New data presented at the European Association for the Study of Diabetes meeting in Rome, prove for the first time how Novartis’ oral dipeptidyl peptidase 4 (DPP-4) inhibitor for type 2 diabetes, Galvus, can lower blood sugar without the risk of producing hypoglycaemic attacks (hypos).

The finding from a study by Dr Bo Ahren of Lund University, Sweden, has major importance for DPP-4 inhibitors supporting a possible future role in attenuating the risk of hypos from insulin. ”Hypos have devastating, sometimes fatal, effects on patients’ health so drugs that help other agents lower blood sugar but avoid hypo’s would be hugely popular in type 2 diabetes therapy,” commented Professor Anthony Barnett of Birmingham University, UK. “Treatments leading to severe hypos terrify patients who are then reluctant to continue taking them to control their hyperglycaemia adequately. Doctors don’t like prescribing them either,” he added.

A risk of hypos is linked to insulin but also to oral drugs, notably sulphonylureas (SUs). A large number of hypos were seen in the intensive treatment arm of the ACCORD trial which experienced excess deaths making clinicians wary of intensive and rapid blood glucose lowering especially in elderly, frail patients.

Dr Ahren’s study at EASD used newly-diagnosed elderly type 2 diabetic patients given Galvus (vildagliptin) 100mg once daily or placebo in a 4-week cross-over period. Patients underwent meal tests and glycaemic clamps at different blood sugar levels to compare how treatment or placebo influenced the response of insulin, glucagon, cortisol, the C-peptide and pancreatic polypetide as well as the autonomic nervous system hormones epinephrine and norepinephrine to different blood sugar states. The results showed Galvus but not placebo enabled both the beta and alpha cells of the pancreas to sense the level of glycaemia and regulate insulin and glucagon in response to high or low blood sugar levels accordingly. Galvus may stimulate the autonomic nervous system to play a role in this, adds Dr Ahren.

DPP-4 inhibitors and other antidiabetic treatments that act by increasing incretin hormones, especially glucagon-like peptide-1 agonists, have been found not to increase the frequency of hypos when added to antidiabetic drugs that can cause them. Earlier data from a study by Fonseca published last year in Diabetologia showed adding Galvus to high-dose insulin actually reduced the number of hypo’s compared to insulin used alone.

So far only incretin-based therapies appear to have the potential of achieving this. Other DPP-4 inhibitors such as Merck & Co’s Januvia (sitagliptin) and Takeda’s alogliptin are now being or have been investigated alongside insulin to try and replicate the results seen with Galvus. Prof Barnett this week urged DPP-4 manufacturers to “hammer the point home that their drugs can stimulate glucagon to help prevent hypos. If they do the studies to get their drugs licensed for use with insulin they will make a fortune,” he predicted. Durability studies to show advantages persist out to three to five years are needed, he added. “But if their potential is realised, DPP-4 inhibitors could be the holy grail of antidiabetic therapy.”

DPP-4 inhibitors are the best tolerated of all antidiabetic drugs, he added. They have neutral effects on weight and few side effects; the main one is a tendency to nasopharyngitis in some patients.

Other data on Galvus at EASD included results from separate studies showing non-inferiority to the SU glimepiride and to thiazolidinediones and pooled safety data showing no concerns with either cardiovascular or renal safety.

GALIANT study
The non-inferiority study against TZDs was the 12-week GALIANT study involving more than 2,400 patients treated by primary care physicians which showed the efficacy of Galvus 100mg once-daily in reducing glycated haemoglobin was non-inferior to that of TZDs in patients with type 2 diabetes inadequately controlled by metformin alone and had additional advantages; Galvus-treated patients lost weight, whereas those on TZDs put on weight.

One-year interim data from the comparison against glimepiride in 2,789 patients were presented during a Novartis-sponsored symposium. Results comparing Galvus 50mg bd plus metformin against glimepiride up to 6mg once-daily plus metformin showed no significant difference in efficacy regarding either glycated haemoglobin (HbA1c) or fasting blood glucose. Patients gained weight with glimepiride but lost it with Galvus, their lipid profile improved with Galvus but deteriorated with glimepiride and there was a 10-fold difference in the incidence of severe hypos (10 with glimepiride vs none with Galvus).

Promising Eucreas data
Also presented during the company-sponsored symposium were data from an 1,179-patient study comparing Eucreas, the single pill combination of vildagliptin 50mg plus either 500mg or 1,000mg metformin twice daily against the two drug components administered as separate tablets. Results showed the combination pill produced superior efficacy and actually reduced the amount of gastrointestinal side effects seen with metformin alone

Safety data presented at EASD include a pooled analysis from approximately 6,000 patients demonstrating a lower overall incidence of cardiovascular and cerebrovascular events for Galvus than placebo. A separate analysis of pooled data from over 1,400 Type 2 diabetes patients with mild-to-moderate renal impairment showed no adverse changes in renal function following long-term treatment with the drug and comparable efficacy was seen in patients with mild renal impairment compared to those with normal renal function. The drug is not approved for patients with moderate or severe renal impairment in Europe.

Galvus was the second DPP-4 inhibitor to gain approval in Europe after Merck’s Januvia, though Novartis gained European approval for its combined pill Eucreas ahead of Merck’s Janumet. Takeda’s alogliptin and Bristol-Myers Squibb/AstraZeneca’s saxagliptin are awaiting approval. Alogliptin was submitted to the FDA in January this year and saxagliptin at the end of June.

Novartis’ licence for Galvus has been held up in the USA pending completion of further studies in patients with hepatic or renal impairment. The company said this week: “In the US some small clinical studies have started amid discussions with the FDA on overall steps needed for approval after an "approvable letter" in February 2007. However, resubmission for US approval is not planned at this time.” By Olwen Glynn Owen in Rome