Vildagliptin: The Evidence For Its Place in The Treatment of Type 2 Diabetes Mellitus
Vildagliptin: The Evidence For Its Place in The Treatment of Type 2 Diabetes Mellitus
Abstract
Introduction: Type 2 diabetes is increasing in prevalence worldwide and is a leading cause of morbidity and mortality, mainly due to the
development of complications. Vildagliptin is an inhibitor of dipeptidyl peptidase 4 (DPP-4), a new class of oral antidiabetic agents.
Evidence review: Clear evidence shows that vildagliptin improves glycemic control (measured by glycosylated hemoglobin and blood
glucose levels) more than placebo in adults with type 2 diabetes, either as monotherapy or in combination with metformin. Vildagliptin
is as effective as pioglitazone and rosiglitazone, and slightly less effective than metformin, although better tolerated. Further glycemic
control is achieved when adding vildagliptin to metformin, pioglitazone, or glimepride. There is evidence that vildagliptin improves
beta-cell function and insulin sensitivity. Vildagliptin does not appear to be associated with weight gain or with a higher risk of hypoglycemia
than placebo or other commonly used oral antidiabetic agents. Economic evidence is currently lacking.
Place in therapy: Vildagliptin improves glycemic control with little if any weight gain or hypoglycemia in adult patients with type 2
diabetes when given alone or in combination with metformin, thiazolidinediones, or sulfonylureas. Since many diabetic patients require
combination therapy, the complementary mechanism of action of vildagliptin and other commonly prescribed antidiabetic drugs
represents an important new therapeutic option in diabetes management.
Key words: dipeptidyl peptidase IV (dipeptidyl peptidase 4) inhibition, glycemic control, LAF 237, type 2 diabetes, vildagliptin
Core evidence place in therapy summary for vildagliptin 50 mg once or twice daily in adults with
type 2 diabetes
Outcome measure Evidence Implications
Disease-oriented evidence
Reduction in glycylated hemoglobin Clear Vildagliptin improves glycemic control more than placebo; 50 mg bid less effective
than metformin 1 g bid; comparable to pioglitazone and rosiglitazone
Reduction in fasting and postprandial Clear Greater reduction with vildagliptin than with placebo; more sustained effect than
plasma glucose rosiglitazone
Glycemic control in combination with metformin, Clear Adding vildagliptin to metformin, thiazolidinediones, or sulfonylureas causes a
pioglitazone, or glimepride further improvement in glycemic control
Increase in postprandial GLP-1 Clear Greater increase with vildagliptin than placebo
Effects on postprandial insulin Substantial Similar with vildagliptin and placebo. Implies improved insulin secretion and
sensitivity, shown by no change in insulin with lower glucose
Improvement in beta-cell function Clear Greater improvement with vildagliptin than placebo
Improvement in insulin sensitivity Substantial Greater improvement with vildagliptin than placebo
Patient-oriented evidence
Hypoglycemia Clear Similar frequency with vildagliptin and placebo, and with metformin
or thiazolidinediones
Weight gain Clear Similar with vildagliptin and placebo; weight gain less than with thiazolidinediones,
but greater than with metformin
Tolerability Clear Well tolerated with few adverse effects; nasopharyngitis, cough, and headache
Liver function Limited Unpublished data reveal similar elevations in liver enzymes compared with
metformin, a thiazolidinedione, a sulfonylurea, or placebo. Liver function tests
necessary before and during treatment with vildagliptin, and the drug should not be
used in patients with liver impairment
Economic evidence
Cost effectiveness No evidence Studies required to verify the impact of vildagliptin alone or in combination with
other oral agents on costs of illness
bid, twice daily; GLP-1, glucagon-like peptide.
Vildagliptin | place in therapy review
Scope, aims, and objectives the following reasons: nonsystematic reviews (n=45); letters,
editorials, news items, notes, comments, and corrections (n=13);
Vildagliptin (Galvus®, LAF 237, Novartis) is an inhibitor of dipeptidyl articles about other drugs or treatments (n=2); articles on other
peptidase 4 (DPP-4) that has been developed for the treatment subjects (n=1). Eight papers remained and were included in the
of type 2 diabetes. The drug was approved for use in the EU in evidence base (Table 1).
February 2008 and is available in Mexico and Brazil.
DPP-4 is a new therapeutic target for the treatment of type 2 Table 1 | Evidence base included in the review
diabetes, and its role and the mechanism of action of vildagliptin Number of records
are discussed in the Disease overview section below.
Category Full papers Abstracts
This article reviews the currently available published evidence on Initial search 69 19
the effects of vildagliptin in type 2 diabetes, and considers its
records excluded 61 6
potential for clinical and economic benefit. The primary emphasis
records included 8 13
is given to clinical studies, but results of preclinical and clinical
pharmacology investigations are also summarized. Additional papers identified 0 0
Search update
records included 8 12
English language literature searches were conducted on
Publications not available on 0 3a
October 10, 2005 in the following databases, searching from
databases and supplied by
the beginning of the database to date unless otherwise stated. manufacturer
The search strategy was “(vildagliptin OR laf 237) AND diabetes”
Publications identified from 4 0
unless otherwise stated. additional sources
was expanded by Automatic Term Mapping to “(((“Vildagliptin” Level 2 clinical evidence (RCT) 15 13
[TIAB] NOT Medline[SB]) OR “Vildagliptin”[Substance Name] OR Level ≥3 clinical evidence
vildagliptin[Text Word]) OR (“1-(((3-hydroxy-1-adamantyl)amino)
trials other than RCT 1 6
acetyl)-2-cyanopyrrolidine”[Substance Name] OR laf 237[Text
Word])) AND ((“diabetes mellitus”[TIAB] NOT Medline[SB]) OR case reports
For definitions of levels of evidence, see Editorial Information inside back cover or on the
Core Evidence website (http://www.coremedicalpublishing.com).
• Database of Abstracts of Reviews of Effectiveness (DARE),
RCT, randomized controlled trial.
National Health Service (NHS) Economic Evaluations Database
(NHSEED), Health Technology Assessment (HTA), www.york.
ac.uk/inst/crd/darehp.htm. All three databases were searched Meeting abstracts from 2002 or later were identified by searching
together. All fields searched. BIOSIS Previews, http://www.datastarweb.com, 1996 to date, using
the search strategy “(vildagliptin OR laf 237) AND diabetes AND
• NHS HTA, www.ncchta.org. PT=MEETING$ AND LG=EN AND (YEAR=2002 OR YEAR=2003
OR YEAR=2004 OR YEAR=2005).” One record was retrieved.
• National Guideline Clearing House, www.guideline.gov.
Abstracts from the American Diabetes Association (ADA) Scientific
• National Institute for Health and Clinical Excellence (NICE), Sessions for 2003–2005 inclusive were searched online at
www.nice.org.uk. http://scientificsessions.diabetes.org/Abstracts/index.cfm using
• Cochrane Database of Systematic Reviews (CDSR), www. a text search for the terms “vildagliptin” or “laf 237”. A further
cochrane.org/index0.htm. Entire site searched. 19 abstracts were obtained, one of which was a duplicate of the
abstract on BIOSIS (Table 1). The manufacturer supplied citation
• Clinical Evidence (BMJ), www.clinicalevidence.com. details for four additional abstracts that were not available on
the databases searched, and these four were also included
• www.clinicaltrials.gov. (Table 1). This produced a total of 23 abstracts, of which three were
excluded as duplicate presentations of data already published
• www.clinicalstudyresults.org.
as full papers and a further four were excluded because their
After removal of duplicates, a total of 69 records were identified. main focus was another compound, thus leaving 16 abstracts for
Records were manually reviewed and 61 were excluded for inclusion (Table 1).
The PubMed literature search was repeated on October 11, “metabolic syndrome” (Kahn et al. 2005). Individuals with diabetes
2007 with search limits “humans, clinical trial, meta-analysis, are two to four times more likely to develop cardiovascular
randomized controlled trial, English language” and yielded disease and have a greater risk of heart attack or stroke than
13 records, of which eight were included, the remainder being individuals without diabetes (IDF 2005a). Indeed, a recent meta
pharmacokinetic or pharmacodynamics studies. Abstracts from analysis of prospective cohort studies in patients with diabetes
the 2006 and 2007 annual meetings of the ADA and European showed that hyperglycemia is associated with an increased risk
Association for the Study of Diabetes (EASD) were also searched of cardiovascular disease (Selvin et al. 2004).
and 12 were included after removal of duplicates, subanalyses,
and out-of-scope records. Finally, four full papers were identified There is also increasing evidence that cardiovascular risk factors
from a meta analysis (Amori et al. 2007) that were not present in are more prevalent in individuals with IFG or IGT compared with
the PubMed search. those with normal glucose levels, and that these individuals have
an increased risk of cardiovascular disease and death (Coutinho et
al. 1999; DECODE Study Group 2001; Saydah et al. 2001). Recent
Disease overview data have shown that abnormal glucose tolerance is a strong risk
factor for future cardiovascular events after myocardial infarction
The increasing prevalence of type 2 diabetes (Bartnik et al 2004). In addition, the presence of cardiovascular
It is estimated that there are currently approximately 194 disease risk factors explains the relationship between prediabetes
million people with diabetes worldwide and the prevalence is and the development of chronic kidney disease (Fox et al. 2005).
projected to exceed 333 million by 2025 (IDF 2005a). Over 90%
These complications place a huge burden on healthcare services.
of those affected have type 2 diabetes. Furthermore, due to its
It is estimated that the total direct and indirect expenditure for
asymptomatic nature, a substantial proportion of individuals with
diabetes in the US alone in 2002 was $US132 billion (Hogan
type 2 diabetes are unaware that they have the disease (WHO
et al. 2003). The European Cost of Diabetes in Europe – type
2003). Global estimates of the number of individuals with impaired
2 (CODE-2) study estimated that three times the healthcare
glucose tolerance (IGT) or impaired fasting glucose (IFG) (often
resources are spent on treating the complications of type 2
referred to as prediabetes) are unavailable. However, the World
diabetes than those spent on controlling the disease before the
Health Organization (WHO) has suggested that it is likely to be
onset of complications (Jonsson 2002). Hospitalization accounted
even greater than the number with diabetes (WHO 2003).
for over 50% of the total cost. In contrast, management of
Type 2 diabetes usually occurs in adults over the age of 40 years glucose control with oral drugs and insulin accounted for only 7%
and is associated with a number of factors, including obesity, of healthcare costs. It is evident that preventing the development
family history of diabetes, physical inactivity, and race/ethnicity. of type 2 diabetes complications could have a beneficial effect on
However, over the last two decades the increasing prevalence of the huge economic and healthcare burden of type 2 diabetes.
type 2 diabetes in children and adolescents has been recognized
as a global health problem (CDC 2005a; Pinhas-Hamiel & Zeitler The UK Prospective Diabetes Study (UKPDS) 41 compared the
2005). Diabetes is one of the most common chronic diseases cost effectiveness of intensive blood glucose control (sulfonylurea
among children in the US with approximately 150 000 young or insulin) with conventional glucose control (primarily diet)
people under the age of 18 years having the condition. It is in patients with type 2 diabetes (Gray et al. 2000). This study
estimated that 8–43% of those affected have type 2 diabetes (CDC showed that although intensive blood glucose control significantly
2005a). To examine the prevalence of diabetes among children increased treatment costs, it substantially reduced the cost of
and adolescents in the US, a 5-year study, SEARCH for Diabetes complications and increased the time free of complications.
in Youth, has been initiated by the Centers for Disease Control
and Prevention (CDC) and the National Institutes of Health. The role of incretin hormones in the pathophysiology of
type 2 diabetes
Type 2 diabetes is most commonly observed in American Indian,
Type 2 diabetes is a complex metabolic disease that has a
African American, Asian, and Hispanic/Latino youths. However,
multifactorial pathogenesis (Stumvoll et al. 2005). Factors
the obesity epidemic and a sedentary lifestyle are thought to
involved in the development and progression of type 2 diabetes
be contributing factors. Generally, children and adolescents
include insulin resistance, reduced pancreatic beta-cell response,
diagnosed with type 2 diabetes are between 10 and 19 years old,
and inappropriately elevated glucagon levels. These in turn can
obese, and have insulin resistance and a strong family history of
be affected by secondary factors such as overeating, lack of
type 2 diabetes (Bloomgarden 2004; CDC 2005b).
exercise, liver damage, hyperlipidemia, and impaired secretion
of incretin hormones.
Medical and socioeconomic burden of type 2 diabetes
Type 2 diabetes is associated with significant morbidity and Beta-cell dysfunction is a major factor in the pathogenesis of type
mortality because of the resulting complications. Diabetes is 2 diabetes. Insulin from the pancreas normally reduces glucose
the leading cause of end-stage renal disease, accounting for output by the liver, enhances glucose uptake by skeletal muscle,
44% of new cases and is the leading cause of blindness in the and suppresses fatty acid release from fat tissue. Individuals
Western world (CDC 2003). People with diabetes are also likely to develop insulin resistance in peripheral tissues and to maintain
have a clustering of cardiovascular risk factors such as obesity, normal glucose levels pancreatic beta cells increase the amount
hypertension, and dyslipidemia, which is often referred to as the of insulin they produce. However, over time there is a progressive
Biguanide (metformin) Only agent associated with potential GI adverse effects common – minimized by Recommended as a first-line glucose-
weight loss slow titration lowering therapy in patients whose blood
Modest lowering of lipid levels Rare risk of lactic acidosis limits its use in glucose is inadequately controlled using
contraindicated patients e.g. patients with lifestyle intervention alone
Improvements in fibrinolysis,
inflammatory markers, and impaired renal function
endothelial function
Prevents development of T2D in patients
with IGT
Relatively inexpensive
Insulin secretagogues Relatively inexpensive Drug interactions First-line therapy if the patient is not
(sulfonylureas) Weight gain overweight or metformin is not tolerated or
contraindicated
Hypoglycemia – requires self-monitoring of
blood glucose by the patient Use in combination with metformin in
overweight or obese patients when glucose
Potential effect on myocardial ischemic control becomes unsatisfactory
preconditioning
Thiazolidinediones Beneficial effects on cardiovascular risk Weight gain Offered as combination therapy if unable
(glitazones/PPAR- determinants: cytokines, inflammatory Edema to take, or if HbA1c remains unsatisfactory
gamma agonists) markers, lipids, blood pressure, with, metformin and insulin secretagogues
endothelial function ADA/AHA and FDA recommend that as combination therapy
glitazones are not used in patients with
Reduced insulin resistance advanced heart failure symptoms (class III
Can be used in patients with reduced or IV NYHA classification)
renal function Increased risk of edema and cardiac failure
in combination with insulin
Relatively high cost
Alfa-glucosidase inhibitors STOP-NIDDM trial demonstrated GI adverse effects e.g. abdominal bloating Acarbose considered as alternative when
reduced risk of myocardial infarction with and cramping unable to use other oral drugs
acarbose Less efficacious than other classes
Delay/prevent the development of T2D Relatively high cost
Do not cause weight gain
No clinically significant drug interactions
Insulin Ability to achieve tight glycemic control Hypoglycemia Offered when inadequate blood glucose
Newer noninjectable formulations Weight gain control on optimized oral drugs
becoming available Daily injections
Self-monitoring (cost and convenience)
ADA, American Diabetes Association; AHA, American Heart Association; GI, gastrointestinal; HbA1c, glycated hemoglobin A1c; IGT, impaired glucose tolerance; NICE, National Institute for Health
and Clinical Excellence; NYHA, New York Heart Association; PPAR, peroxisome proliferators-activated receptor; STOP-NIDDM, noninsulin dependent diabetes mellitus; SU, sulfonylurea; T2D,
type 2 diabetes.
developing, and the progression of, microvascular complications tissue abnormalities of the disease (i.e. sensitize specific tissues
are substantially reduced with intensive blood glucose control to the effects of insulin or enhance the insulin-producing activity of
(HbA1c approximately 7%) (UKPDS 1998a,b). Most of the the pancreas) rather than treating the underlying causes of these
commonly used oral glucose-lowering drugs are only able to abnormalities, which is the declining function of pancreatic beta
reduce HbA1c by approximately 1% (Kimmel & Inzucchi 2005). cells that results in a reduction in endogenous insulin secretion.
This reduction is not sufficient for patients who have HbA1c levels Antidiabetic medications are required that can preserve beta-cell
much greater than the recommended target. function and prevent continuing loss and disease progression.
Despite the ability of insulin to achieve tight glycemic control,
Long-term glycemic control is difficult to sustain with oral glucose- physicians and people with diabetes are reluctant to use it
lowering drugs. One of the main reasons for the lack of long-term to treat type 2 diabetes until after the failure of multiple oral
glycemic control with oral medications is that they target the glucose-lowering drugs. This is partly due to the burden of
multiple daily injections that are associated with poor patient for further treatments to delay or prevent the progression of IGT to
compliance. Therefore, there is a need for oral medications that type 2 diabetes.
can achieve similar prolonged glycemic control to that of insulin.
Furthermore, the emerging epidemic of type 2 diabetes in children
Addressing unmet need: new classes of
and adolescents presents a new challenge, as this population will
antidiabetic medications
have a lifetime risk of complications and may require effective
glycemic control over a prolonged period of time. To address some of these unmet needs in patients with type
2 diabetes, new classes of noninsulin antidiabetic drugs been
developed, including the dual PPAR agonists (e.g. muraglitizar,
Safety and tolerability
subsequently discontinued), amylin analogs (e.g. pramlintide
Current treatments for type 2 diabetes are also often limited by acetate, an injectable adjunct to insulin), incretin mimetics
their contraindications and side-effect profile that may affect (GLP-1 analogues), and the DPP-4 inhibitors, that act as incretin
patient compliance and quality of life (Table 2). enhancers. In addition, a number of alternative methods of
delivery of insulin are being studied.
One of the most common side effects with sulfonylureas,
thiazolidinediones, and insulin is weight gain. The UKPDS Incretin mimetics and DPP-4 inhibitors address the need to act
33 study demonstrated that weight gain was significantly higher on the underlying disease rather than on its symptoms. They
(mean 2.9 kg) in patients with type 2 diabetes receiving blood enhance glucose-dependent insulin secretion by pancreatic
glucose control with sulfonylureas or insulin compared with beta cells, and consequently there is little risk of hypoglycemia.
conventional treatment with diet (P<0.001) (UKPDS 1998a). This They also suppress elevated glucagon secretion and increase
is of particular concern given that people with diabetes are often satiety. It has been hypothesized that they may restore beta-cell
overweight before they commence therapy. sensitivity to glucose, which could mean that they may be able
to delay the onset of type 2 diabetes, slow its progression, and
Another common side effect of the sulfonylureas and insulin is
reduce its cardiovascular and metabolic complications (Holst &
hypoglycemia. Regular self-monitoring of blood glucose levels
Gromada 2004).
by fingertip glucose measurements is required to try and avoid
hypoglycemic events. However, this extensive monitoring is
The GLP-1 analog exenatide (Byetta®; Amylin Pharmaceuticals
inconvenient to the patient and incurs extra costs.
and Eli Lilly) was the first in this new class of diabetes treatment
Finally, agonists of peroxisome proliferators-activated receptor to be approved by the FDA in June 2005. It is approved as an
(PPAR) gamma have been associated with fluid retention and adjunctive therapy in patients with type 2 diabetes who have not
concerns over cardiac failure, and metformin is associated with achieved adequate control on metformin and/or a sulfonylurea.
gastrointestinal intolerance and is contraindicated in patients All GLP-1 analogs are injectable, which may pose a barrier to
with renal impairment or poor left ventricular function due to the their use as many doctors and people with diabetes are reluctant
risk of lactic acidosis. to use injected therapies.
Clinical evidence with vildagliptin been shown that insulin secretion stimulated by the neuropeptide
pituitary adenylate cyclase-activating peptide was unaffected by
In-vitro studies have shown that vildagliptin is a potent, reversible, vildagliptin, which appears to act by prolonging the half life of
competitive inhibitor of human and rat DPP-4, with high selectivity L- and K-cell derived incretin hormones (Hjøllund et al. 2007).
for DPP-4 over other peptidase enzymes (Hughes et al. 2002;
Villhauer et al. 2003; Brandt et al. 2005). In vivo, vildagliptin has The clinical evidence on vildagliptin published to date is mainly
been shown to inhibit plasma DPP-4 activity in rats (Villhauer et concerned with disease-oriented outcomes (such as HbA1c,
al. 2003) and in cynomolgus monkeys for up to 10 hours (Hughes blood glucose, and insulin levels), and patient-oriented evidence
et al. 2002). on weight gain and adverse events.
Table 3 | Effects of vildagliptin on blood glucose and glycosylated hemoglobin (HbA1c) in active-controlled comparative studies (all
level 2 evidence)
Design Treatment Outcome Reference
and dose
Mean change from % patients Mean change from Mean change
baseline in HbA1c reaching HbA1c baseline in fasting from baseline in
(percentage points) <7.0%a plasma glucose 4 h-postprandial
(mmol/L) plasma glucose
(mmol/L)
V 50 mg qd + V 50 mg qd + P 15 mg V 50 mg qd + P V 50 mg qd + P 15 mg V 50 mg qd + P 15 mg
P 15 mg qd qd –1.7 (P=0.039 vs 15 mg qd 54% qd –2.4 (P=0.022 vs qd –3.8 (P=0.024 vs
(n=139) placebo + P) placebo + P) placebo + P)b
(P<0.001 vs placebo
+ V and placebo + P)
R 8 mg qd R 8 mg qd –1.3 NR R 8 mg qd –2.3 NR
(n=238) (P<0.001 vs V)
Double-blind RCT, 52 V 50 mg bid V 50 mg bid –1.0 V 50 mg bid 35% V 50 mg bid –0.9 NR Goeke et al. 2006;
weeks (n=526) Schweizer et al.
2007
V 50 mg qd + V 50 mg qd + P 45 mg V 50 mg qd + P V 50 mg qd + P V 50 mg qd + P
P 45 mg qd qd –0.8 (P=0.001 vs 45 mg qd 28.7% 45 mg qd –0.8 45 mg qd –1.2b,c
(n=124) placebo) (P=0.007 vs placebo)
many again when vildagliptin 100 mg once daily was Although a similar reduction in HbA1c was achieved, vildagliptin
combined with pioglitazone 30 mg once daily compared with 50 mg twice daily was not found to be noninferior to metformin
either agent alone (Rosenstock et al. 2007a; Table 3). Fewer 2 g daily (Goeke et al. 2006; Schweizer et al. 2007; Table 3).
patients with a higher baseline HbA1c (>8.5%) achieved the target Vildagliptin appears to be as effective as pioglitazone (Baron et
of <7.0% when vildagliptin 50 or 100 mg/day was added to al. 2006; Garber et al. 2007b), and rosiglitazone (Rosenstock et
metformin compared with those with intermediate (7.9–8.5%) al. 2007b) at reducing HbA1c (Table 3).
baseline levels (7.5% and 16.3% versus 22.2% and 31.4%)
(Bosi et al. 2007).
Table 4 | Effects of vildagliptin on blood glucose and glycosylated hemoglobin (HbA1c) in placebo-controlled studies (all
level 2 evidence)
V 50 mg qd or bid V 50 mg qd or bid NR NR NR
+ G 4 mg qd (n=132) + G 4 mg qd –0.7b
(P<0.001 vs placebo)
Double-blind, Placebo (n=88) Placebo 0 Placebo 13.6% Placebo +0.1 NR Pi-Sunyer et al.
placebo-controlled 2007
V 50 mg bid (n=84) V 50 mg qd –0.5 V 50 mg qd 25%c V 50 mg qd –0.5 NR
RCT, 24 weeks
Double-blind, Placebo (n=72) Placebo +0.28 NR Placebo +0.13 Placebo +0.2d Kikuchi et al.
placebo-controlled 2006; Mimori et
V 10 mg bid (n=71) V 10 mg bid –0.53 NR V 10 mg bid –0.62 V 10 mg bid
RCT, 12 weeks al. 2006
–3.5d
continued overleaf...
...table continued
Design Treatment Outcome Reference
and dose
Mean change from % patients Mean change from Mean change
baseline in HbA1c reaching HbA1c baseline in fasting from baseline in
(percentage points) <7.0%a plasma glucose 4 h-postprandial
(mmol/L) plasma glucose
(mmol/L)
Double-blind, Placebo (n=28) Placebo –0.6 Placebo NR Placebo +0.23 Placebo +0.2 Pratley et al.
placebo-controlled 2006; Pratley &
V 25 mg bid (n=70) V –0.6 V 47% V –0.9 V –1.7
RCT, 12 weeks Galbreath 2004
(P=0.0012) (P=0.0043) (P<0.0001)
Double-blind, Placebo (n=58) NR Placebo 23% Placebo –0.41 Placebo –0.61 Ristic et al. 2005
placebo-controlled,
V 25 mg bid (n=51) NR V 25 mg bid 44% V 25 mg bid –0.44 V 25 mg bid –1.03
multicenter RCT,
12 weeks V 25 mg qd (n=54) NR V 25 mg qd 28% V 25 mg qd –0.30 V 25 mg qd –1.50
V 100 mg qd (n=63) V 100 mg qd –0.53 V 100 mg qd 46% V 100 mg qd –0.95 V 100 mg qd –1.50
(P=0.004 vs placebo)
Other doses NSD vs P values NR All doses NSD vs All other doses NSD
placebo placebo vs placebo
Double-blind, Placebo (n=51, of At 12 weeks: Placebo 10.7% Greater decrease with V Greater decrease Ahrén et al.
placebo-controlled, whom 29 completed V –0.6 V 41.7% than with placebo at with V than with 2004a
multicenter RCT, extension) Placebo 0.1 P value NR 12 weeks (P=0.0057) placebo at 12 weeks
12 weeks (P<0.0001) (P<0.0001)
Optional extension V 50 mg qd (n=56, of In extension study: Greater decrease with V Greater decrease
for further 40 weeks whom 42 completed V +0.0128 per month than with placebo at with V than with
extension) Placebo +0.0656 per 52 weeks (P=0.031) placebo at 52 weeks
month (P=0.0001)
All patients were also
taking stable doses (P=0.0243)
of M 1.5–3 g/day
Double-blind, Placebo (n=19) Placebo –0.15 NR Placebo –0.4 Placebo –0.4 Ahrén et al.
placebo-controlled, 2004b
V 100 mg qd (n=18) V –0.53 (P<0.001) NR V –1.1 (P=0.037) V –1.9 (P<0.001)
multicenter RCT,
4 weeks
Effects on blood glucose broadly consistent with a dose-related effect reaching a plateau
at 50 or 100 mg/day (Ristic et al. 2005; Table 4).
Most of the published evidence shows that vildagliptin 50 mg/day
or 100 mg/day is more effective than placebo in reducing both Between-group changes in fasting plasma glucose (FPG)
fasting plasma glucose and 2 and 4 hours postprandial plasma with vildagliptin 50 and 100 mg/day (–0.8 and –1.7 mmol/L,
glucose (Tables 3 and 4). In the dose-ranging study, the changes respectively) and in 2 hours postprandial glucose (–1.9 and
from baseline did not reach statistical significance compared with –2.3 mmol/L) also showed significant improvements compared
placebo (except for the change in 4 hours postprandial glucose with placebo in patients receiving metformin ≥1.5 g/day (Bosi et
with vildagliptin 50 mg once daily), but the numerical values were al. 2007). Vildagliptin caused a significantly smaller reduction in
Table 5 | Effects of vildagliptin on plasma insulin, glucagon, and GLP-1 levels (all level 2 evidence).
Design Treatment and dose Outcome Reference
Double-blind, placebo- Placebo (n=51, of whom 29 NSD between groups at NR NR Ahrén et al. 2004a
controlled, multicenter completed extension) 12 weeks
RCT, 12 weeks V 50 mg qd (n=56, of whom Greater increase with V
Optional extension for 42 completed extension) than placebo at 52 weeks
further 40 weeks All patients were also taking (P=0.015)
stable doses of metformin
1.5–3 g/day
Double-blind, placebo- Placebo (n=19) Insulin response to meal Significant reduction in Significant increase in Ahrén et al. 2004b
controlled, multicenter V 100 mg qd (n=18) ingestion NSD between V group (P=0.005) V group (P<0.001)
RCT, 4 weeks groups No significant change in Placebo NR
placebo group
Double-blind, placebo- Placebo (n=20) Insulin response to meal Placebo +2 Placebo +0.9 Ahrén et al. 2003
controlled RCT, 4 weeks V 100 mg qd (n=20) ingestion NSD between V 12 V +4.7
groups
(P<0.01) (P<0.001)
Double-blind, placebo- Placebo (n=11) NR 3.5 h mean glucagon: Greater increase with V Mari et al. 2005
controlled, single center V 100 mg bid (n=9) lower with V than than placebo in 13.5 h
RCT, 4 weeks placebo but NSD mean GLP-1 (P<0.001)
bid, twice daily; NR, not reported; NSD, not statistically significantly different; qd, once daily; RCT, randomized controlled trial; V, vildagliptin.
FPG than rosiglitazone (Table 4), suggesting a more sustained Effects on beta-cell function
effect throughout the day (Rosenstock et al. 2007b). Evidence suggests that vildagliptin can increase the secretion
of insulin in response to glucose, indicating an improvement
Effects on glucagon, insulin, and GLP-1 in beta-cell function (Table 6). The dose-ranging study found
As expected from its mechanism of action, evidence consistently that only the highest dose of vildagliptin (100 mg/day) was
shows that vildagliptin increases postprandial GLP-1 levels significantly superior to placebo, whereas other studies have
relative to placebo (Table 5). Vildagliptin also consistently shown statistically significant differences from placebo at lower
doses (Table 6). However, this may reflect the variety of measures
lowers plasma glucagon relative to placebo, but most of the
used to assess beta-cell function, which makes it difficult to
evidence appears to show little effect on plasma insulin levels
compare results across different studies. In patients inadequately
(Table 5). However, it has been argued that plasma insulin levels
controlled with metformin ≥1.5 g/day, the insulin secretory
are not necessarily a direct measure of plasma insulin secretion,
response increased by 5.2 and 5.7 pmol/min/m2 with vildagliptin
and that beta-cell function can be improved without appreciable
50 and 100 mg/day, respectively, compared with placebo (Bosi et
changes in plasma insulin (Mari et al. 2005). Moreover, this
al. 2007). Adding vildagliptin to pioglitazone also improved beta-
observation probably reflects improved insulin secretion and
cell function (Rosenstock et al. 2007a; Table 6).
sensitivity, shown by the same insulin level in response to lower
glucose levels. Inhibition of DPP-4 might not be expected to have
a significant effect on fasting GLP-1 or GIP because incretin release Effects on insulin sensitivity
depends on nutrient intake. However, there is some evidence from Evidence from one randomized controlled trial (Ahrén et al. 2005b)
a small study that a high dose of vildagliptin, 100 mg twice daily, indicates that long-term vildagliptin treatment can increase
significantly increased GLP-1 and GIP in patients with type 1 (n=11) insulin sensitivity during oral glucose intake (Table 7). The same
or type 2 (n=9) diabetes after 4 weeks (Kelley et al. 2006). study also found that vildagliptin increased the adaptation index
V 50 mg qd + P 15 mg qd NR NR V 50 mg qd + P 15 mg NR
(n=139) qd +8.0 (P=0.046 vs
placebo + P)
V 100 mg qd + P NR NR V 100 mg qd + NR
30 mg qd (n=146) P 30 mg qd +5.5
V 50 mg bid + P 45 mg NR NR V 50 mg bid + P NR
qd (n=136) 45 mg qd +7 (P<0.01
vs placebo)b
V 50 mg qd (n=156) NR NR NR V 50 mg qd +5 vs
placebo (P<0.001)
Double-blind, Placebo (n=51, of whom NR Greater increase Greater with V than NR Ahrén et al. 2004a,
placebo-controlled, 29 completed extension) with V than placebo at 12, 24, and 2005b
multicenter RCT, V 50 mg qd (n=56, of placebo at 52 weeks (P<0.05)
12 weeks whom 42 completed 12 weeks
Optional extension extension) (P=0.0007) and
for further 40 weeks 52 weeks
All patients were also (P=0.0005)
taking stable doses of
metformin 1.5–3 g/day
Double-blind, placebo- Placebo (n=51, of whom Greater with V than placebo at Greater with V than placebo at Ahrén et al. 2005b
controlled, multicenter RCT, 29 completed extension) 24 and 52 weeks (P<0.05) 12, 24 (P<0.05), and 52 weeks
12 weeks V 50 mg qd (n=56, of whom (P<0.01)
Optional extension for further 42 completed extension
40 weeks All patients were also taking
stable doses of metformin
1.5–3 g/day
(Table 7), which is considered by the authors to be a measure of but did not increase the risk of reactive hypoglycemia (El-Ouaghlidi
the ability of beta cells to adapt insulin secretion to the prevailing et al. 2003, 2004).
insulin sensitivity (Ahrén et al. 2005b).
These early studies have been verified in larger, randomized
placebo-controlled trials. The combination of vildagliptin 50 mg
Effects on bodyweight
once or twice daily plus metformin caused a significant decrease
Excess bodyweight is a major risk factor in type 2 diabetes (see of HbA1c compared with metformin alone, and a significantly
Disease overview section). Thus, it is important that medications greater proportion of patients achieved levels <7.0% (Dejager
for the treatment of diabetes should not cause an increase in et al. 2007b; Table 3). Similarly, there was a significantly greater
bodyweight. reduction in HbA1c when vildagliptin 50 mg or 100 mg daily
was added to pioglitazone 15, 30, or 45 mg daily compared with
Vildagliptin is not associated with significantly more weight gain
pioglitazone 30 or 45 mg alone (Garber et al. 2007b; Rosenstock
than placebo according to level 1 evidence from a meta analysis;
et al. 2007a; Table 3).
there was a small increase of 0.42 kg [95% confidence interval
(CI): 0.12, 0.72] (Amori et al. 2007). Weight reduction was greater
with vildagliptin compared with pioglitazone or rosiglitazone Effects in prediabetes
(mean 1.7 kg difference), but less than that with metformin (mean There is some preliminary evidence that vildagliptin is effective in
2.2 kg difference). The effects of vildagliptin on bodyweight are people with prediabetes. In a 12-week randomized trial, vildagliptin
shown in Table 8. 50 mg once daily (n=90) significantly (P<0.001) increased GLP-1
and GIP compared with placebo (n=89), and improved beta-
Combination with other agents cell function (Rosenstock et al. 2007c). Furthermore, vildagliptin
Some evidence from animal models suggested that pioglitazone reduced prandial glucose excursions by 22% compared with
and vildagliptin could have synergistic effects on glucose baseline, and by 32% compared with placebo. Vildagliptin 100 mg
clearance after an oral glucose load (Burkey et al. 2002). The once daily also improved insulin sensitivity and beta-cell function
combination has subsequently been studied in humans. One in 22 patients with prediabetes after 6 weeks (Utzschneider et
study investigated the combination in 12 patients with type 2 al. 2007).
diabetes (Serra et al. 2005). Patients received pioglitazone
45 mg once daily for 8 weeks, and were then randomized to Safety and tolerability
receive add-on placebo or vildagliptin 100 mg once daily for Level 1 evidence from a meta analysis of 12 randomized
28 days, followed by vildagliptin alone for 7 days. Coadministration controlled trials comparing vildagliptin with placebo (Ristic et al.
did not alter the pharmacokinetic behavior of either compound, 2005; Mimori et al. 2006; Pratley et al. 2006; Pi-Sunyer et al.
but the combination reduced postprandial glucose significantly 2007; Dejager et al. 2007), metformin with or without placebo
(P<0.05) more than pioglitazone alone (Serra et al. 2005). (Ahrén et al. 2004a; Bosi et al. 2007; Schweitzer et al. 2007),
pioglitazone with or without placebo (Garber et al. 2007b;
A crossover study in 15 patients with type 2 diabetes found that Rosenstock et al. 2007a), rosiglitazone (Rosenstock et al.
coadministration of glyburide 10 mg once daily and vildagliptin 2007b), or insulin (Fonseca et al. 2007) revealed that vildagliptin
100 mg twice daily did not modify the peak plasma concentration, was well tolerated with few adverse effects (Amori et al. 2007).
area-under-the-curve, or half-life of either agent. Two hypoglycemic There was no risk of gastrointestinal adverse effects compared
events occurred in patients receiving glyburide alone, but none in with placebo; urinary tract infection and headache were more
patients receiving the combination (Barilla et al. 2004). frequent with vildagliptin versus comparator (3.6% versus 1.3%,
and 6.3% versus 4.4%, respectively). Nasopharyngitis occurred
A study in 16 healthy volunteers reported that vildagliptin
in 7.3% of vildagliptin recipients and upper respiratory tract
significantly enhanced glibenclamide-stimulated insulin secretion,
Design Treatment and dose Mean change from baseline in body weight (kg) Reference
Double-blind RCT, 52 weeks V 50 mg bid (n=526) V 50 mg bid +0.3 Schweizer et al. 2007
M 1 g bid (n=254) M 1 g bid –1.9 (P<0.001 vs V)
Double-blind, placebo- Placebo + P 45 mg qd (n=138) V 50 mg qd + P 45 mg qd +0.1a Garber et al. 2007b
controlled RCT, 24 weeks V 50 mg qd + P 45 mg qd (n=124) V 50 mg bid + P 45 mg qd +1.3 (P=0.003
V 50 mg bid + P 45 mg qd (n=136) vs placebo)a
Double-blind, placebo- Placebo (n=51, of whom 29 completed At 12 weeks: Ahrén et al. 2004a
controlled, multicenter RCT, extension) Placebo –0.5
12 weeks V 50 mg qd (n=56, of whom 42 completed V –0.4
Optional extension for further extension)
40 weeks Extension phase:
All patients were also taking stable doses
of metformin 1.5–3.0 g/day Placebo –0.2
V –0.2
(P values NR)
Double-blind, placebo- Placebo (n=19) Placebo +0.12 Ahrén et al. 2004b
controlled, multicenter RCT, V 100 mg qd (n=18) V +0.21
4 weeks
NSD vs placebo
Change versus placebo + P.
a
bid, twice daily; M, metformin; NR, not reported; NSD, not statistically significantly different; P, pioglitazone; qd, once daily; RCT, randomized controlled trial; V, vildagliptin.
infection in 6.8%, compared with 7.3% and 8.0%, respectively, This reduction in complications should offset the additional cost
with comparator. of intensive blood glucose management. A new antidiabetic
agent that achieves better glycemic control, and in turn lowers
Mild to moderate hypoglycemia occurred with the same frequency complication rates, would have the potential to make significant
in patients taking vildagliptin (1.4%) or comparator drugs (1.2%) savings in the total resource utilization for diabetes management.
(Amori et el. 2007). Economic evidence for vildagliptin is not currently available and
its effect on healthcare resources has not been assessed.
Liver function
Vildagliptin has shown some evidence of improved glycemic
A pooled analysis of clinical trial data from more than
control (measured by HbA1c) compared with placebo, either
8000 patients was submitted by the manufacturer to European
as monotherapy or as an add-on to metformin (Tables 3 and 4).
regulatory authorities in November 2007 following concerns over
The magnitude of the reduction in HbA1c demonstrated by the
liver function with vildagliptin. Elevations more than three times
evidence so far is up to 1 percentage point (Tables 3 and 4),
the upper limit of normal levels of aspartate aminotransferase
comparable to that achieved with other oral glucose-
and alanine aminotransferase were revealed in 0.86%, 0.34%,
lowering drugs. Vildagliptin improves beta-cell function
and 0.21% of patients taking vildagliptin 100 mg once daily, 50
(Table 6) and insulin sensitivity (Table 7), which in turn
mg twice daily, and 50 mg once daily, respectively (Anon 2007).
improves control of blood glucose. In theory, since vildagliptin
The corresponding rates were 0.20% in approximately 4400
acts by enhancing the physiologic response to ingestion of
patients receiving metformin, a thiazolidinedione, a sulfonylurea,
a meal, it may provide finer control of blood glucose than is
or placebo, and 0.40% for placebo alone.
possible with agents such as sulfonylureas or insulin that act
more directly.
Resource utilization
There is evidence that glycemic control is maintained in the
Type 2 diabetes is a disease with a high social and economic cost, long term (52 weeks) with vildagliptin used as monotherapy
and is steadily increasing in prevalence (see Disease overview or in combination with metformin (Ahrén et al. 2004a; Schweizer
section). The bulk of this cost is attributable to the complications et al. 2007). Successful long-term glycemic control is an
of diabetes. As discussed earlier, intensive control of blood important clinical benefit, as it should contribute to a lower
glucose increases short-term costs compared with conventional risk of complications, but this needs to be confirmed by
management, but may reduce the long-term complication rate. further studies.
While long-term glycemic control is clearly important, if with a sulfonylurea, or 50 mg twice daily with metformin or a
vildagliptin (and other DPP-4 inhibitors) is shown to have thiazolidinedione such as pioglitazone. A 100 mg formulation
disease-modifying effects by protecting against the prolonged of vildagliptin is available in Brazil and Mexico. A fixed dose
decline in beta-cell function that continues with other drugs, combination of vildagliptin 50 mg plus metformin 850 mg or
this could be of greater potential benefit in people with diabetes. vildagliptin 50 mg plus metformin 1000 mg (Eucreas®) has also
Inhibiting disease progression and hence reducing or delaying the been approved for twice-daily use in patients inadequately
development of diabetic complications could provide substantial controlled with metformin alone or who are already receiving
economic benefits. each drug separately.
Evidence is also needed to compare vildagliptin with injected Liver function tests should be conducted before beginning
insulin in type 2 diabetes. An oral glucose-lowering drug that treatment with vildagliptin, every 3 months in the first year of
could reduce HbA1c as effectively as insulin, without weight gain treatment, and periodically thereafter. Vildagliptin should not be
or hypoglycemia, would have a considerable advantage over used in patients with liver impairment, those with type 1 diabetes,
injected insulin in terms of patient convenience. patients with moderate to severe renal impairment, or those with
congestive heart failure.
However, direct evidence will be necessary to assess the likely
impact of vildagliptin on resource utilization.
Place in therapy
Patient group/population Metformin is currently first line treatment for people with type
2 diabetes, with sulfonylureas established as second line, until
Vildagliptin acts by prolonging the life of GLP-1 and thereby
newer agents such as DPP-4 inhibitors and PPAR agonists
enhancing its effect on beta cells, so vildagliptin relies on the
can demonstrate a clear advantage in terms of efficacy, safety,
patient having an intact GLP-1 response to food and at least some
disease progression, or cost.
beta-cell function. Vildagliptin would therefore not be expected to
work in people with diabetes with little or no beta-cell function, There is clear evidence of improved glycemic control (measured
such as those with type 1 diabetes, and these patients have been by HbA1c, blood glucose or numbers of patients achieving
excluded from the trial populations. It is possible that vildagliptin HbA1c <7.0%) with vildagliptin compared with placebo,
may work better in patients with less advanced type 2 diabetes, either as monotherapy or in combination with metformin,
and there is some evidence that it is effective in patients with the thiazolidinediones pioglitazone and rosiglitazone, or the
prediabetes (Rosenstock et al. 2007c). sulfonylurea glimepride. Since most patients with type 2 diabetes
Patients with significant diabetic or cardiovascular complications ultimately require more than one drug for effective glycemic
were excluded from the published studies, so there is no evidence control, this evidence indicates a valuable place for vildagliptin in
relating to the use of vildagliptin in this population with more combination therapy. The drug is effective in drug-naïve patients,
severe disease. those poorly controlled with current treatment, in the elderly,
and in different ethnicities. There is also evidence of improved
Vildagliptin has been investigated in patients not previously beta-cell function and improved insulin sensitivity compared
treated for diabetes, and as an add-on to metformin in patients with placebo.
with an inadequate response to metformin therapy. All studies
of vildagliptin were conducted in adults (aged ≥18 years). Vildagliptin was not associated with significantly more weight
Pooled analyses indicate that the drug is effective in different gain than placebo, and is not associated with a higher rate of
ethnicities (Rosenstock et al. 2007d) and in elderly patients hypoglycemia (Amori et al. 2007). The drug is well tolerated
(Pratley et al. 2007b), and has a tolerability profile similar to that with few adverse effects. The incidence of liver enzyme
of metformin, pioglitazone, and rosiglitazone in patients with elevations with vildagliptin 50 mg once daily in clinical trials is
moderate renal insufficiency [glomerular filtration rate (GFR) 30 to comparable to that seen with metformin, a thiazolidinedione, or
<60 mL/min/1.73 m2), but better than metformin in those with a sulfonylurea; the incidence with 50 mg twice daily is less than
mild dysfunction (GFR 60 to <90 mL/min/1.73 m2) (Thuren et that with placebo.
al. 2007).
The present evidence base supports the use of vildagliptin in adults
Thus, the majority of the present evidence base relates to the use with type 2 diabetes and no significant diabetic or cardiovascular
of vildagliptin in adult patients with type 2 diabetes but without complications. It can be inferred from the drug’s mechanism of
diabetic or cardiovascular complications and who may be either action that it may be of most benefit in patients in the early stages
drug-naïve or who have not responded adequately to metformin of type 2 diabetes. As some authorities advocate earlier use of
therapy. Further results may extend this population to patients insulin in people with diabetes at this stage, studies comparing
with prediabetes. vildagliptin with early insulin would be valuable. There is evidence
that vildagliptin is effective in patients with prediabetes.
Dosage, administration, and formulations The main area where further evidence is required is on the effect
of vildagliptin on important patient-oriented outcomes such
Vildagliptin (Galvus) can be prescribed to patients with as disease progression, impact on cardiovascular risk, long-
type 2 diabetes at a dosage of 50 mg once daily in combination term complications, health-related quality of life, and adherence
to therapy. As the majority of the costs of managing diabetes Barilla D, He Y, Balez S, et al. No pharmacokinetic interactions or acute
are attributable to managing complications, this evidence would clinical safety issues preclude combination of the DPP-4 inhibitor LAF237 with
glyburide. Presented at the American Diabetes Association Scientific Sessions,
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