VOLUME 10 NUMBER 1 • MARCH 2013
15
SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
In patients with type 2 diabetes, regular physical activity is
associated with increased cardiovascular fitness, decreased insulin
resistance and improved glucose control, blood lipid profile and
blood pressure. It helps to maintain weight loss, decreases stress
and anxiety and improves general well-being. Patients should be
advised to perform at least 150 minutes of moderate-intensity
aerobic physical activity and, provided there are no contraindications,
resistance training three times per week.
4
Additional lifestyle advice
that may be beneficial for achieving and maintaining weight loss is
listed in Table 1.
Despite the health benefits of diet and exercise, weight loss with
lifestyle change alone is often modest and is difficult to achieve and
maintain.
33
An additional approach is to combine insulin with other insulin-
sparing treatments that do not exacerbate weight gain. In two
separate studies, metformin, when added to insulin, was able
to reduce insulin requirements by almost 30% within a year and
was associated with at least as good, or better control of HbA
1c
levels.
37,38
However, patients on metformin still continue to gain
weight, albeit in one study at a lower rate than those on insulin
monotherapy (mean 6.1 vs 7.6 kg;
p
= 0.02).
38
Incretin-based therapies
Recently a new class of medication has been introduced for the
treatment of type 2 diabetes. These incretin-based therapies
potentiate or mimic the actions of glucagon-like peptide 1 (GLP-1),
an incretin hormone that is released by the intestine shortly after
ingestion of food. GLP-1 has a potent blood glucose-lowering
action and inhibits glucagon release in a glucose-dependent
manner. It also induces weight loss by acting on receptors in the
central nervous system that induce perceptions of satiety regardless
of the presence of food in the gastric system.
39
In vivo
, the half-life
of GLP-1 is very short, because it is rapidly degraded by the enzyme
dipeptidyl peptidase-4 (DPP-4).
The incretin-based therapies include the oral DPP-4 inhibitors
(sitagliptin, saxagliptin and vildagliptin) and the GLP-1 agonists,
exenatide and liraglutide, which are injected subcutaneously.
All of these therapies reduce plasma glucose with a low risk of
hypoglycaemia, but they have different effects on body weight;
the DPP-4 inhibitors are weight neutral, whereas exenatide and
liraglutide are associated with weight loss.
5,40
Clinical studies have demonstrated that the GLP-1 agonists
significantly reduce HbA
1c
levels, both when administered as
monotherapy and in combination with oral antidiabetic drugs,
without increasing the risk of hypoglycaemia and with concomitant
weight loss.
5,13
When used as second-line therapy in combination
with metformin, these drugs reduce HbA
1c
levels to a greater degree
than sulphonylureas, glinides, thiazolidinediones, alpha-glucosidase
inhibitors and DPP-4 inhibitors, and to a degree comparable with
basal insulin and biphasic insulin.
13,41
In a recent meta-analysis comparing liraglutide to other
commonly used antidiabetic medications, including glimepiride,
rosiglitazone, glargine, exenatide and sitagliptin, the GLP-1 agonist
was found to be 2.0- to 10.5-fold more likely to achieve a composite
outcome of HbA
1c
< 7%, with no hypoglycaemia and no weight
gain.
42
Furthermore, liraglutide induced greater weight loss in
patients with higher BMI, primarily due to a decrease in abdominal
subcutaneous and visceral adipose tissue.
39,43
The addition of liraglutide to insulin therapy in obese, poorly
controlled type 2 diabetes patients has been compared to
intensification of insulin therapy.
44
Adding liraglutide was associated
with a reduction in HbA
1c
level that was comparable to increasing
the dose of insulin (–1.9 vs –1.77%,
p
> 0.05), but with a higher
percentage of patients achieving HbA
1c
≤ 7%, with no weight gain
and no hypoglycaemia (67 vs 19%,
p
< 0.001).
Body weight, waist circumference, body mass index and total daily
insulindosewere significantly decreasedafter the additionof liraglutide,
while all of these parameters increased significantly after increasing the
dose of insulin. Sixty-two per cent of patients in the liraglutide group
achieved at least 5% reduction in body weight. Severe hypoglycaemia
was reported in two patients in the insulin-intensification group and
none in the liraglutide group, while minor hypoglycaemic episodes
occurred in 31.0 and 11.9%, respectively (
p
= 0.033).
In another study, insulin detemir was added to therapy in patients
uncontrolled on metformin plus liraglutide (HbA
1c
≥ 7%).
45
After 26
weeks, HbA
1c
level was decreased by 0.5%, with 43% of patients
achieving HbA
1c
< 7%. Mean body weight was decreased by 0.16
kg. There were no episodes of severe hypoglycaemia after the
addition of insulin detemir, although minor hypoglycaemic events
were more common than in patients who did not receive insulin
(9.2 vs 1.3%). On the basis of this study, in 2012 the American
Food and Drug Administration (FDA) approved a label update for
liraglutide to include combination therapy with basal insulin for the
treatment of adults with type 2 diabetes.
46
When used in combination with basal insulin (with or without
metformin ± thiazolidinedione), exenatide was associated with
significant reductions in HbA
1c
level and postprandial glucose (with
or without a decrease in fasting plasma glucose), compared to
control groups receiving basal insulin with or without metformin
± thiazolidinedione. More patients in the GLP-1 agonist groups
reached target HbA
1c
≤ 7%. Furthermore, these results were achieved
with lower doses of insulin than in control groups and with mild,
infrequent or no additional risk of hypoglycaemia.
47
Body weight
increased in the control groups, but decreased or remained stable in
the exenatide groups.
Themost common adverse effects associatedwithGLP-1 agonists
are nausea, vomiting, diarrhoea, headache and constipation.
However, these gastrointestinal adverse effects tend to become less
frequent with continued use.
5,47
In addition to their metabolic benefits, GLP-1 agonist therapy
has also been shown to be associated with variable improvements
in systolic blood pressure, serum cholesterol and triglyceride levels
and cardiovascular biomarkers, including brain natriuretic peptide,
plasminogen activator-1 and high-sensitivity CRP.
42,47,48
The effect of
GLP-1 agonists on cardiovascular events is being studied in large,
long-term outcomes studies, which are ongoing.
Conclusion
Achieving adequate long-term control of plasma glucose remains
a problem in patients with type 2 diabetes. Almost all require
intensification of treatment over time, which is associated with
major challenges, including treatment-related adverse effects,
maintenance of patient compliance and adherence to treatment,
psychological co-morbidities and treatment-associated weight gain.
Involving the patient in treatment decisions and appropriate patient
education is essential to overcome some of these obstacles. Using
a GLP-1 agonist as add-on therapy has significant advantages,
including further reductions in HbA
1c
level and postprandial
glucose, while reducing basal insulin requirements. GLP-1 agonists
