Cotadutide, an experimental therapy that alters
glucose and lipid metabolism, led to weight loss and improvements in metabolic,
cardiovascular and liver fibrosis biomarkers in overweight people with diabetes
and fatty liver disease, but nausea was a common side effect, according to a report at the 2020 Digital
International Liver Congress.
Non-alcoholic fatty liver disease (NAFLD) and its more
severe form, non-alcoholic steatohepatitis (NASH), are increasingly recognised as manifestations of the metabolic syndrome,
characterised by abdominal obesity, high blood pressure, elevated blood sugar
and abnormal cholesterol or triglyceride levels.
The build-up of fat in the liver
triggers inflammation, which over time can lead to fibrosis, cirrhosis, liver
cancer and liver failure. There are currently no approved medications,
and lifestyle modification and weight
loss are the mainstays of NAFLD/NASH management. The development of NAFLD/NASH therapies
has proved challenging; several approaches aim to improve liver health
indirectly by targeting metabolic abnormalities associated with fatty liver
Abnormal fat deposits in the liver.
Ambery of AstraZeneca presented findings from a phase IIb clinical trial
testing cotadutide in people with overweight or obesity, diabetes and signs of
fatty liver disease.
is a dual receptor agonist that modifies the activity of glucagon and
glucagon-like peptide-1 (GLP-1). These hormones affect glucose and lipid metabolism,
reduce liver fat build-up and increase bile acid production. Previous research
showed that the drug improved liver steatosis (fat accumulation) and
inflammation in mice fed a fatty diet.
study included 834 people who were overweight or obese and had type 2 diabetes
treated with metformin. More than half were women and the median age was
approximately 57. The median body mass index was about 35 (30 is the cut-off
for obesity). More than 90% had a fatty liver index score of at least 60 (indicating
a high likelihood of having NAFLD) and ALT and AST liver enzymes were less than
three times the upper limit of the normal range.
were randomly assigned to receive one of three doses of cotadutide (100, 200 or
300mcg) via once-daily subcutaneous injection, daily injections of the diabetes
drug liraglutide (a GLP-1 agonist) or a placebo.
weeks of treatment, people assigned to all three doses of cotadutide and
liraglutide lost significantly more weight than those in the placebo arm. Those
in the high-dose cotadutide group saw a weight reduction of 5%, which is
considered clinically beneficial.
cotadutide doses and liraglutide led to significant reductions in HbA1c levels,
a measure of blood sugar levels over two to three months, compared with the
taking cotadutide saw greater reductions in ALT and AST liver enzyme levels,
with significant decreases in the high-dose group compared with liraglutide or
the intermediate dose of cotadutide and liraglutide led to similar weight loss,
those taking cotadutide had significantly greater declines in ALT and AST.
Ambery noted that these reductions were independent of weight loss, and
therefore could not be attributed to people not eating as much due to nausea or
losing weight due to vomiting and diarrhoea.
doses of cotadutide and liraglutide reduced NAFLD fibrosis scores, but the
difference was only significant for the high-dose group. The intermediate and
high doses also led to significant reductions in FIB-4 scores, a noninvasive
the intermediate and high doses of cotadutide significantly reduced
triglyceride levels, while smaller reductions were seen with the lowest dose
was generally safe, but side effects were common. Nausea occurred in 23%, 33%
and 41% of those taking the low, intermediate and high doses of cotadutide,
compared with 16% with liraglutide and 11% with the placebo. Rates of vomiting
were 10%, 20% and 17% in the cotadutide groups versus 3% with liraglutide and
5% with the placebo. The corresponding rates of diarrhoea were 13%, 19%, 11%,
4% and 9%.
one in five people (22%) taking the high dose of cotadutide stopped treatment
due to adverse events, as did 13% taking the low dose and 15% taking the
intermediate dose, compared with 2% and 5% in the liraglutide and placebo
"The improvements seen in the NAFLD
fibrosis score and FIB-4 are encouraging, and support the need for prospective
clinical trials with cotadutide in patients with NASH," Ambery said. He pointed out that nausea and vomiting
declined substantially over time in all dose groups.
II study of cotadutide for people with obesity and NASH is underway using an
even higher dose with an optimized titration schedule – for example, a
prolonged dosing interval – in an effort to reduce side effects.