Incretin Mimetics and Dipeptidyl Peptidase-4 Inhibitors:

Innovative Treatment Therapies for Type 2 Diabetes

The prevalence of diabetes and impaired glucose tolerance is predicted to dramatically increase over the next two decades. Clinical therapies for type 2 diabetes mellitus (T2DM) have traditionally included lifestyle modification, oral
anti-diabetic agents, and ultimately insulin initiation. In this report, we review
the clinical trial results of two innovative T2DM treatment therapies that are
based on the glucoregulatory effects of incretin hormones. Incretin mimetics
are peptide drugs that mimic several of the actions of glucagon-like peptide-1
(GLP-1) and have been shown to lower glycated hemoglobin (A1C) levels in
patients with T2DM. Additionally, incretin mimetics lower postprandial and
fasting glucose, suppress elevated glucagon release, and are associated with
progressive weight reduction. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endogenous GLP-1 levels by inhibiting the enzymatic degradation of
GLP-1. Clinical studies in patients with T2DM have shown that DPP-4 inhibitors
reduce elevated A1C, lower postprandial and fasting glucose, suppress glucagon release, and are weight neutral. Collectively, these new drugs, given in
combination with other antidiabetic agents, such as metformin, sulfonylureas,
and/or thiazolidinediones, can help restore glucose homeostasis in poorly controlled patients with T2DM. (Arq Bras Endocrinol Metab 2008; 52/6:1039-1049)
Keywords: Type 2 diabetes; Exenatide; DPP-4 inhibitor; GLP-1; Incretin

Resumo
Incretinomimticos e Inibidores da Dipeptidil Peptidase-4: Terapias Inovadoras para o Tratamento do Diabetes Tipo 2.
previsto que a prevalncia de diabetes e a intolerncia glicose aumente dramaticamente ao longo das prximas duas dcadas. As terapias clnicas para diabetes melito tipo 2 (DM2) tm tradicionalmente includo modificao do estilo de
vida, agentes antidiabticos orais e, por ltimo, o incio da insulina. Neste artigo,
revisamos os resultados dos estudos clnicos de duas terapias inovadoras no tratamento do DM2 baseadas nos efeitos glicorregulatrios dos hormnios incretina.
Os incretinomimticos so medicamentos peptdeos que mimetizam vrias das
aes do peptdeo semelhante ao glucagon-1 (GLP-1) e tm demonstrado reduzir
nveis de hemoglobina glicada (A1C) em pacientes com DM2. Adicionalmente,
incretinomimticos reduzem as glicemias ps-prandial e de jejum, suprimem a
liberao elevada do glucagon, e so associados com reduo de peso. Os inibidores da dipeptidil peptidase-4 (DPP-4) aumentam os nveis de GLP-1 endgeno
pela inibio da degradao enzimtica do GLP-1. Estudos clnicos em pacientes
com DM2 tm demonstrado que inibidores da DPP-4 reduzem A1C elevada, reduzem as glicemias ps-prandial e de jejum, suprimem a liberao elevada do
glucagon e so neutros quanto ao peso. Coletivamente, estas novas medicaes,
administradas em combinao com outros agentes antidiabticos, como metformina, sulfonilurias e/ou tiazolidinedionas (TZDs), podem ajudar a recuperar a
homeostase glicmica de pacientes com DM2 no-controlados. (Arq Bras Endocrinol Metab 2008; 52/6:1039-1049)
Descritores: Diabetes tipo 2; Exenatida; Inibidor da DPP-4, GLP-1; Incretina
Arq Bras Endocrinol Metab 2008;52/6

perspectiva

Jaime A. Davidson
Erika B. Parente
Jorge L. Gross

Department of Medicine, Division

of Endocrinology, University of
Texas Southwestern Medical
School, Dallas, TX, USA (JAD);
Lilly Research Laboratories, Eli Lilly
and Company, Brazil Ltda, So
Paulo, SP, Brazil (EBP);
Servio de Endocrinologia,
Hospital de Clnicas de Porto
Alegre, Federal University of Rio
Grande do Sul, Porto Alegre, RS,
Brazil (JLG).

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Abstract

Recebido em 14/1/2008
Aceito em 20/5/2008
1039

Innovative Therapies for Type 2 Diabetes

Davidson, Parente & Gross

Introduction

64 million people in Latin America

and the Caribbean will suffer from diabetes in
2025 (1). The prevalence of diabetes in this world region ranges from 6% (in Guadeloupe) to 18% (in Jamaica) and has resulted in an economic burden of $65
billion in Latin America and the Caribbean (1). According to estimates from the International Diabetes Federation, approximately 5.6 million people in Brazil
alone have diabetes and another 7.5 million have impaired glucose tolerance (2). The diabetes epidemic is
largely credited to sedentary lifestyles, obesity and the
migration of rural populations to cities (3-8).
Elevated blood glucose is a defining feature of
T2DM. The pathogenesis of T2DM includes insulin
resistance (9) and progressive -cell dysfunction. In the
prediabetic state, insulin release increases to compensate for insulin resistance. Progression to impaired glucose tolerance is characterized by declining pancreatic
-cell function and mass (10-12) and leads to the loss
of adequate insulin release. In parallel, postprandial
blood glucose control is lost. The excess release of glucagon from abnormally-functioning pancreatic cells
further exacerbates the elevation of blood glucose
(13-15) and accelerates -cell apoptosis (11). Left untreated, -cell function continues to deteriorate and
patients progress to impaired fasting glucose and ultimately to T2DM (16,17).
Lifestyle modification and early and aggressive clinical intervention for diabetes patients and those at
risk can prevent progression of T2DM (18-21). In the
early stages of T2DM, patients are typically treated
with a variety of oral anti-diabetic agents (22-24).
These clinical therapies include oral drugs that are
classified as insulin sensitizers (e.g., biguanides and
thiazolidinediones), insulin secretagogues (e.g., sulfonylureas and meglitinides), and -glucosidase inhibitors. Current therapies can improve overall glucose
control but most do not effectively target postprandial glycemia. Recent breakthroughs in the understanding of incretin-based therapies have provided options
for treating patients with T2D.
The two key incretin hormones that have been
identified are glucagon-like peptide-1 (GLP-1) and
glucose-dependent inhibitory peptide (GIP). Both
peptides are secreted in response to nutrient intake
and stimulate glucose-dependent insulin secretion
(25). The incretin effect, which has been attributed to

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n estimated

1040

GLP-1 and GIP, is recognized as a significantly greater insulin secretory response to oral glucose compared to intravenous glucose. This effect helps regulate
postprandial glucose levels and accounts for 60% of
insulin secretion in response to an oral glucose load
(26). Since the insulinotropic activity of GLP-1, not
GIP, is preserved in patients with T2DM, GLP-1 has
been considered as a potential treatment for these patients (27).
GLP-1 is a multifunctional hormone which also
inhibits glucagon secretion, slows gastric emptying
and functions as a regulator of satiety (28-34). Although not demonstrated in humans, experimental
in vivo and in vitro studies have reported that GLP-1
promotes -cell proliferation and function, induces
islet neogenesis and reduces apoptosis (35;36). Despite GLP-1s possible proliferative and anti-apoptotic
effects on -cells, its therapeutic potential is limited
by its short half-life (~2 minutes) as it is rapidly degraded by the endogenous protease, DPP-4 (37-39).
Consequently, incretin mimetics, peptides that mimic several of the glucoregulatory actions of GLP-1
but are resistant to degradation by DPP-4, continue
to be investigated for the treatment of patients with
T2DM. A second strategy has focused on developing
inhibitors of the DPP-4 enzyme, which increases endogenous GLP-1 levels (24,40). Here we review the
clinical findings of three approved incretin-based
T2DM therapies; specifically the incretin mimetic,
exenatide and two DPP-4 inhibitors, sitagliptin and
vildagliptin.

Incretin mimetic-exenatide
Exenatide (Amylin Pharmaceuticals, Inc. and Eli Lilly
and Company) is a 39amino acid peptide incretin mimetic, currently available for the treatment of patients
with T2DM in many countries including the United
States, the European Union (EU) and parts of Latin
America. It is a synthetic form of exendin-4 and although it shares 50% amino acid sequence identity with
human GLP-1, these two peptides are transcribed from
separate genes (41). Exenatide is injected twice a day,
daily (5 or 10 mcg) within 1 hour before the two main
meals of the day (approximately 6 hours or more apart)
and has multiple glucoregulatory modes of actions,
many of which are similar to those of endogenous
GLP-1 (Table 1).
Arq Bras Endocrinol Metab 2008;52/6

Innovative Therapies for Type 2 Diabetes

Davidson, Parente & Gross

Characteristic of type 2 diabetes

Biological action of antidiabetes agent

Incretin mimetics

DPP-4 inhibitors

Increases glucose-dependent insulin

secretion

Yes

Yes

Decreases hepatic glucose production

Yes

Yes

Suppresses inappropriately elevated

postprandial glucagon secretion

Yes

Yes

Accelerated gastric emptying

Slows gastric emptying

Yes

Marginal

Increased food intake

Decreases food intake

Yes

No

Lack of biphasic secretory response

Restores biphasic insulin secretory

response

Yes

Unknown

Reduced pancreatic beta-cell mass

and insulin content

Increases beta-cell mass and improves

beta-cell function (reported in animal
studies)

Yes

Yes

Enhances insulin sensitivity

No

No

Weight reduction

Yes

No

Defective glucose-stimulated insulin

secretion
Inappropriately elevated hepatic
glucose production
Hyperglucagonemia

Reduced insulin sensitivity

Obesity

Exenatide Clinical Trials

in Patients with T2DM
Key primary and secondary efficacy results from three
placebo-controlled developmental trials, exenatide in
combination with metformin (44), a sulfonylurea (45),
or both (46), are given in Table 2. In these clinical
trials, patients with T2DM were given 5mcg of exenatide twice a day, daily for 4 weeks and 10mcg thereafter. Participants did not receive additional dietary
instruction and exercise counseling. Exenatide treatment (10mcg) resulted in significant mean A1C reductions from baseline ranging from 0.77% to 0.86%.
Patients also had statistically significant reductions in
mean body weight from baseline (1.6kg to -2.8kg).
Sustained reduction in mean A1C (1.0%) and progressive body weight loss (5.3kg) have also been observed in patients (n=217) that took part in the
subsequent 3 year open-label extensions of the original
30-week placebo-controlled trials (47).
The effects of exenatide added to a TZD (rosiglitazone or pioglitazone) with or without metformin in
T2DM patients has also been investigated (48) (see Table 2). In a 16-week placebo-controlled trial, A1C was
reduced 0.89% from baseline in patients taking exenatide with a TZD compared with an increase of 0.09% in
the control group. Patients treated with exenatide and
a TZD lost 1.8kg over 16 weeks compared to a -0.2kg
reduction in the control group. Glycemic control comArq Bras Endocrinol Metab 2008;52/6

pared with starter insulin therapies (insulin glargine,

IG; biphasic insulin aspart, BIA) has also been studied
in separate open-label, randomized, controlled, noninferiority trials (49,50). Patients received insulin or
exenatide added to maximal effective doses of metformin and a sulfonylurea. IG was titrated to maintain fasting glucose levels of less than 100mg/dL, while in the
BIA trial, insulin doses were adjusted to achieve an optimal balance between glycemic control and risk of hypoglycemia as dictated by the best clinical practice.
Reductions in A1C from baseline of approximately
1.1% were observed in both treatment groups after 26
weeks in the IG trial (49). In the BIA trial (50), patients achieved similar reductions in A1C (exenatide,
1.04%; BIA, -0.89%) after 52 weeks. In contrast to the
non-inferiority observed with regard to A1C reductions, exenatide therapy significantly reduced mean
body weight (IG trial, 2.3kg; BIA trial, 2.5kg) compared with weight gain in the insulin groups (IG trial,
+1.8kg; BIA trial, +2.9kg). Key efficacy measures for
exenatide are summarized for each trial in Table 2 along
with baseline clinical characteristics.
The most common adverse events associated with
exenatide therapy have been gastrointestinal in nature
(eg, nausea, vomiting, and diarrhea) and therefore exenatide use is not recommended in patients with severe
gastrointestinal disease. Nausea of mostly mild-to-moderate severity was reported in 33% to 57% of exenatide-treated patients across clinical trials summarized in
1041

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Table 1. Modes of action of incretin mimetics and DPP-4 Inhibitors (29,42,43).

Innovative Therapies for Type 2 Diabetes

Davidson, Parente & Gross

Table 2. Summary of clinical trials of 10mcg exenatide (twice-daily).

Reference

Baseline:
A1C (%)
Body Weight (kg)
BMI (kg/m2)

Diabetes
duration (y)

Change from
baseline
A1C (%)

Percentage of
Change from
Change from
patients
baseline fasting baseline body
achieving target glucose (mg/dL)
weight (kg)
A1C 7%

Buse e cols., (45)

8.6
95
33

6.6

0.86

34%

10.8

1.6

DeFronzo e cols., (44)

8.2
101
34

4.9

0.78

40%

10.8

2.8

Kendall e cols., (46)

8.5
98
34

8.7

0.77

30%

10.8

1.6

Heine e cols., (49)*

8.2
88
31

9.9

1.11

46%

25.7

2.3

Nauck e cols. 50)*

8.6
86
31

9.8

1.04

32%

32.4

2.5

Zinman e cols., 48)*

7.9
98
34

7.3

0.89

62% **

28.6

1.8

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* 5 mcg twice-daily for 4-week, 10 mcg twice-daily thereafter; ** Per protocol population; Glucose values were converted from mmol to mg/dL (conversion factor 0.05551).

Table 2. Escalating the dose of exenatide from 5mcg to

10mcg after 4 weeks led to a transient increase in nausea which diminished with continued exposure to the
higher dose. Severe nausea was uncommon and data
from open label extension trials (51) have not shown a
significant correlation between nausea and the progressive weight loss observed in patients receiving exenatide therapy. In the oral anti-diabetic agent trials
(44-46,48), the overall incidence of hypoglycemia for
exenatide and the control groups ranged from 5-36%
and 3-13%, respectively. In the insulin comparator trials
(49,50); the overall rates were similar across the treatment groups (exenatide, range 4.7 7.3 events/patient-year; insulin, range 5.6 6.3 events/patient-year).
Across all clinical trials, hypoglycemia was reported
most commonly in combination with a sulfonylurea
and for this reason a reduction in the dosage of sulfonylurea should be considered when initiating exenatide therapy.
Pre- and post-meal glucose levels were assessed by
7point self monitored blood glucose (SMBG) profiles
in the TZD add-on (48) and insulin comparator trials
(49,50). In the TZD add-on trial, significant reductions from baseline were observed at all SMBG time
1042

points in the exenatide group while the placebo group

showed little change. Although in both insulin comparator trials patients receiving insulin generally had lower endpoint glucose levels before meals, those
receiving exenatide had significantly lower 2-hour
postprandial glucose levels following the morning
(p<0.001) and evening meals (p<0.001). In these same
three trials, pancreatic -cell function changes were estimated by homeostasis model assessment (HOMA-).
In those subjects treated with exenatide, HOMA- increased 19% from baseline, compared with a 6% decrease with TZD plus placebo (between-group, p=0.005).
Exenatide was also associated with a 19% increase in
HOMA- (baseline to endpoint change, p<0.001) in
the BIA comparator trial.
Few significant baseline-to-endpoint changes in
fasting lipid parameters were reported in the clinical
trials summarized in Table 2. However, the open-label
extension trials (47,51) have shown subsequent baseline-to-endpoint improvements in fasting lipids (see Table 3). Twice-daily exenatide given for 3.5 years
(completer analysis, n=151) was also associated with
significant lowering of systolic (3.5 mmHg) and diastolic blood pressure (3.3 mmHg) (47).
Arq Bras Endocrinol Metab 2008;52/6

Innovative Therapies for Type 2 Diabetes

Davidson, Parente & Gross

Table 3. Summary of baseline to endpoint changes in fasting lipids

Total Cholesterol

LDL-C

Triglycerides

HDL-C

Mean % Change

Mean % Change

Mean % Change

Mean % Change

Scott e cols., (52)*

Monotherapy

+3.4%

+5.5%

+3.6%

+4.6%

Rosenstock e cols., (53)

TZD Add-on

+1.6%

+5.8%

+1.1%

+0.6%

Charbonnel e cols., (54)

Metformin Add-on

+1.9%

+3.3%

+7.7%

+1.3%

Mean % Change

Mean % Change

Mean % Change

Mean % Change

Decrease <3%

Increase <3%

Increase ~5%

Increase <1%

3.1%

1.4%

18.1%

+12.1%

Changed <4%

Changed <4%

Changed <4%

Changed <4%

-2.4%

2.8%

+5.3%

+2.6%

Mean Change
(mg/dL)

Mean Change
(mg/dL)

Mean Change
(mg/dL)

Mean Change
(mg/dL)

Blonde e cols., (51)

82-week Open-label Extension

2.4

1.6

38.6

+4.6

Klonoff e cols., (47)

3.5-year Open-label Extension

10.8

11.8

44.4

+8.5

Sitagliptin (100mg once-daily)

Vildagliptin (100mg once-daily)

Bosi e cols., (55)
Metformin Add-on
Rosenstock e cols., (56)
TZD Add-on
Fonseca e cols., (57)*
Insulin Add-on
Schweizer e cols. (58)
Metformin Comparator
Exentide (10mcg twice-daily)

DPP-4 Inhibitors
Two DPP-4 inhibitors, sitagliptin and vildagliptin, have
been approved for the treatment of T2DM. The two
approved DPP-4 inhibitors have multiple glucoregulatory modes of actions, some of which are similar to
exenatide (Table 1); however, the lack of effect of
DPP-4 inhibitors on gastric emptying and body weight
are notable differences. Sitagliptin and vildagliptin inhibit the rapid degradation of GLP-1 by the ubiquitous
DPP-4 protease. Other DPP-4 substrates include GIP,
GLP-2, pituitary adenylate cyclase-activating polypeptide, neuropeptide Y, peptide YY, substance P, and growth releasing hormone (39). These orally active DPP-4
inhibitors increase GLP-1 endogenous levels and lower
elevated blood glucose.
Sitagliptin
Sitagliptin (MK-0431, Merck & Company) was the first
DPP-4 inhibitor approved for the T2DM treatment as
Arq Bras Endocrinol Metab 2008;52/6

adjunctive therapy to diet and exercise. Sitagliptin is approved to be used in 42 countries around the world including the EU, the United States, and parts of Latin
America including Brazil and Mexico. The recommended dose of once-daily oral sitagliptin is 100 mg. At this
dose, sitagliptin can inhibit ~80% of endogenous DPP-4
activity over a 24-hour period (59). At doses of 12.5 mg
or higher, sitagliptin is associated with a 2-fold increase
in active total GLP-1 levels (59).
Clinical trial results of sitagliptin given alone or in
combination with oral anti-diabetic agents are summarized in Table 4. Most trials were designed as short term
studies (12 to 24 weeks) with similar characteristics, including diet and exercise counseling for patients and
wash-out periods of oral anti-diabetic therapy and dose
stabilization periods ranging from 6 to 19 weeks. In the
monotherapy trials, sitagliptin therapy compared to placebo resulted in statistically significant improvements in
A1C and fasting glucose (52,60-62). Similar reductions
from baseline in 2-hour PPG values were observed in
these trials (41.4mg/dL to 48.6 mg/dL) (61,62). Si1043

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*These trials used a sitagliptin dose of 50mg twice-daily.

Innovative Therapies for Type 2 Diabetes

Davidson, Parente & Gross

tagliptin given as add-on therapy to metformin (54) resulted in similar A1C and fasting glucose reductions as in
the monotherapy trials (Table 4). However, there was a
more pronounced 2-hour PPG reduction (-61.3mg/
dL) in this trial (54), which may be due partly to metformin acting as a weak DPP-4 inhibitor (64).
In a similarly designed trial, the efficacy of sitagliptin as add-on therapy to a TZD was assessed in patients
with T2DM (53). In this 24-week trial patients were
treated with pioglitazone (30 or 45mg/day) and sitagliptin or pioglitazone and placebo. Significantly greater baseline to endpoint reductions in mean A1C and
fasting glucose (between-treatment differences of -0.7%
and 17.7mg/dL, respectively) were observed in patients treated with sitagliptin and pioglitazone versus
the control group. The non-inferiority of sitagliptin
versus glipizide added to metformin therapy (1500
mg) was investigated in a 52-week clinical trial (63).
Reductions from baseline in A1C and fasting glucose
were similar with sitagliptin and glipizide, demonstrating non-inferiority (63).

Increases in HOMA- ranging from 4% to 20% have

been shown in the sitagliptin trials. Limited to modest
baseline to endpoint improvements in fasting lipids (Table 3) were reported in patients treated with sitagliptin
alone, or in combination with metformin or pioglitazone (52-54). Sitagliptin therapy has been shown to be
weight neutral in all clinical trials except in one study in
which sitagliptin given with metformin resulted in weight reduction of 1.5kg after 52 weeks of treatment (63).
In the clinical trials summarized in Table 4, gastrointestinal adverse events occurred in 12% to 21% of patients
and were generally mild-to-moderate in severity
(53,54,60-63). Other adverse events reported in patients
(>3%) taking sitagliptin included upper respiratory tract
infection, nasopharyngitis and headache (53,54,61-63).
The incidence of hypoglycemia was low in these trials
(<2%) and was similar to the placebo/control arms.
Dose reduction of sitagliptin has been recommended for
patients with moderate or severe renal insufficiency or
end-stage renal disease (65). However, overall, sitagliptin was generally well-tolerated.

Table 4. Summary of clinical trial results for 100 mg once-daily sitagliptin.

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Reference

Baseline:
A1C (%) body
weight (kg)
BMI (kg/m2)

Diabetes
duration (y)

Change from
baseline A1C
(%)

Percentage of
Change from Change from
patients achieving baseline fasting baseline body
target A1C 7%
glucose
weight (kg)
(mg/dL)

Scott e cols. (52)*

7.8
NR
30.4

4.2

0.54

NR

18.2

Neutral

Nonaka e cols. (60)

7.5
NR
25.2

4.0

0.65

58%

22.5

Neutral

Raz e cols. (61)

8.0
89.7
31.8

4.5

0.48

36%

12.6

Neutral

Aschner e cols. (62)

8.0
85
30.3

4.3

0.61

41%

12.6

Neutral

Charbonnel e cols. (54)

8.0
86.7
30.9

6.0

0.67

47%

16.2

Neutral

Rosenstock e cols. (53)

8.1
90.9
32

6.1

0.85

45%

16.7

+1.8

Nauck e cols. (63)**

7.5
89.5
31.2

6.5

0.67

63%

10.1

1.5

*Scott e cols. (2007) used a sitagliptin dose of 50 mg twice-daily; ** Per protocol population; NR = not reported; glucose values were converted from mmol to mg/dL
(conversion factor 0.05551) (52).

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Arq Bras Endocrinol Metab 2008;52/6

Innovative Therapies for Type 2 Diabetes

Davidson, Parente & Gross

Vildagliptin
Vildagliptin (LAF237, Novartis Pharmaceuticals), another oral treatment developed for the treatment of
T2DM, also acts by inhibiting circulating DPP-4 activity. It is available in Brazil and Mexico as both a 50mg
and 100mg daily dose and at the publication of this
review, had been approved for use in the European
Union (EU), recommended as a 50mg once-daily dose
with a sulfonylurea or as 50 mg twice-daily in combina-

tion with either metformin or a TZD. Vildagliptin has

been studied as a monotherapy (66-69) in combination
with other oral antidiabetic agents (55-57,70,71), and
against active comparator therapies including TZDs
(72) and metformin (58). The maximum daily dose
used in clinical trials of vildagliptin was 100mg (oncedaily or 50mg twice-daily); other lower doses regimens
were also investigated. In this review we present clinical
results on the highest dose regimens reported in each
of the clinical trials (Table 5).

Table 5. Summary of clinical trial results for 100mg once-daily vildagliptin.

Ristic e cols. (69)

Pratley e cols. (68)*

Pi-Sunyer e cols. (67)

Dejager e cols. (66)

Ahren e cols. (70)*

Bosi e cols. (55)

Garber e cols. (71)

Rosenstock e cols. (56)

Fonseca e cols. (57)*

Rosenstock e cols. (72)

Schweizer e cols. (58)

Baseline:
A1C (%)
Body weight (kg)
BMI (kg/m2)
7.6
92
31
8.0
NR
30
8.3
91
32
8.4
92-94
32
7.7
NR
29
8.4
95
33
8.7
NR
32
8.8
82
30
8.4
95
33
8.7
91
32
8.7
91
32

Diabetes
duration (y)

Change from
baseline A1C
(%)

Percentage of Change from Change from

patients
baseline fasting
baseline
achieving
glucose
body weight
target A1C <7%
(mg/dL)
(kg)

3.0

0.53

46%

17.1

0.07

4.6

0.6

NR

16.2

NR

2.1

0.8

39%

19.8

0.4

2.4

0.9

NR

14.4

0.8

5.6

0.6

42% (after 52
weeks)

18.0

0.4

5.8

0.9

54%
(For patients
with baseline
A1C 7.9)

NR

+0.2

4.6

1.0

36%

19.8

NR

2.0

1.9

65%

50.4

+2.1

14.4

0.5

NR

14.4

+1.3

2.3

1.1

NR

23.4

0.3

1.0

1.0

35%

16.2

+0.3

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Reference

*These trials used doses other than 100 mg once-daily; NR = not reported; Glucose values were converted from mmol to mg/dL (conversion factor 0.05551).

Arq Bras Endocrinol Metab 2008;52/6

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Innovative Therapies for Type 2 Diabetes

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Davidson, Parente & Gross

In placebo-controlled trials, vildagliptin monotherapy reduced A1C (range 0.5% to 0.9%) and fasting
glucose (14.4mg/dL to 19.8mg/dL) from baseline.
The A1C reductions observed with monotherapy were
statistically significantly greater than placebo in all trials.
Vildagliptin was studied as add-on therapy to several
anti-diabetic agents including insulin, metformin and
TZDs. A1C and fasting glucose reductions from baseline ranged from 0.5% to 1.9% and 14.4mg/dL to
50.4mg/dL, respectively, with the greatest changes
observed in a subgroup of patients given vildagliptin
combined with pioglitazone (100/30mg daily). In studies of vildagliptin with active comparator therapies,
A1C and fasting glucose reductions from baseline ranged from 1.0% to 1.1% and 16.2mg/dL to
23.4mg/dL, respectively.
Estimates of -cell function and mealtime glucose
levels were derived from standard meal challenges performed in monotherapy and add-on trials. Meal challenge tests were performed in two monotherapy trials.
In one of the monotherapy trials (68), the mean 4hour
prandial glucose level was statistically significantly reduced (34.2mg/dL vs. placebo) in the vildagliptin
(25mg twice-daily) group. Meal tests were performed
in four out of five of the add-on trials; dissimilar methodologies were used to assess mealtime glucose levels. Ahren e cols. (70) reported a statistically significant
reduction in the mean 4-hour prandial glucose level
(39.6 mg/dL vs. placebo) in the vildagliptin (25mg
twice-daily plus metformin) group. Greater reductions
in 2-hour postprandial glucose levels were observed
with vildagliptin compared with placebo in two other
add-on trials, one with metformin (55) the other with
a TZD (71). Finally, Rosenstock e cols. (56) reported a
significant reduction in the peak prandial glucose excursion in the vildagliptin plus TZD group, both baseline to endpoint (36.0 mg/dL) and compared with
the placebo plus TZD group.
Vildagliptin therapy was associated with an increase
HOMA- (11% and 23%) in two monotherapy trials
(68,69), but improvement relative to placebo was only
observed in one trial (69). In three of the add-on trials
(55,56,71), -cell function was defined by the ratio of
insulin secretory rate AUC to glucose AUC. This assessment was statistically significantly increased in two of
the 100mg vildagliptin groups at endpoint (56,56),
and also improved more than control in two trials
(55,71). Ahren e cols. (70) also demonstrated an association between vildagliptin therapy and improved
1046

-cell function using a different estimate, the corrected

insulin response at peak glucose.
Limited to modest baseline to endpoint improvements in fasting lipids (Table 3) were reported in patients treated with vildagliptin alone, or in combination
with metformin, TZDs or insulin. Significant improvements in total cholesterol and LDL-C relative to control
groups were more commonly reported. Monotherapy
(50mg twice-daily) was associated with a 4.5% decrease
in total cholesterol vs. placebo (66). Vildagliptin added
to TZD was associated with a 5.6% decrease in total cholesterol vs. TZD alone and a 10.5% decrease in LDL-C
vs. TZD alone (56). Added to insulin, vildagliptin decreased total cholesterol and LDL-C, 4.0% and 5.8% vs.
insulin alone, respectively (57). The largest improvements relative to control were observed in an active
comparator trial with rosiglitazone. Relative to rosiglitazone, vildagliptin decreased total cholesterol and LDLC by 14% and 16%, respectively (72).
Vildagliptin therapy has been shown to have little
effect on weight in most clinical trials to date with the
exception of two studies. Given with a TZD, this therapy resulted in weight gain of 2.1kg (56), and given
with insulin resulted in weight gain of 1.3kg (57), both
after 24 weeks of treatment.
Overall, vildagliptin was generally well-tolerated.
In the clinical trials summarized in Table 5, gastrointestinal adverse events were reported in 1% to 22% of patients and were generally mild-to-moderate in severity.
Gastrointestinal adverse events were not reported in
four trials (56-58,70). Other adverse events commonly
reported in patients taking monotherapy or in combination with other antidiabetic therapies included headache, nasopharyngitis, dizziness, and upper respiratory
tract infection. The incidence of hypoglycemia was low
in these trials and was similar to the placebo or control
arms. Recently, dose-dependent elevation in liver markers was reported in a pooled analysis of over 8000
patients treated with vildagliptin. Further, investigation
is being conducted.
Discussion
Incretin-based therapies offer an alternative treatment
option for T2DM patients by targeting pancreatic -cell
dysfunction. This review of clinical trial results of three
approved incretin-based therapies highlights some of the
similarities and differences in the studies. Incretin mimetics and DPP-4 inhibitors reduce A1C and both are
Arq Bras Endocrinol Metab 2008;52/6

Innovative Therapies for Type 2 Diabetes

Davidson, Parente & Gross

Acknowledgements: This review was supported by

Eli Lilly and Company. Drs. Davidson and Gross are
consultants for Eli Lilly and Company. No honorarium
was offered to, or received by, Drs. Davidson and Gross.
Dr. Parente is an employee of Eli Lilly and Company
working in Medical division with Clinical Research in
Diabetes Area. Eli Lilly and Company has a global
agreement with Amylin Pharmaceuticals, Inc. to colla
borate on the development and commercialization of
exenatide. The authors thank Dr. Juliana Helena Abreu
Oliveira, Dr. Maria Claudia Jimenez Hamann, and Mr.
Justin Northrup for their contributions to the development
of the manuscript.

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effective in reducing fasting glucose and PPG, the 2 key

components of A1C (19). A recent systematic review of
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Advances in the investigation of incretin therapies will
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T2DM and help them reach target goals.

Innovative Therapies for Type 2 Diabetes

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Corresponding to:
Jaime A. Davidson
Department of Medicine, Division of Endocrinology,
University of Texas Southwestern Medical School
Dallas, TX 75230, USA
Email: [email protected]

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