This article focuses on the place of vildagliptin in the treatment of type 2 diabetes in New Zealand. For more extensive
information on the management of type 2 diabetes, including advice on lifestyle interventions, managing cardiovascular
risk and escalating pharmacological treatment, see:
Glucagon-like peptide-1 (GLP-1) is a hormone that is rapidly released from the intestine after eating.1 GLP-1
signals to the pancreas to increase insulin release, and reduce glucagon release, after a meal. In combination, these
effects lead to higher insulin levels and a lowering of blood glucose levels. The effects of GLP-1 are usually confined
to the period immediately after eating, as it is broken down within minutes by the enzyme dipeptidyl peptidase-4 (DPP-4).1
Several anti-diabetic medicines have been developed which aim to amplify the effects of GLP-1. These include oral DPP-4
inhibitors, which inhibit the DPP-4 enzyme and result in increased and prolonged action of GLP-1, and injectable synthetic
versions of GLP-1 which are not broken down by DPP-4, known as GLP-1 mimetics or receptor agonists.
Vildagliptin is a DPP-4 inhibitor subsidised from 1 October, 2018
Vildagliptin is an oral DPP-4 inhibitor approved for the treatment of type 2 diabetes. By inhibiting DPP-4 and increasing
GLP-1 levels, it results in higher insulin levels and lower glucose levels, particularly after eating.2 Vildagliptin
is typically used in combination with metformin; in people with type 2 diabetes who are already taking metformin, adding
vildagliptin once or twice daily to their treatment regimen reduces HbA1c levels by a further 7–12 mmol/mol
after 12 weeks of treatment.3, 4 When vildagliptin is used alone in people who do not tolerate metformin, it
reduces HbA1c levels by an average of 6-9 mmol/mol.5
Vildagliptin will be fully subsidised without restriction, and available in three formulations, all taken either once
or twice daily:6
- 50 mg vildagliptin tablet
- 50 mg vildagliptin + 850 mg metformin tablet
- 50 mg vildagliptin + 1 g metformin tablet
Lifestyle interventions are the cornerstone of treatment for people with type 2 diabetes. Metformin is the preferred
first-line pharmacological treatment option, particularly for people who are overweight or obese.7 If a sufficient
reduction in HbA1c levels is not achieved with metformin, treatment is typically escalated by reinforcing
the importance of diet and exercise, and adding a second oral pharmacological treatment.
For patients with higher HbA1c levels at diagnosis, e.g. >75 mmol/mol, initiating two oral medicines
simultaneously or discussing the use of insulin with metformin is recommended to reduce HbA1c levels rapidly.8,
9
For further information on lifestyle management of type 2 diabetes and the use of metformin, see:
www.bpac.org.nz/BPJ/2015/December/diabetes.aspx
Dual therapy: adding a second oral anti-diabetic medicine
The addition of vildagliptin to the pharmaceutical schedule now provides another option for clinicians when deciding
on adding a second (or third) oral medicine to metformin treatment. Subsidised options now include:
- Vildagliptin, taken either as separate metformin and vildagliptin tablets, or a combination vildagliptin + metformin
formulation
- A sulphonylurea, such as gliclazide or glipizide
- Pioglitazone
Current international guidelines* , including from the United States, United Kingdom, Scotland and Australia, do not
favour any one of these subsidised options as the preferred choice; clinicians and patients can jointly decide which of
these medicines to use after taking into account any contraindications, medicines interactions or adverse effects (Figure
1).3, 8, 10, 11 Guidelines refer to DPP-4 inhibitors and sulphonylureas as a class, as existing evidence
does not clearly show any differences between individual medicines in terms of efficacy or rates of adverse effects.10
In clinical trials where vildagliptin has been compared with placebo medicines, sulphonylureas, pioglitazone or metformin,
there has not been any differences between groups in the rates of myocardial infarction, stroke, heart failure or death.12 Similar
results have been found in observational studies in patients taking these medicines.13
People who have contraindications to using metformin, or who trial metformin but are unable to continue use due to adverse
effects, can initiate vildagliptin, a sulphonylurea or pioglitazone alone.
* A joint consensus statement from the American and European Diabetes Associations was released in October, 2018; it recommends
that a DPP-4 inhibitor or pioglitazone be favoured over a sulphonylurea if there is a need to avoid hypoglycaemia or minimise weight gain. We will
cover this new statement more comprehensively at a later date. The statement can be found here:
http://diabetologia-journal.org/wp-content/uploads/2018/09/EASD-ADA.pdf
Triple therapy: insulin is typically initiated if treatment with two oral medicines is insufficient
If further escalation of treatment is required, clinicians can discuss the option of initiating insulin or using three
oral medicines in combination. The addition of insulin is the typical course of action and should be considered for patients
with a HbA1c level > 65 mmol/mol despite lifestyle interventions and treatment with two oral anti-diabetic
medicines.3, 7, 8
Vildagliptin can be continued if insulin is initiated; clinical trials have found that adding vildagliptin to insulin
treatment results in an additional 6–7 mmol/mol reduction in HbA1c levels, without an increase in episodes
of hypoglycaemia.14 If patients initiate more complex insulin regimens, e.g. by adding rapid-acting insulin
at meal-times, continuing the use of vildagliptin is possible.15 However, in clinical practice, oral antidiabetic
medicines are often withdrawn if patients initiate complex insulin regimens in order to simplify their treatment.8
For further information on lifestyle management, escalating treatment and initiating insulin, see:
www.bpac.org.nz/BPJ/2015/December/diabetes.aspx
Figure 1: An overview of management for patients with type 2 diabetes.3, 7, 8, 10 For further information on lifestyle management,
escalating treatment and initiating insulin, see: www.bpac.org.nz/BPJ/2015/December/diabetes.aspx
*
Vildagliptin can be prescribed with metformin either as separate metformin and vildagliptin tablets or in combination metformin + vildagliptin formulations
How does adding vildagliptin to treatment compare with adding a sulphonylurea or pioglitazone?
Clinicians in New Zealand will be familiar with the usual therapeutic and adverse effects of metformin and sulphonylurea
medicines, as these have been available subsidised for several years. Pioglitazone has been available for clinicians in
primary care to prescribe since 2007; initially with Special Authority criteria, which were removed in December, 2012.16,
17
Key prescribing points to help clinicians and patients decide between treatment with vildagliptin and other subsidised
medicines include the following:
Vildagliptin may be slightly less potent at lowering HbA1c than other options: Evidence suggests that vildagliptin reduces HbA1c
by approximately 2 mmol/mol less than a sulphonylurea when used as monotherapy (Table 1).3 However, a
similar reduction in HbA1c is achieved when adding either a DPP-4 inhibitor or a sulphonylurea
to metformin treatment.3,18 Adding a thiazolidinedione (e.g. pioglitazone) to metformin is slightly more effective in
reducing HbA1c than adding a DDP-4.3,18 There is, however, some evidence that differences in efficacy between vildagliptin
and other options may not be significant when vildagliptin is used longer-term, e.g. after two years.3
DPP-4 inhibitors are not associated with weight gain: Adding a sulphonylurea or pioglitazone treatment
to metformin typically leads to weight gain of approximately 2 kg, whereas DPP-4 inhibitors have a neutral effect on weight
and are not associated with gain or loss.18 Metformin is typically associated with a small degree of weight
loss (Table 1).
DPP-4 inhibitors have low risks of hypoglycaemia: Treatment with vildagliptin is associated with a lower
risk of hypoglycaemia than treatment with a sulphonylurea due to differences in how these medicines stimulate insulin
release. Over one to two years of treatment 24–27% of patients taking sulphonylureas experience hypoglycaemia, compared
to 3–4% of patients taking DPP-4 inhibitors.19
People newly diagnosed with diabetes who do not tolerate metformin may be more likely to benefit from vildagliptin
treatment: People who are younger and who are closer to diagnosis, e.g. who have had diabetes for less than a
year, are more likely to achieve HbA1c targets with vildagliptin treatment.20 This is probably
due to people earlier in the disease process having better pancreatic function, which enables them to increase insulin
release to a greater extent in response to higher GLP-1 levels than people who have had type 2 diabetes for many years.
Table 1: Effects of oral diabetes medicines on HbA1c, weight and risk of hypoglycaemia. Adapted from Scottish
Intercollegiate Guidelines Network (SIGN) and American Diabetes Association (ADA)3,8
Medicine |
Efficacy* for lowering HbA1c |
Effects on weight |
Risk of hypoglycaemia |
Metformin |
High |
Weight loss of approximately 1 kg 21 |
Low |
Sulphonylureas |
High |
Weight gain of approximately 2 kg 22 |
High |
Pioglitazone |
High |
Weight gain of approximately 2 kg 22 |
Low |
Vildagliptin |
Intermediate |
No change |
Low |
* High = mean HbA1c reduction of >11-22 mmol/mol; Intermediate = mean HbA1c reduction of >5.5-11 mmol/mol8
Vildagliptin is prescribed as one 50 mg tablet, either once or twice daily, depending on the extent of HbA1c reduction
required and whether patients have renal impairment (Table 2). Vildagliptin can be prescribed either alone, or in combination
formulations of 50 mg vildagliptin with 850 mg or 1 g of metformin.
If vildagliptin is prescribed in combination with a sulphonylurea, e.g. in patients who are unable to tolerate metformin
and require more than one oral glucose lowering medicine, once daily dosing should be used as twice daily dosing does
not provide any additional benefit.23
Formulations of vildagliptin in combination with metformin may be simpler for patients and more effective
Observational data suggest patients are more likely to reach their target HbA1c level if vildagliptin and
metformin are prescribed as a single tablet, which may be due to increased adherence with a simpler regimen.20
When taken alone vildagliptin does not need to be taken with food, however, patients prescribed a combination vildagliptin
+ metformin tablet should be advised to take their medicine with food as they would if taking metformin alone. Rates of
gastrointestinal adverse effects with vildagliptin + metformin treatment are similar to rates when metformin is taken
alone.24
Contraindications and cautions
Vildagliptin should not be taken by people who are in a state of ketoacidosis.25 Prescribing vildagliptin
to women who are pregnant or breastfeeding is not recommended due to a lack of clinical trials or data in these patient
populations (Table 2).25 Vildagliptin has been studied in people with heart failure, however, those with severe
heart failure (New York Association functional class IV) were excluded from trials and therefore prescribing in patients
with severe heart failure is not recommended due to a lack of data.23, 26
Testing liver function prior to initiation and monitoring during treatment is recommended
In clinical trials a small proportion of people (0.5% or fewer) have experienced elevations in ALT or AST levels to
greater than three times the upper limit of normal.27 Assessing liver function before initiating treatment
and monitoring every three months for the first year is recommended.25 Initiating vildagliptin is not recommended
if patients have ALT or AST levels over two and a half times the upper limit of normal prior to treatment.23 When
prescribing vildagliptin, inform people of symptoms associated with acute liver dysfunction, including nausea, jaundice,
vomiting, abdominal pain and fatigue and advise them to seek medical attention if these occur.25 If elevations
in ALT or AST to greater than three times the upper limit of normal occur during treatment, re-test liver function after
considering and addressing other possible causes of hepatic dysfunction. Vildagliptin should be withdrawn if patients
persistently have ALT or AST levels greater than three times the upper limit of normal.23
Prescribing in patients with renal impairment
Approximately one-quarter of a dose of vildagliptin is excreted unchanged by the kidneys, and the remainder metabolised
by hydrolysis. In patients with eGFR < 50 mL/min/1.73m2, dosing should be once daily only.25
The manufacturer recommends to avoid prescribing vildagliptin + metformin formulations in patients with an eGFR < 60
mL/min/1.73m2 due to the risk of metformin accumulation in patients with impaired renal function.28 However,
in clinical practice metformin can be prescribed to patients with impaired renal function provided appropriate dose reductions
are used and renal function is monitored. For patients with an eGFR < 60 mL/min/1.73m2, prescribing vildagliptin
and metformin in separate tablets may be easier to allow an appropriate dose of metformin to be used in combination with
vildagliptin.
Adverse effects of vildagliptin
A minority of people taking vildagliptin experience adverse effects, including:29
- Nasopharyngitis: 9%
- Headache: 7%
- Dizziness: 6%
- Back pain: 6%
- Diarrhoea: 6%
These adverse effects are typically mild; approximately 2–5% of people choose to discontinue vildagliptin due to adverse
effects.30, 31
The use of DPP-4 inhibitors is associated with an increased risk of pancreatitis, however, there is still considerable
uncertainty regarding the strength of this association. A meta-analysis of three randomised controlled trials reported
a statistically significant increased odds of acute pancreatitis in participants taking DPP-4 inhibitors, however, the
difference in absolute risk was low, at 0.13%.32
Patients taking ACE inhibitors have a higher risk of angioedema, but the absolute rate is still low
Patients with type 2 diabetes are often prescribed ACE inhibitors to treat hypertension or to reduce the risk or progression
of diabetic nephropathy. Evidence suggests there may be an interaction between vildagliptin and ACE inhibitors which leads
to an increased risk of angioedema, with a meta-analysis reporting an increased odds of angioedema of 4.57 (95% CI: 1.57–13.28)
in people taking an ACE inhibitor who were also taking vildagliptin, compared to ACE inhibitor use alone.33 However,
the absolute risk remains small with an incidence rate of 0.5% or lower.33 Reported cases have often occurred
in the first three months of initiating vildagliptin in people already taking an ACE inhibitor.34 Vildagliptin
use alone is not associated with angioedema.33
Switching patients from a sulphonylurea or pioglitazone
Patients who have been using a sulphonylurea or pioglitazone but are experiencing adverse effects such as hypoglycaemia
may wish to switch to vildagliptin. The half-life and duration of effect of sulphonylurea medicines is less than 24 hours,
and patients taking these medicines could switch to vildagliptin the next day.35 Pioglitazone has a half-life
of seven hours or less, however, it is expected to have a prolonged duration of effect as a result of increasing insulin
sensitivity.35 Patients taking pioglitazone could initiate vildagliptin the next day with a more cautious approach
to avoid hypoglycaemia, e.g. initially only taking vildagliptin once daily, before increasing to twice daily use.
Table 2: Cautions and associated dosing recommendations for prescribing vildagliptin23, 25, 28
Patient population |
Prescribing or dosing recommendation |
Explanations |
Women who are pregnant or breastfeeding |
Prescribing not recommended |
There is a lack of safety data in women who are pregnant or breastfeeding |
Patients with renal impairment: |
|
|
Prescribing vildagliptin |
Maximum once daily dosing of vildagliptin recommended in patients with eGFR < 50 mL/min/1.73m2 |
Some vildagliptin is excreted unchanged by the kidneys |
Prescribing vildagliptin + metformin |
Prescribing not recommended in patients with eGFR < 60 mL/min/1.73m2 |
Prescribing metformin and vildagliptin in separate tablets may be preferable to allow for an appropriate reduced
dose of metformin |
Patients with severe heart failure (New York Association functional class IV) |
Prescribing not recommended |
There is a lack of safety data in this patient population |
Patients with elevations of ALT or AST to over 2.5 times the upper limit of normal prior to initiation |
Prescribe with caution and monitor liver function (see: “Contraindications and cautions”) |
A minority of patients (0.5%) have shown increases in ALT and AST levels to over three times the upper of normal
in clinical trials |