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SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
VOLUME 8 NUMBER 2 • JUNE 2011
71
that liraglutide can be used in combination with metformin and/
or SU and in combination with metformin and TZD (Table 3).
46
It is
administered as a once-daily subcutaneous injection independent
of mealtimes (Table 3).
46
Liraglutide is associated with significant
improvements in HbA
1C
levels (0.8–1.5%) and weight loss of up
to 2.8 kg compared with baseline, in the majority of phase III
studies.
64–68
However, when combined with glimepiride, treatment
with liraglutide 1.2 mg resulted in minor weight gain of 0.3 kg.
68
Interestingly, most of the observed weight loss has been associated
with a reduction in visceral fat, as shown by dual-energy X-ray
absorptiometry in a substudy of 160 type 2 diabetes patients
treated with liraglutide as monotherapy (liraglutide is currently not
licensed for monotherapy use in the UK) or in combination with
metformin.
69
Furthermore, liraglutide has been shown to reduce
systolic blood pressure across the majority of phase III trials, which
may imply a beneficial effect on cardiovascular outcomes.
64–68
Improvements in surrogate markers of beta-cell function have
also been documented.
67,68,70,71
Liraglutide has been reported to
reduce HbA
1C
levels more than exenatide (1.12 vs 0.79%,
p
<
0.0001) with similar weight reductions (–3.2 vs –2.9 kg), when
added to metformin or SU.
66
Moreover, in type 2 diabetes patients
inadequately controlled on metformin, the addition of liraglutide
induced greater lowering of HbA
1C
levels compared with addition
of sitagliptin (HbA
1C
–1.24 and –1.5% for liraglutide 1.2 and 1.8
mg, respectively, vs –0.9%;
p
<
0.0001) and also led to greater
weight loss (–2.86 and –3.38 kg for liraglutide 1.2 and 1.8 mg,
respectively, vs –0.96 kg;
p
<
0.0001).
72
The most frequent side
effects of liraglutide, as with exenatide, are nausea and vomiting.
The associated nausea is generally transient and does not appear to
account for the weight loss effect. The incidence of hypoglycaemia
is low with liraglutide, but may be increased when the drug is
combined with SUs.
46
Of note, seven cases of pancreatitis were
reported among 4 257 patients treated with liraglutide during the
phase II and phase III development programme, compared with
one case among the 2 381 patients in the comparator groups,
representing a 4:1 imbalance between liraglutide and comparators
after adjustment for patient-years of exposure.
73
However, as
the risk of pancreatitis is increased in type 2 diabetes patients
compared with the general population, no causal relationship has
been established between liraglutide and pancreatitis at this time
due to the small number of reported cases. In view of the existing
evidence, additional data are required to clarify the association
between GLP-1 receptor agonists and pancreatitis.
74
DPP-4 inhibitors
Three DPP-4 inhibitors – sitagliptin, vildagliptin and saxagliptin
– are currently licensed (Table 3). Sitagliptin, as monotherapy or
as add-on to other oral anti-diabetic drugs, has been reported to
reduce HbA
1C
levels by 0.5–1.9%, with neutral effects on body
weight in the majority of clinical trials.
75–79
Of note, recent data
have demonstrated that adding sitagliptin to insulin therapy, with
or without concomitant metformin, improves glycaemic control –
with a 0.6% reduction in HbA
1C
compared with placebo (
p
<
0.001)
– and is generally well tolerated.
80
Hence, the EMA has extended
the license for sitagliptin to be used as add-on to insulin, with or
without metformin, when diet and exercise plus insulin therapy do
not provide adequate glycaemic control.
47
Vildagliptin as adjuvant
therapy to oral antidiabetic drugs leads to a 0.66–1.0% reduction
in HbA
1C
levels, also without major changes in body weight.
81–85
Similarly, saxagliptin, as monotherapy and in combination with
other oral therapy, has been demonstrated to reduce HbA
1C
levels
by 0.5–2.5%, while no apparent effect on body weight was
reported.
49
These agents are generally well tolerated and do not
appear to significantly increase the risk of gastrointestinal side
effects.
63
Of note, 88 post-marketing cases of acute pancreatitis
in patients using sitagliptin, with or without metformin, have been
reported to the FDA between October 2006 and February 2009.
86
In 2009 NICE issued a partial update of the 2008 clinical
guidelines for type 2 diabetes, addressing the use of newer agents
for glycaemic control.
21,60
According to these recommendations,
sitagliptin or vildagliptin may be preferable to TZDs when further
weight gain is expected to cause or exacerbate significant problems
associated with a high BMI. Thus, the weight-neutral effect of
DPP-4 inhibitors may offer an additional option to support weight-
management strategies in obese type 2 diabetes patients who
require intensification of glucose-lowering treatment.
Conclusions
Managing obesity in type 2 diabetes patients poses a difficult
challenge. Intensification of glucose-lowering therapy is frequently
associated with weight gain. This adverse effect can hamper
glycaemic control by discouraging adherence and delaying required
adjustments in treatment regimens. To overcome weight gain and
reduce the requirements for pharmacotherapy of hyperglycaemia,
a weight-management plan must always be integrated into the
treatment strategy for obese patients with type 2 diabetes. Lifestyle
modifications for weight loss are first-line interventions that must
complement all others. Orlistat may be considered early in the
weight-management plan, while bariatric surgery could be offered
as a final option. A relatively new option, incretin-based treatments,
may be appropriate add-on therapy for selected obese type 2
diabetes patients with suboptimal glycaemic control, in order to
both achieve glycaemic goals and support weight loss. It is likely
that the position of incretin-based therapies in the management
Key messages
•
Obesity is a chronic condition and weight-loss interventions
should be offered to all obese patients, with or without
type 2 diabetes, focusing on realistic goals and lifelong
management
•
Effective weight management is crucial for obese patients
with type 2 diabetes and even a 5–10% sustained weight
loss can produce multiple metabolic benefits
•
Lifestyle modification should be the first step in weight
management and should complement all other interventions
•
Orlistat should be considered in obese patients with type 2
diabetes and bariatric surgery should be offered in selected
patients as a final option
•
Incretin-based therapies can be added to the treatment
regimen of obese type 2 diabetic patients with suboptimal
glycaemic control to improve hyperglycaemia and support
weight management
