OBJECTIVE

To determine if the dipeptidyl peptidase-4 inhibitor vildagliptin more effectively inhibits glucagon levels than the sulfonylurea glimepiride during a meal.

RESEARCH DESIGN AND METHODS

Glucagon responses to a standard meal were measured at baseline and study end point (mean 1.8 years) in a trial evaluating add-on therapy to metformin with 50 mg vildagliptin b.i.d. compared with glimepiride up to 6 mg q.d. in type 2 diabetes (baseline A1C 7.3 ± 0.6%).

RESULTS

A1C and prandial glucose area under the curve (AUC)0–2 h were reduced similarly in both groups, whereas prandial insulin AUC0–2 h increased to a greater extent by glimepiride. Prandial glucagon AUC0–2 h (baseline 66.6 ± 2.3 pmol · h−1 · l−1) decreased by 3.4 ± 1.6 pmol · h−1 · l−1 by vildagliptin (n = 137) and increased by 3.8 ± 1.7 pmol · h−1 · l−1 by glimepiride (n = 121). The between-group difference was 7.3 ± 2.1 pmol · h−1 · l−1 (P < 0.001).

CONCLUSIONS

Vildagliptin therapy but not glimepiride improves postprandial α-cell function, which persists for at least 2 years.

Glucagon levels are increased in type 2 diabetes because of impaired glucose-mediated suppression of glucagon secretion resulting in increased hepatic glucose output with subsequent hyperglycemia (1). Improved glycemia by the dipeptidyl peptidase-4 inhibitor, vildagliptin (2), is mediated primarily by improved β- and α-cell sensitivity to glucose (3). As an add-on to metformin, vildagliptin displays equal efficacy as glimepiride, with the added benefits of a much lower risk of hypoglycemia and no weight gain (4). Here we report prandial assessments of glucagon levels and insulin secretion rates after up to ∼2 years of therapy with the two drugs.

The study was an extension to 2 years of a previously described study (4). Standard meal challenge was performed in selected centers at last treatment visit after administration of a morning dose of metformin plus 50 mg vildagliptin or up to 6 mg glimepiride (mean treatment period 1.8 years). Doses were selected to achieve comparable improvements in glycemia. After an overnight fast, a mixed meal was served (orange juice [180 ml], two slices [60 g] of white bread, 30 g jam, 15 g butter or margarine, 120 ml whole milk [3–4% fat] or equivalent amount of cheese plus 120 ml water, and, if desired, decaffeinated coffee or tea; 510 kcal, with 50% from carbohydrate, 38% from fat, and 12% from protein). Blood samples were taken before the meal and at 15, 30, 60, 90, 120, 180, and 240 min.

Analytical determinations

Plasma glucose concentration was determined by the glucose oxidase method (Beckman Glucose Analyzer II; Beckman Instruments, Fullerton, CA). Plasma insulin, C-peptide, and glucagon concentrations were determined by radioimmunoassay (Diagnostics Products, Los Angeles, CA). Plasma intact glucagon-like peptide (GLP)-1 concentration was measured by ELISA using an NH2-terminal–specific antibody (Linco Research, St. Charles, MO) by Novartis.

Calculations

Insulin secretory rate was determined as described previously (5). The absolute and incremental/decremental areas under the curve (AUCs) for time 0–2 h after the meal were calculated using the trapezoidal method. End point changes from baseline were assessed using ANCOVA.

Ethics

The study was conducted in accordance with the Declaration of Helsinki. It was reviewed by an independent ethics committee or institutional review board for each center. Written informed consent was obtained from each subject.

Baseline characteristics were as follows: patient demographics of the subpopulation who participated in the meal challenge (n = 259) were essentially the same as reported previously (4). Mean baseline A1C was 7.3 ± 0.6%.

A1C, glucose, and insulin

At the follow-up meal test (up to 2 years after start; mean 1.8 years), A1C was reduced by −0.1 ± 0.9% in the vildagliptin group (n = 137) versus −0.2 ± 0.8% in the glimepiride group (n = 121). Prandial glucose AUC0–2 h was similarly reduced in both groups (−1.7 mmol · h−1 · l−1 for vildagliptin vs. −2.1 mmol · h−1 · l−1 for glimepiride), whereas prandial insulin 1 AUC0–2 h increased to a greater extent in the glimepiride group (33 ± 18 pmol · h−1 · l−1 for vildagliptin vs. 91 ± 19 pmol · h−1 · l−1 for glimepiride) (P = 0.017).

Glucagon, GLP-1, and insulin secretion

Prandial glucagon AUC0–2 h decreased from baseline with vildagliptin treatment but increased with glimepiride (−3.4 ± 1.6 pmol · h−1 · l−1 for vildagliptin vs. 3.8 ± 1.7 pmol · h−1 · l−1 for glimepiride; P < 0.001; Fig. 1,A). Prandial intact GLP-1 AUC0–2 h increased in both groups but was much larger after vildagliptin (18.8 ± 1.8 pmol · h−1 · l−1 for vildagliptin vs. 1.6 ± 1.7 pmol · h−1 · l−1 for glimepiride; Fig. 1,B). Insulin secretion rate relative to glucose (0–2 h) increased in both groups (4.3 ± 0.9 pmol/min/m2/mmol/l for glimepiride vs. 1.6 ± 0.9 pmol/min/m2/mmol/l for vildagliptin; P = 0.022; Fig. 1 C). Prandial insulin-to-glucagon ratio (AUC0–2 h for insulin/AUC0–2 h for glucagon) changed by −1.1 ± 9.3 (baseline 7.4 ± 0.4) pmol insulin/pmol glucagon in the vildagliptin group versus −7.3 ± 9.8 (baseline 7.1 ± 0.4) pmol insulin/pmol glucagon in the glimepiride group (P = 0.62).

Figure 1

Changes in prandial glucagon AUC0–2 h, prandial GLP-1 AUC2 h, insulin secretory rate relative to glucose (ISR/G), and HOMA-IR after up to a 2-year (mean 1.8 years) add-on treatment with vildagliptin (50 mg b.i.d.; n = 137) or glimepiride (up to 6 mg; n = 121) in patients with type 2 diabetes inadequately controlled with prior metformin therapy. Means ± SD are shown. The asterisk indicates P < 0.001 (A), P < 0.001 (B), P = 0.022 (C), and P < 0.001 (D) between the groups.

Figure 1

Changes in prandial glucagon AUC0–2 h, prandial GLP-1 AUC2 h, insulin secretory rate relative to glucose (ISR/G), and HOMA-IR after up to a 2-year (mean 1.8 years) add-on treatment with vildagliptin (50 mg b.i.d.; n = 137) or glimepiride (up to 6 mg; n = 121) in patients with type 2 diabetes inadequately controlled with prior metformin therapy. Means ± SD are shown. The asterisk indicates P < 0.001 (A), P < 0.001 (B), P = 0.022 (C), and P < 0.001 (D) between the groups.

Close modal

Insulin resistance

Fasting insulin (15.2 ± 1.6 pmol/l for glimepiride vs. 5.7 ± 1.6 pmol/l for vildagliptin; P < 0.001) and HOMA-IR (0.11 ± 0.10 for vildagliptin vs. 0.63 ± 0.10 for glimepiride; P < 0.001; Fig. 1 D) increased in both treatment groups with larger increases with glimepiride.

Vildagliptin reduces glucagon levels after a standard mixed meal in patients with type 2 diabetes who are treated with metformin, as was previously demonstrated in individuals with IGT (6), IFG (7), and type 1 diabetes (8). This effect appears to be the result of a GLP-1–induced improvement in glucose sensitivity of the α-cells (3,9). In contrast, glimepiride increases glucagon levels, which may be the result of attenuation of the glucose sensitivity of the α-cells with uncoupling of glucose dependency (10).

With respect to β-cell function, vildagliptin increases glucose sensitivity (11), whereas indirect data suggest that sulfonylurea uncouples the glucose dependency of the β-cells, which attenuates glucose sensitivity (10). In this study, this resulted in increased insulin secretion by both treatments, although vildagliptin did not increase the insulin secretion rate as much as glimepiride. The greater insulin secretion rate in the glimepiride group was balanced by less insulin resistance in the vildagliptin group, as reflected by HOMA-IR and lower postprandial glucagon levels resulting in similar glucose levels.

In summary, prandial glucagon is increased by glimepiride but reduced by vildagliptin. Hence, vildagliptin effectively targets glucagon secretion in the treatment of diabetes. This together with the lesser increase in insulin by vildagliptin than by glimepiride may provide a pathophysiological explanation for the observation that vildagliptin's effect of reducing A1C levels below 7% is associated with much less hypoglycemia than glimepiride while being associated with the same A1C reduction (4).

Clinical trial reg. no. NCT00106340, clinicaltrials.gov.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This study was funded by Novartis Pharmaceuticals. D.R.M. is a Senior Investigator of the National Institute of Health Research (NIHR), U.K., and acknowledges NIHR funding support. E.F. has received consulting fees from Novartis Pharmaceuticals. V.A.F. has received funding for research and consulting/speaking for Novartis as well as from other manufacturers of drugs in this class, including Merck, Novo-Nordisk, Eli Lilly, Takeda, and Glaxo. B.Z. has received research support and consulting fees from Novartis Pharmaceuticals. B.A. has received funding and consulting fees from Novartis Pharmaceuticals. D.R.M. has received consulting fees from Novartis as well as from other manufacturers of drugs in this class, including Novo-Nordisk and Merck. He has also received lecturing honoraria from Eli Lilly and Novo-Nordisk. J.F. and S. D. are employees of Novartis Pharmaceuticals. No other potential conflicts of interest relevant to this article were reported.

The authors gratefully acknowledge the investigators, those who participated in any part of the study (listed previously in Ferrannini et al. [4]), staff at the 402 participating sites, and the editorial assistance of Gali Venkateswara Prasad and Shivali Arora, PhD (both from Novartis, India).

1.
Balas
B
,
Baig
MR
,
Watson
C
,
Dunning
BE
,
Ligueros-Saylan
M
,
Wang
Y
,
He
YL
,
Darland
C
,
Holst
JJ
,
Deacon
CF
,
Cusi
K
,
Mari
A
,
Foley
JE
,
DeFronzo
RA
.
The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients
.
J Clin Endocrinol Metab
2007
;
92
:
1249
1255
2.
Ahrén
B
,
Landin-Olsson
M
,
Jansson
PA
,
Svensson
M
,
Holmes
D
,
Schweizer
A
.
Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes
.
J Clin Endocrinol Metab
2004
;
89
:
2078
2084
3.
Ahrén
B
,
Foley
JE
.
The islet enhancer vildagliptin: mechanisms of improved glucose metabolism
.
Int J Clin Pract Suppl
2008
;
159
:
8
14
4.
Ferrannini
E
,
Fonseca
V
,
Zinman
B
,
Matthews
D
,
Ahrén
B
,
Byiers
S
,
Shao
Q
,
Dejager
S
.
Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy
.
Diabetes Obes Metab
2009
;
11
:
157
166
5.
Pratley
RE
,
Schweizer
A
,
Rosenstock
J
,
Foley
JE
,
Banerji
MA
,
Pi-Sunyer
FX
,
Mills
D
,
Dejager
S
.
Robust improvements in fasting and prandial measures of beta-cell function with vildagliptin in drug-naïve patients: analysis of pooled vildagliptin monotherapy database
.
Diabetes Obes Metab
2008
;
10
:
931
938
6.
Rosenstock
J
,
Foley
JE
,
Rendell
M
,
Landin-Olsson
M
,
Holst
JJ
,
Deacon
CF
,
Rochotte
E
,
Baron
MA
.
Effects of the dipeptidyl peptidase-IV inhibitor vildagliptin on incretin hormones, islet function, and postprandial glycemia in subjects with impaired glucose tolerance
.
Diabetes Care
2008
;
31
:
30
35
7.
Utzschneider
KM
,
Tong
J
,
Montgomery
B
,
Udayasankar
J
,
Gerchman
F
,
Marcovina
SM
,
Watson
CE
,
Ligueros-Saylan
MA
,
Foley
JE
,
Holst
JJ
,
Deacon
CF
,
Kahn
SE
.
The dipeptidyl peptidase-4 inhibitor vildagliptin improves β-cell function and insulin sensitivity in subjects with impaired fasting glucose
.
Diabetes
2008
;
31
:
108
113
8.
Foley
JE
,
Ligueros-Saylan
M
,
He
YL
,
Holst
JJ
,
Deacon
CF
,
Dunning
BE
,
Leone-Jones
A
,
Yu
T
,
Kelley
DE
.
Effect of vildagliptin on glucagon concentration during meals in patients with type 1 diabetes
.
Horm Metab Res
2008
;
40
:
727
730
9.
Ahrén
B
,
Schweizer
A
,
Dejager
S
,
Dunning
BE
,
Nilsson
PM
,
Persson
M
,
Foley
JE
.
Vildagliptin enhances islet responsiveness to both hyper- and hypoglycemia in patients with type 2 diabetes
.
J Clin Endocrinol Metab
2009
;
94
:
1236
1243
10.
de Heer
J
,
Holst
JJ
.
Sulphonylurea compounds uncouple the glucose dependence of the insulinotropic effect of glucagon-like peptide 1
.
Diabetes
2007
;
56
:
438
443
11.
Mari
A
,
Scherbaum
WA
,
Nilsson
PM
,
Lalanne
G
,
Schweizer
A
,
Dunning
BE
,
Jauffret
S
,
Foley
JE
.
Characterization of the influence of vildagliptin on model-assessed β-cell function in patients with type 2 diabetes and mild hyperglycemia
.
J Clin Endocrinol Metab
2008
;
93
:
103
109
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