjects, suggesting that post-receptor
signalling might be altered in obesity and type 2 diabetes.
33
Presently available evidence suggests that GLP-1 and its analogues
have a beneficial effect on the heart. But it is unclear whether the
effect is class- or dose-dependent. GLP-1 based therapies may be
an interesting supplementary option for myocardial infarction and
heart failure in the future, if large clinical trials confirm the above-
mentioned findings.
GLP-1 and the nervous system
GLP-1 administration enhances satiety and reduces caloric intake,
possibly mediated by effects on the nervous system. In a study
involving 42 subjects with varying degrees of body fat percentage
(7–44%), a positron emission tomography (PET) scan was employed
to detect changes in regional blood flowwithin the brain, depending
on hunger or satiety. Peak
and post-prandial increases in GLP-1 concentrations were associated
with increased blood flow to the left dorsolateral prefrontal cortex
(involved in satiety) and hypothalamus (involved in regulation of
food intake).
34
The prevalence of diabetes is higher in obese subjects and the
current epidemic of diabetes is partly driven by the increasing
incidence of obesity.
35,36
The action of GLP-1 analogues on satiety
makes them an attractive option for treatment of diabetes, because
it induces clinically significant weight loss. Most other therapies for
diabetes either cause weight gain or are weight neutral.
In animal studies, GLP-1 is shown to manifest neuroprotective
properties. In a rat model, administration of the DPP-4 inhibitor,
vildagliptin, protected from nerve fibre loss when compared with
untreated rats, suggesting a possible beneficial effect of incretin-
based therapies on the development and progression of diabetic
neuropathy.
37
Exenatide was also shown to promote neurogenesis
and normalise dopamine imbalance in a rodent model of Parkinson’s
disease.
38
Randomised controlled trials investigating whether the
neuro-protective effect is replicated in humans are required.
In animal models, injection of GLP-1 and its analogues show
positive effects on higher brain functions. Injection of liraglutide for
four to eight weeks in mice was associated with an improvement
in the recognition index, indicating an enhancement of memory.
39,40
In addition to an improvement in cognition, an anti-depressant-
like effect was noted in mice treated with exenatide.
41,42
A double-
blind human trial comparing the effect of exenatide versus placebo
on cognitive improvement in patients with Alzheimer’s disease is
currently ongoing (ClinicalTrials.gov identifier: NCT01255163). A
similar trial with liraglutide, investigating whether a change in intra-
cerebral amyloid deposits is seen in patients with Alzheimer’s disease
has completed (ClinicalTrials.gov identifier: NCT01469351). These
trials might broaden the clinical indications of GLP-1 analogues;
hence, the results are highly anticipated.
Renal effects of GLP-1
Intravenous infusion of GLP-1 in obese men enhances renal sodium
excretion and reduces glomerular hyperfiltration, suggesting an
action at the proximal renal tubule and a potential reno-protective
effect.
43
Natriuresis seems to be mediated by action on the sodium/
hydrogen exchanger in the proximal tubule.
24
DPP-4 inhibitors also
have natriuretic properties and might have a role in salt-sensitive
hypertension.
44
In vitro
studies indicate that GLP-1 may act as an anti-
inflammatory agent, protecting mesangial cells from the adverse
effects of advanced glycation products.
45
In a rat model, exenatide
administration for eight weeks ameliorated albuminuria,
glomerular hyper-filtration and glomerular hypertrophy. The
effect was independent of blood glucose lowering and changes
in blood pressure.
In vitro
experiments demonstrate activation of
the GLP-1 receptor in the kidney, thereby attenuating the effects
of proinflammatory cytokines.
46
Current management of diabetic nephropathy involves
aggressive management of glycaemia and hypertension, in addition
to blockade of the renin–angiotensin system. Currently, there are no
drugs targeting the inflammatory pathways implicated in diabetic
nephropathy. Human studies of GLP-1 based therapies with renal
endpoints are currently ongoing.
GLP-1 and the gastrointestinal tract
In a study involving healthy human volunteers, GLP-1 was infused
intravenously and its effect on gastric volume was evaluated using
single photon emission computer tomography (SPECT). It was
shown that GLP-1 increases gastric volumes and retards gastric
emptying.
47
The effect of GLP-1 on reducing gastric motility is
doserelated and is one of the contributors to the glucose-lowering
effect of incretin-based therapies.
48
A recent clinical trial indicates
that twice daily exenatide produces a more prominent decrease
in gastric emptying than once weekly, long-acting exenatide. This
suggests that continuous activation of the GLP-1 receptor in the
stomach may result in reducing the pharmacological response.
49
The most common adverse effects of GLP-1 analogues are
transient (usually within the first few weeks of therapy) nausea
and vomiting, possibly related to gastric distension. Although the
incidence of nausea may be as high as 25–30% when starting
liraglutide, only 5–10%of patients report gastrointestinal symptoms
after four weeks.
19
Up to 5% of patients may have persistent
symptoms requiring discontinuation of therapy.
18,19,50
GLP-1 and the exocrine pancreas
There is an ongoing debate about the possible effects of GLP-
1-based therapies on the exocrine pancreas, specifically the
risk of inducing acute pancreatitis and pancreatic cancer.
51–53
A
retrospective study of the FDA’s (US Food and Drug Administration)
database of reported adverse events notes that use of sitagliptin
or exenatide increases the odds ratio for pancreatitis six-fold.
54
