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29th December 2021
Glucose-lowering drugs do not always address beta cell dysfunction
in type 2 diabetes, according to findings presented at last month’s
19th World Congress on Insulin Resistance, Diabetes and
Cardiovascular Disease. Ralph DeFronzo, Chief of the Diabetes
Division, UT Health San Antonio, argues that medication that protects
the beta cells should be first-line therapy – and not many anti-
diabetes drugs fulfil this requirement. Dr Susan Aldridge reports.
Very early on in the course of type 2 diabetes, the tissues of the body
become resistant to insulin and the beta cells respond by pumping
out more insulin. As long as beta cells maintain this high insulin-
secretory response, normal glucose tolerance and normal glucose are
maintained – but the beta cell becomes exhausted. “If we had a way
of maintaining beta cell function, we’d keep HbA1c in normal range.
Overt diabetes does not occur in the absence of progressive beta cell
failure,” said Professor DeFronzo. “Once type 2 diabetes is actually
diagnosed, 90% of the insulin-producing beta cells in the pancreas
has actually stopped functioning.”
The UK Prospective Diabetes Study (UKPDS), which was the first trial
to show that a decrease in HbA1c decreases the risk of
complications, compared the effect of lifestyle change, metformin or
glibenclamide (a sulphonylurea). HbA1cdecreased in all groups at the
start of the study, but, over the course of 15 years, it crept back up
again and six years into the study, it was back where it started – at
around 7%. By 15 years, HbA1chad increased even further. As the
study went on, therapy was intensified in response to the rise in
HbA1c, so that by the 15-year mark, many were on insulin too and
HbA1c was, on average, 8.6%. “The UKPDS taught us about
complications but also that sulphonylureas and metformin don’t work
long term, because they don’t have an effect on the beta cell.” A
similar pattern was found in the GRADE study, which compared
glimepiride, sitagliptin, liraglutide and insulin glargine. After an initial
dip in HbA1c, it was back up to 7% at year 4. “These findings are all
because of ongoing beta cell failure,” he said.
Similar results were seen with a trial of the GLP-1 receptor agonist
exenatide, while another study showed that even a single dose of
liraglutide restores beta cell response to hyperglycaemia. “The GLP-1
receptor agonists also preserve beta cell function, as well as doing
other good things.” Further evidence comes from a study comparing
C-peptide secretion on exenatide and insulin glargine. Levels were
around three times higher on exenatide after three years.
“In conclusion, there are only two drugs that are going to preserve
your beta cells on a long- term basis – pioglitazone and GLP-1
receptor agonists. These should be first-line therapy,” said Professor
DeFronzo. “Pioglitazone may be controversial, but in my opinion, it’s a
fantastic drug. Even with advanced type 2 diabetes, these drugs will
work.”
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