- Aust Prescr 2010;33:89-95
- 1 June 2010
- DOI: 10.18773/austprescr.2010.048
Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
50 mg tablets
Approved indication: type 2 diabetes
Australian Medicines Handbook section 10.1.3
Patients with type 2 diabetes often need more than one drug to control their blood glucose. When first-line treatment fails, the incretin mimetics and enhancers are a class of drugs which can be added to treatment (see Aust Prescr 2008;31:102-8). Within this class are the inhibitors of dipeptidyl peptidase 4 (DPP4) such as sitagliptin. These drugs block incretin metabolism and this leads to reductions in blood glucose concentrations.
Vildagliptin is a DPP4 inhibitor which is taken twice daily with metformin or a thiazolidinedione and once daily with a sulfonylurea. A 50 mg dose will inhibit most DPP4 activity for at least 12 hours. Most of the dose is converted to inactive metabolites. This metabolism does not involve the cytochrome P450 system so the potential for metabolic drug interactions is reduced. The elimination half-life is three hours with most of the metabolites being excreted in the urine. Vildagliptin is not recommended for patients with hepatic or moderate or severe renal impairment.
A systematic review which included 14 trials of vildagliptin involving 6121 patients concluded that treatment reduces glycated haemoglobin (HbA1c) by 0.6%.1 Several studies have investigated if this makes a significant difference when vildagliptin is added to other drugs.
Vildagliptin 50 mg daily was added to the treatment of 56 people whose diabetes was not completely controlled by metformin. After 12 weeks their mean HbA1c had reduced by 0.6% from a baseline of 7.7%. There was no change in control in 51 other patients who were given a placebo to take with their metformin. Some of the patients continued in an extension of the trial with 32 of the vildagliptin group and 26 of the placebo group completing one year of treatment. There was no significant change in the vildagliptin group, but HbA1c increased in the placebo group so that there was a difference of 1.1% between the groups after a year. An HbA1c below 7% was achieved by 41.7% of those who added vildagliptin, but only 10.7% of those who added a placebo.2
Another trial studied vildagliptin 100 mg, as well as 50 mg, as an addition to treatment with metformin. After 24 weeks the HbA1c concentration had fallen by 0.9% in the 185 people randomised to add 50 mg twice daily, by 0.5% in the 177 randomised to add 50 mg once daily, and increased by 0.2% in the 182 randomised to add a placebo. The proportion of patients achieving an HbA1c under 7% depended on their baseline concentrations. If the baseline HbA1c was greater than 8.5%, it was only reduced below 7% in 16.3% of patients given vildagliptin 100 mg, 7.5% of those given 50 mg and 2.1% of those given placebo.3
When type 2 diabetes is not controlled by metformin alone a sulfonylurea can be added. This approach has been compared with adding vildagliptin in a study of 2789 patients. There were 1396 who were randomised to add vildagliptin 50 mg twice daily and 1393 who were randomised to add glimepiride. After 52 weeks the mean reduction in HbA1c was 0.44% with vildagliptin and 0.53% with glimepiride. From a mean baseline of 7.3%, a target HbA1c of under 7% was reached by 54% of the vildagliptin group and 56% of the glimepiride group.4
Vildagliptin has also been added to the treatment of patients with diabetes which was inadequately controlled by a sulfonylurea. Their mean HbA1c was 8.5%.While 170 patients were randomised to add vildagliptin 50 mg once daily and 169 to add vildagliptin 50 mg twice daily, another 176 patients were given a placebo. All the patients also took glimepiride. After 24 weeks the mean HbA1c declined 0.58% with vildagliptin 50 mg and 0.63% with vildagliptin 100 mg while it increased by 0.07% in the placebo group. Only 12% of the patients in the placebo group achieved an HbA1c below 7% compared to 21% of the vildagliptin 50 mg group and 25% of the 100 mg group. As there was no significant advantage with the higher dose, the recommended daily dose of vildagliptin, in combination with a sulfonylurea, is 50 mg.5
Although monotherapy with a thiazolidinedione is not the usual first-line therapy, a trial, in 463 people with type 2 diabetes, has studied the effect of adding vildagliptin to treatment with pioglitazone. After 24 weeks, adding vildagliptin 50 mg once daily reduced the mean HbA1c by 0.8%, twice daily reduced it by 1%, while placebo reduced it by 0.3%. The HbA1c fell below 7% in 29% of those given 50 mg, 36% of those given 100 mg and 15% of those given a placebo.6
In trials of monotherapy the incidence of adverse events has been similar for vildagliptin and placebo. However, the frequency of infections (1.4% vs 0.3%) and neurological symptoms (0.9% vs 0.6%) was greater with vildagliptin than with placebo. Tremor, dizziness and headache are common when vildagliptin is given with metformin or a sulfonylurea. Peripheral oedema is more frequent with vildagliptin, than with placebo, when added to treatment with a thiazolidinedione.6 Adding vildagliptin to other oral hypoglycaemic drugs can increase the risk of hypoglycaemia. The frequency with glimepiride is 1.2% and 1% with metformin. Hypoglycaemia is more likely to occur if glimepiride, rather than vildagliptin, is combined with metformin.4 There have been rare cases of angioedema and hepatitis during treatment with vildagliptin. Liver function should be checked before and during treatment. The patient's renal function should also be checked before treatment with vildagliptin.
In animal studies vildagliptin has caused problems with skin ulceration and cardiac conduction, while the significance in humans is unknown. Animal studies also show increased mammary tumours at high doses.
Sulfonylureas can cause patients to gain weight and there was a significant difference between the weight of patients who added glimepiride compared to those who added vildagliptin to treatment with metformin. However, over a year the weight of the patients taking vildagliptin only fell an average of 0.23 kg.4 This was similar to the 0.2 kg reduction seen in both groups in the 52 week placebo-controlled trial of metformin and vildagliptin.2 A role for the DPP4 inhibitors as add-on treatments is yet to be established, particularly in patients who are already using more than one drug. Their long-term safety is also unknown. The systematic review concluded that DPP4 inhibitors currently have no advantage over other drugs which lower blood glucose.1
The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).
At the time the comment was prepared, information about this drug was available on the website of the Therapeutic Goods Administration (www.tga.gov.au/industry/pm-auspar.htm).