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Cardio Diabetes Medicine 2017 447

total of 63.2% of the patients in the liraglutide group pancreatic lipase by cetilistat reduces the conversion
as compared with 27.1% in the placebo group lost of TGs into free fatty acids, and thus the TGs are
at least 5% of their body weight (P<0.001), Other excreted unchanged in the urine. In a 12-week study,
benefits in addition to weight loss are improvements weight loss of 3.3–4.1 kg (placebo not available) was
in glycaemic control, blood pressure and lipids. demonstrated.
Liraglutide 3.0 mg was generally well tolerated, with Most common side effects reported as
the most common adverse effect being nausea and gastrointestinal-related (38,39). As a result of phase
diarrhea during the first few weeks of treatment. III data, cetilistat has been approved in Japan since
Incidences of pancreatitis were low, although events September 2013; however, it has not yet been filed
were reported more frequently with liraglutide 3.0 for approval in the USA and Europe.
mg [3.1 events/100 patient-years of expo- sure (PYE)
and 0.4 events per 100 patient-years at risk (PYR),
respectively] than with placebo (1.4 events/100 PYE Belonarib
and < 0.1 events/100 PYR, respectively). Belonarib is administered subcutaneously and that
acts via inhibition of methionine amino peptidase 2
Based on the results of phase III SCALE clinical trial (MetAP2) (41).
programme, the FDA approved liraglutide 3.0 mg in
December 2014 as an adjunct to a reduced-calorie In a 12-week, phase II study, participants receiving
diet and increased exercise in adult patients with a belonarib 0.6 mg, 1.2 mg or 2.4 mg lost 5.5 kg, 6.9
2
2
BMI of ≥ 30 kg/m , or ≥ 27 kg/m in the presence of kg or 10.9 kg, respectively, compared to 0.4 kg
at least one weight-related comorbid condition (98).). in the placebo group (p < 0.001) (108). Belonarib
Liraglutide is the first once daily GLP-1 analogue was generally well tolerated, although more sleep
to be licensed for treatment of obesity in the USA disturbances and gastrointestinal AEs were reported
and Europe; post-marketing surveillance studies are in the belonarib group compared to the placebo
ongoing to assess long-term safety. groups. These events were generally dose related;
mild-to moderate in severity, transient Phase III trials
Orlistat are ongoing.
Orlistat was the only FDA approved anti-obesity
drug until 2012. It acts locally to potently inhibit Bupropion/Zonisamide
pancreatic and gastric lipase and thus the hydrolysis Bupropion/zonisamide (a mitochondrial carbonic
of triglycerides. This results in lower rate of fat anhydrase inhibitor) is another combination
absorption by almost 30 percent. Clinical trials with pharmacotherapy for obesity (43). Currently phase II,
orlistat demonstrated significantly greater weight loss preliminary findings in 18 patients have demonstrated
compared with placebo [5.8 kg vs. 3.0 kg; p < 0.001 a 7.2kg weight loss with bupropion/zonisamide vs.
(34]; however, a meta-analysis of up to 15 trials with 2.9 kg with zonisamide alone over 12 weeks (44),
orlistat revealed an overall mean placebo-adjusted with the most frequent adverse effect as headache,
weight loss of only around 2.9 kg (2.9%) with up to nausea and insomnia.
4 years’ treatment. Major safety concern has arisen
with orlistat is its potential link with liver toxicity. Tesofensine
However, a recent meta analysis of its use in the Tesofensine is a triple monoamine reuptake inhibitor
UK demonstrated no increased risk of liver toxicity. inhibits reuptake of serotonin, noradrenaline, and
Gastrointestinal side effects such as flatulence dopamine and thereby suppresses appetite and
steatorrhea abdominal pain and discomfort, oily or increases thermogenesis. The clinical Phase 2b trial
liquid stool and faecal urgency are very common; (TIPO-1), reported in The Lancet, showed levels of
Long-term tolerability remains problematic, overall weight loss over a six-month period that were of high
median discontinuation rate in most studies for clinical relevance, Patients lost an average of 12.8 kg
orlistat was 30%. Other Drugs in Clinical Development on a 1 mg dose, 11.3 kg on a 0.5 mg dose and 6.7 kg
Cetilistat on a 0.25 mg dose compared with a 2.2 kg loss in
the placebo group.
Cetilistat, It is a pancreatic lipase inhibitor that is
undergoing phase III clinical trials, works in a manner The drug was fairly tolerated, adeverse effects are dry
similar to orlistat, Pancreatic lipase is a key enzyme mouth, dizziness, constipation, abdominal pain, and
that causes breakdown of TGs into free fatty acids nausea being the common side effects. It received
that are absorbed in the intestine. Inhibition of approval to initiate a Phase 3 study for tesofensine
in obese Mexican patients. received in April 2017.

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