New data on Novartis’s nateglinide, a novel hypoglycaemic agent for type
2 diabetes, were reported this week at the European Association for the Study
of Diabetes congress in Jerusalem.
Nateglinide is in late stage clinical trials. It is an amino acid derivative
and is reported to have a fast onset and short duration of action. It is being
developed specifically for use to restore “early phase” insulin secretion
after a meal and so prevent the postprandial glucose “peak” that occurs
in patients with diabetes.
Because of its short action, Novartis hopes that there will be minimal overall
exposure to insulin, and minimal risk of hypoglycaemia.
One study reported at the EASD was a comparison of nateglinide with glibenclamide
in 152 patients. The two drugs were reported to reduce overall glucose exposure
to a similar degree but nateglinide primarily reduced postprandial glucose excursions
(glucose peaks) while glibenclamide primarily reduced fasting glucose levels.
Overall insulin exposure was higher in the sulphonylurea treated patients. The
study was reported by Dr Priscilla Hollander (Baylor University Medical Centre,
Dallas) who said that the data indicated that the new drug produced a more “physiological”
type of insulin response.
In another study reported at EASD, nateglinide was used in combination with
metformin. While nateglinide (like sulphonylureas) acts on beta cell dysfunction,
metformin targets insulin resistance, the other fundamental defect in type 2
diabetes. The combination of nateglinide with metformin was more effective than
either drug alone in reducing glycosylated haemoglobin levels. These data were
reported by Professor Edward Horton (professor of medicine, Harvard Medical
School) who said that they showed the value of combining medications with complementary
modes of action.
Speaking to The Journal after a recent Novartis meeting, Professor Anthony Barnett
(professor of diabetology, Birmingham Heartlands hospital) said that the early
nateglinide clinical data were promising. Publication of peer-reviewed data
was now needed, together with long-term studies, he said.
Professor Barnett said that there was increasing evidence of a relationship
between postprandial hyperglycaemia and the risk of macrovascular disease (heart
attack and stroke), the main cause of morbidity and mortality in patients with
diabetes. In the large UK Prospective Diabetes Study (UKPDS), improved glucose
control had been associated with a reduction in microvascular disease (retinopathy,
nephropathy, etc) but there had been little effect on macrovascular disease.
The important question now was whether restoring “early phase” insulin
secretion would be able to reduce cardiovascular risk.
Commenting on the metformin/ nateglinide combination data, Professor Barnett
said that a combination of the new drug with rosiglitazone could be even more
potent, since rosiglitazone was a more effective insulin sensitiser than metformin.
Nateglinide is not the first drug to be developed for use before meals to target
postprandial glucose. Novo Nordisk’s repaglinide (Novonorm) is already
marketed for this purpose. Professor Barnett said that repaglinide did have
a more rapid onset of action than standard drugs, such as the sulphonylureas,
but it was longer acting than nateglinide.
Novo Nordisk said on September 19 that a study presented at EASD found that
patients taking repaglinide reported improved quality of life. This was because
of the flexibility of treatment, which allowed them to miss or delay a meal,
the company said.