Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors - ScienceDirect

Atherosclerosis

Volume 227, Issue 2, April 2013, Pages 349-354

Atherosclerosis

https://doi.org/10.1016/j.atherosclerosis.2012.12.018 Get rights and content

Abstract

Objective

Blood glucose fluctuations have been found to be relevant to the progression of atherosclerosis in patients with type 2 diabetes and to be more detrimental for the development of atherosclerosis than the sustained hyperglycemia. We aim at evaluating the effect of blunted daily acute glucose fluctuations by DPP-IV inhibitors on intima-media thickness (IMT), a surrogate marker for early atherosclerosis.

Methods

Data from a 12-week prospective, randomized, open-label parallel group trial with a blinded-endopoint study on 90 patients with DMT2, assessing the role of Dipeptidyl Peptidase-4 inhibition in lowering oxidative stress and inflammation by reducing daily acute glucose fluctuations (MAGE), were included in the present analysis.

Results

Administration of both sitagliptin and vildagliptin treatment resulted in a significant decline in IMT. Indeed, vs baseline data Vildagliptin vs Sitagliptin resulted in a greater IMT reduction.

After 3 months therapy changes in IMT significantly correlated with changes in MAGE but not with change in HbA1c in the whole population. Only change in MAGE and LDL plasma levels resulted to be independent predictors of the reduced carotid intima-media thickness after adjusting for conventional cardiovascular risk factors in patients with type 2 diabetes. Significant correlations between change in MAGE, change in IMT and change in fasting and interprandial inflammation score and nitrotyrosine plasma levels were found.

Conclusion

Reduction of glucose excursion due to DPP-IV inhibitors administration, may prevent atherosclerosis progression in patients with type 2 diabetes probably through the reduction of daily inflammation and oxidative stress.

Highlights

► We examined the effect of blunted daily acute glucose fluctuations (MAGE) on IMT. ► Type 2 diabetes patients treated by DPP-IV inhibitors were evaluated. ► Change in MAGE resulted to be independent predictors of the reduced IMT. ► Both sitagliptin and vildagliptin treatment resulted in a significant decline in IMT. ► Vildagliptin vs Sitagliptin resulted in a greater IMT reduction.

Introduction

Type 2 diabetes is well known to accelerate the clinical course of atherosclerosis, a condition associated with arterial endothelial dysfunction and several metabolic abnormalities [1], [2]. Blood glucose fluctuations have been found to be relevant to the progression of atherosclerosis in patients with type 2 diabetes and to be more detrimental for the development of atherosclerosis than the sustained hyperglycemia [3], [4], [5], [6], [7]. Such studies strongly suggest that glucose fluctuations over a daily period excursions (MAGE) exhibited a more specific triggering effect on oxidative stress than chronic sustained hyperglycemia [8], [9], [10], [11], [12].

In such context, failure of therapeutic strategy targeting chronic sustained hyperglycemia on reducing cardiovascular events might have been due to the fact that mere control of fasting glucose and HbA1c without control of glycemic excursions over a daily period may be not sufficient for reducing oxidative stress and inflammation and for preventing atherosclerosis.

Recently, a prospective, randomized, open-label parallel group trial in type 2 diabetes [13] showed inhibitors of the Dipeptidyl Peptidase IV (DPP-4), such as vildagliptin or sitagliptin, to reduce glycemic fluctuations over a daily period [13] assessed by mean amplitude of glycemic excursions (MAGE). Reduction of MAGE was significantly associated with reduced markers of systemic vascular inflammation (such interleukin-6, IL-6 and interleukin-18, IL-18) as well as oxidative stress (as estimated from measurement of nitrotyrosine) [13].

As a whole, such data suggest that blunted daily glycemic excursions might prevent endothelial damages and thus macrovascular complications probably through the effect on inflammatory and oxidative stress parameters. Indeed, whether the effects of glycemic excursion reduction may have clinical implication in term of prevention of the progression of atherosclerosis and cardiovascular events is unknown.

Interestingly enough, diabetic patients assigned to vildagliptin treatment had the greatest reduction in glycemic swings over a daily period which correlated with a grater reduction in fasting oxidative stress (as estimated from measurement of nitrotyrosine) and proinflammatory cytokines. These different effects were probably due to a significantly better daily GLP1 profile, having vildagliptin higher GLP1 plasma levels not only during prandial and postprandial but also during interprandial periods [13]. Higher prandial and interprandial GLP1, affecting not only fasting but also interprandial cytokine and nitrotyrosine plasma levels may result in a better inflammatory and oxidative stress profile during over daily period.

Thus, to better evaluate the effect of blunted daily acute glucose fluctuations on the prevention of atherosclerotic process in patients with type 2 diabetes, we extended the data analysis, evaluating the association among reduction of MAGE, intima-media thickness, as a surrogate of carotid atherosclerosis, and oxidative stress and inflammatory parameters during prandial and interprandial periods.

Section snippets

Patients

A prospective, randomized, open-label parallel group trial with a blinded-endopoint (PROBE design) study [13] on 90 patients with DMT2, inadequately controlled by metformin and randomly assigned to receive sitagliptin 100 mg once daily (sitagliptin group) or vildagliptin 50 mg twice daily (vildagliptin group), for a 12-week treatment period was designed [13]. All subjects gave informed consent to participate into the study, which was approved by the Ethical Committee of our Institutions. The

Experimental results

At baseline, anthropometric and clinical data were not different between the two study groups [13]. Basal gluco-metabolic data (HbA1c, fasting and postprandial glucose and MAGE), values of inflammatory and oxidative stress markers were similar in the two study groups. Users and no users of statin drugs were equally distributed between the two groups (Chi square: 0.92; p = 0.33). In the whole population MAGE and postprandial glucose levels were independently associated with both fasting

Discussion

Our study demonstrates that reduction of glucose excursion by DPPVI inhibitors may prevent atherosclerosis progression in patients with type 2 diabetes probably through reduction of over daily inflammation and oxidative stress. The effect was more pronounced in patients treated with vildagliptin.

Diabetes mellitus is one of the major risk factors for atherosclerosis, an inflammatory disease of the arterial wall, in which leukocytes and oxidized lipoproteins accumulate leading to formation of

Conclusions

In conclusion our study firstly demonstrates that reduction of glucose excursion may prevent atherosclerosis progression in patients with type 2 diabetes probably through reduction of over daily inflammation and oxidative stress and support a therapeutic role of DPP-IV inhibitors in preventing cardiovascular complication of diabetes. The effect is more pronounced in patients treated with vildagliptin. Longer follow-up studies, also including a placebo group, in add-on therapy with other

Conflict of interest

None declared.

References (36)

Y. Hu et al.
Postchallenge plasma glucose excursions, carotid intima-media thickness, and risk factors for atherosclerosis in Chinese population with type 2 diabetes
Atherosclerosis
(2010 May)
M. Terasaki et al.
Effects of PKF275-055, a dipeptidyl peptidase-4 inhibitor, on the development of atherosclerotic lesions in apolipoprotein E-null mice
Metabolism
(2012 Jul)
T. Iwai et al.
Glucagon like peptide-1 inhibits LPS-induced IL-1beta production in cultured rat astrocytes
Neurosci Res
(2006)
L. Monnier et al.
Continuous glucose monitoring in patients with type 2 diabetes: why? when? whom?
Diabetes Metab
(2007 Sep)
F. Picconi et al.
Impact of glycemic variability on cardiovascular outcomes beyond glycated hemoglobin. Evidence and clinical perspectives
Nutr Metab Cardiovasc Dis
(2012 Sep)
I.M. Stratton et al.
Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS35)
BMJ
(2000)
M. Coutinho et al.
The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years
Diabetes Care
(1999)
A. Ceriello
Hyperglycaemia and the vessel wall: the pathophysiological aspects on the atherosclerotic burden in patients with diabetes
Eur J Cardiovasc Prev Rehabil
(2010 May)
G. Su et al.
Association of glycemic variability and the presence and severity of coronary artery disease in patients with type 2 diabetes
Cardiovasc Diabetol
(2011 Feb 25)
S. Buscemi et al.
Glycaemic variability using continuous glucose monitoring and endothelial function in the metabolic syndrome and in type 2 diabetes
Diabet Med
(2010 Aug)

A. Di Flaviani et al.

Impact of glycemic and blood pressure variability on surrogate measures of cardiovascular outcomes in type 2 diabetic patients

Diabetes Care

(2011)

L. Monnier et al.

Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes

JAMA

(2006)

I.M. Wentholt et al.

Glucose fluctuations and activation of oxidative stress in patients with type 1 diabetes

Diabetologia

(2008)

L. Quagliaro et al.

Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells: the role of protein kinase C and NAD(P)H-oxidase activation

Diabetes

(2003)

E.M. Horva'th et al.

Rapid ‘glycaemic swings’ induce nitrosative stress, activate poly-(ADP-ribose) polymerase and impair endothelial function in a rat model of diabetes mellitus

Diabetologia

(2009)

S. Theodora et al.

Postchallenge plasma glucose and glycemic spikes are more strongly associated with atherosclerosis than fasting glucose or HbA1c level

Diabetes Care

(2000)

M.R. Rizzo et al.

Reduction of oxidative stress and inflammation by blunting daily acute glucose fluctuations in patients with type 2 diabetes: role of dipeptidyl peptidase-IV inhibition

Diabetes Care

(2012 Oct)

J.R. Crouse et al.

B-mode ultrasound: a noninvasive method for assessing atherosclerosis

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Moreover, Zheng TP and collaborators showed that in T2DM patients greater DPP4 activity correlates with the presence of carotid atherosclerosis, independently from systemic inflammation and insulin resistance [19]. The effects of DPP4-I treatment in ameliorating vascular function in T2DM was investigated in a number of clinical trials showing contrasting results [36–47]. In particular, some studies succeeded in demonstrating FMD amelioration, IMT stabilization and reduced CV disease incidence in T2DM patients treated with DPP4-I in comparison to placebo or standard of care [36–42], whereas other investigations found no significant effects [43–47].
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