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Incretin Mimetics
Table 1: Summary of Liraglutide Clinical Trials – Liraglutide Effect and Action in Diabetes (LEAD) Trials
Study/Publication Description/Baseline Data Comparators Δ HbA
1c
(%) Δ SBP (mmHg)
LEAD 1
20
26-week RCT, 1,018 patients on SU Addition of:
HbA
1c
: 8.4% Liraglutide 1.2mg -1.08 -2.6
Bodyweight: 81.6kg Liraglutide 1.8mg -1.13 -2.8
Placebo +0.23 -2.3
Rosiglitazone 4mg -0.44 -0.9
LEAD 2
19
26-week RCT, 1,091 patients on MET Addition of:
HbA
1c
: 8.4% Liraglutide 1.2mg -0.97 -2.8
Bodyweight: 88.6kg Liraglutide 1.8mg -1.00 -2.3
Placebo +0.09 -1.8
Glimepiride 4mg -0.98 +0.4
LEAD 3
18
52-week RCT, 746 patients, approximately one- Monotherapy:
third OAD-naïve and two-thirds with up to 50% Liraglutide 1.2mg -0.84 -2.1
maximum dose of OAD monotherapy Liraglutide 1.8mg -1.14 -3.6
HbA
1c
: 8.2% Glimepiride 8mg -0.51 -0.7
Bodyweight: 92.6kg
LEAD 4
22
26-week RCT, 533 Patients on MET + TZD Addition of:
HbA
1c
: 8.5% Liraglutide 1.2mg -1.48 -6.7
Bodyweight: 97.0kg Liraglutide 1.8mg -1.48 -5.6
Placebo -0.54 -1.1
LEAD 5
23
26-week RCT, 581 patients on MET + SU Addition of:
HbA
1c
: 8.2% Liraglutide 1.8mg -1.33 -4.0
Bodyweight: 85.4kg Placebo -0.24 -1.4
Insulin glargine -1.09 +0.5
LEAD 6
21
26-week RCT, 464 patients on MET, SU Addition of:
or combination Liraglutide 1.8mg -1.12 -2.5
HbA
1c
: 8.2% Exenatide 10µg BID -0.79 -2.0
Bodyweight: 93.5kg
BID = twice daily; MET = metformin; OAD = oral antidiabetic agent; RCT = randomised controlled trial; SBP = systolic blood pressure; SU = sulphonylurea; TZD = thiazolidinedione.
the two treatment approaches.
27
However, there are some concerns observed in the first 16 weeks was maintained over the 52-week
that DPP-4 inhibitors may be immunomodulatory, and a meta-analysis study.
18
This maintenance of weight loss is confirmed by exenatide
of sitagliptin safety data suggested a 34% increased relative risk of studies that demonstrated maintenance of weight loss over a two-year
developing infection versus controls (odds ratio [OR] 1.34, 95% period.
35
However, patients in all BMI subgroups experienced weight
confidence interval [CI] 1.10–1.64; p=0.004).
30
loss with liraglutide, with the greatest decrease in bodyweight occurring
in subjects with a high baseline BMI (≥35kg/m
2
). By contrast, the DPP-4
Patients who receive repeated doses of recombinant protein inhibitors sitagliptin and vildagliptin are weight-neutral.
27,36,37
therapeutics may develop neutralising antibodies, which in certain
cases result in a reduction in product efficacy.
31
However, although a Blood Pressure
minority of patients (4–13%) in the LEAD studies developed liraglutide Individuals with type 2 diabetes face an increased risk of hypertension
antibodies, there was no evidence that this affected the clinical efficacy compared with healthy individuals.
38
Hypertension raises the risk of CV
of liraglutide. Higher levels of antibody induction were observed in three disease, and treatments that can reduce hypertension can have a
exenatide trials. Low-titre exenatide antibodies were observed in 38% of profound benefit. For example, a reduction of 5.6mmHg in systolic
patients (366 of 963). An additional 6% of patients (58 of 963) had high- blood pressure (SBP) has been shown to reduce death from CV disease
titre antibodies, which caused a loss of exenatide’s glycaemic effect in by 18% in patients with type 2 diabetes.
39
SBP reductions of this
3% of patients.
11
magnitude have been reported with liraglutide: across the LEAD trials,
SBP was reduced by 2.3–5.6mmHg with the 1.8mg dose, suggesting
Weight that liraglutide could have a very positive impact on reducing CV risks
Obesity, together with dyslipidaemia, coagulation abnormalities and in individuals with diabetes. Blood pressure reductions have been
hypertension, forms the basis for the dramatic increase in observed in trials of exenatide versus placebo;
35,40,41
in one trial,
cardiovascular (CV) risk in individuals with type 2 diabetes. For example, reductions in SBP of 3.7 and 0.3mmHg were observed with exenatide
a five-unit increment in body mass index (BMI) can increase coronary 10µg twice daily (BID) and placebo, respectively (p=0.010 for combined
heart disease (CHD) mortality by 30%.
32
In addition, an individual’s exenatide group versus placebo). By contrast, blood pressure reduction
concern about weight gain may be a barrier to intensifying diabetes has not yet been widely studied with DPP-4 inhibitors.
treatment.
33,34
Human GLP-1 induces feelings of satiety and delays
gastric emptying, which suggests benefits in terms of weight reduction Pancreatic Islet and β-cell Function
(see Table 2). Liraglutide treatment was associated with weight loss Type 2 diabetes is characterised by a progressive loss of pancreatic
of around 2–3kg, which was significantly better than the weight gains of β-cell function, which leads to increasing impairment of insulin
1–2kg observed with comparator treatments in LEAD 1–5 (see Table 2). secretion.
41
Liraglutide has been shown to increase β-cell mass and
In LEAD 6, an equivalent weight loss of 2–3kg was seen in patients on decrease apoptosis in in vitro and in vivo rodent models.
42,43
In human
liraglutide and exenatide (see Table 2). In LEAD 3, the weight loss studies, liraglutide treatment is also associated with improvements in
40 EUROPEAN ENDOCRINOLOGY
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