hypertension and type 2 diabetes mellitus ( dm ) are among the main risk factors for the development of cardiovascular disease ( cvd ) .
endothelial dysfunction , associated with dm and hypertension , is considered an early marker of vascular complications and a pathophysiological determinant of atherogenic processes .
pharmacotherapy for dm should not only improve blood glucose control , but also provide beneficial glucose - independent cardiovascular effects .
dipeptidyl peptidase-4 ( dpp-4 ) inhibitor is an incretin - based drug approved for the treatment of dm .
this medication reduces the breakdown of glucagon - like peptide 1 ( glp-1 ) , thereby increasing circulating glp-1 levels , improving metabolic control by increases in insulin secretion , followed by decreases in glucagon secretion .
recently , several methods have been developed to assess endothelial function , and predict the presence or absence of coronary heart disease ( chd ) .
applanation tonometry ( at ) of the radial artery is a noninvasive method that indirectly assesses arterial stiffness by calculating the central blood pressure ( bp ) and the augmentation index ( aix ) .
the aix is associated with cardiovascular risk , and is a predictor of chd development .
more recently , the central systolic blood pressure ( sbp ) of the aortic or carotid arteries has become more important than the brachial sbp in the assessment of cardiovascular risk .
this case report describes a possible pleiotropic action of a dpp-4 inhibitor ( vildagliptin ) on the central sbp assessed by at in a hypertensive diabetic woman .
this pharmacological class seems to have action in reduction of central bp and arterial stiffness .
thus , we justify the possible pathophysiological mechanisms involved in the association between hyperglycemia , endothelial dysfunction , and vascular stiffness , besides how the glp-1 system provides beneficial effect on the endothelium .
the patient was a 54-year - old white woman with a 4-year history of hypertension and dm .
she was taking metformin ( 850  mg / d ) , pioglitazone ( 30  mg / d ) , simvastatin ( 10  mg / d ) , amlodipin ( 5  mg / d ) , and enalapril ( 10  mg / d ) ; however , she did not adhere to a diet to control the diabetes .
her physical examination revealed bp : 123/85 mm hg , heart rate : 78  bpm , body mass index ( bmi ) : 29.1  kg / m , and waist circumference : 91  cm .
she had no abnormalities of the heart , lungs , or abdomen . according to complementary exams , the patient had poor diabetic control with glycosylated hemoglobin ( hba1c ) : 11.2% ; however , microalbuminuria and other biochemical parameters were normal .
the patient received guidance to modify her lifestyle including diet and exercise , and vildagliptin ( 100  mg / d ) was added to her drug regimen .
the patient was submitted to examinations of the radial artery using a commercially available automated at system ( hem-9000ai ; omron healthcare co. , ltd , kyoto , japan ) before receiving vildagliptin and 3 months after to evaluate the drug 's effect on the central sbp and aix .
this examination was performed in a quiet controlled environment ( temperature between 21c to 24c ) , between 8 am and 10 am , after the patient was rested for at least 10 minutes sitting with the legs uncrossed , the bladder empty , and away from acute stressors .
the patient was instructed to fast starting the night before testing and to refrain from ingesting alcohol or caffeine .
the at equipment uses a radial ultrasonic transducer and cuffs with the correct size for the arm circumference as recommended by the guidelines to evaluate bp .
pulse wave analyses were performed at least 3 times and the mean of measurements was calculated .
variations of bp between the measurements should not be > 5% . at the end of the 3-month follow - up period ,
the patient had good adherence to diet and exercise and had lost 3  kg , presenting with a bmi of 27.5  kg / m , and an office bp of 100/70  mm hg .
central sbp and aix were lower than in the baseline results . before the association of vildagliptin and metformin , the peripheral sbp was 129  mm hg during the at .
the central sbp ( aortic ) and adjusted aix for a heart rate of 75  bpm ( aix75 ) were 127  mm hg and 96% , respectively ( figure 1a ) .
after receiving vildagliptin for 3 months , the peripheral sbp was 116  mm hg , central sbp was 101  mm hg , and aix75 was 72% ( figure 1b ) during the at .
so , there were reductions in both the central sbp and aix with central sbp becoming 15  mm hg lower than the peripheral sbp .
i affirm that the patient has given the informed consent for publication of the case .
( a ) before association of vildagliptin and metformin , sys1 was 129  mm hg .
sys2 and adjusted aix for a heart rate of 75  bpm ( aix75 ) were 127  mm hg e 96% , respectively .
sys2 ( central ) was only 2  mm hg lower than the peripheral systolic blood pressure and this difference should be about 15 to 20  mm hg or 15% lower than sys1 .
( b ) after 3 months of vildagliptin and metformin association , sys1 was 116  mm hg , sys2 was 101  mm hg , and aix75 was 72% .
both sys2 and aix presented reduction and sys2 had become 15  mm hg lower than the sys1 .
aix  =  augmentation index , aix75  =  adjusted augmentation index for a heart rate of 75  bpm , sys1  =  peripheral systolic blood pressure , sys2  =  central systolic blood pressure .
preventive strategies are important to reduce cardiovascular risk . an assessment and stratification of cardiovascular risk
should be considered in order to identify individuals at higher risk of developing cardiovascular events .
thus , the adoption of preventive and pharmacological strategies is important to delay possible cardiovascular complications . in recent years
, several methods have been developed to predict cardiovascular risk , including the use of ultrasound to measure the carotid intima - media thickness ( cimt ) and the aortic pulse wave velocity , and computed tomography to identify and quantify calcification of coronary arteries , among others . in this case , the at of the radial artery was used to assess vascular disease . in young healthy individuals , the central sbp ( aortic ) should be between 15 and 20  mm hg lower than the peripheral sbp ( brachial ) . before dpp-4 inhibitor use in this patient , the central sbp was only 2  mm hg lower than the peripheral sbp .
after 3 months in use of vildagliptin , the difference between the central sbp and peripheral sbp increased to 15  mm hg .
this finding might be explained by the effect of the drug on the arterial tree , that is , it may represent a reduction in arterial stiffness .
, aix also improved after dpp-4 inhibitor use , even though both were normal at baseline .
aix is associated with cardiovascular risk as it identifies the presence or absence of chd , and thus it is also considered a marker of vascular stiffness . according to european society of hypertension guidelines ,
the evaluation of asymptomatic target organ damage ( tod ) is crucial in determining the cardiovascular risk in hypertensive individuals . among the tod to be assessed
is vascular stiffness , which can predict cardiovascular mortality independently of the stratification scores of cardiovascular risk .
the evaluation of central hemodynamic , including carotid - femoral pulse wave velocity , central bp , and aix , is important to determine the true cardiovascular risk .
the guidelines state that the measurement of central hemodynamic parameters is of great interest to mechanistic analyses in pathophysiology , pharmacology , and therapeutics , and that the central bp represents the true load imposed on heart , brain , kidney , and large arteries instead of the brachial bp .
thus , both central bp and aix present better predictive value for cardiovascular events and for the differential effect of antihypertensive drugs compared to the brachial bp .
endothelial dysfunction is considered an early marker of vascular complications and a pathophysiological determinant of the atherogenesis that occurs in the early stages of chd .
exposure to cardiovascular risk factors may trigger the atherosclerotic process that evolves with oxidative stress and nitric oxide ( no ) inactivation .
endothelial dysfunction comprises a number of functional alterations such as impaired endothelium - dependent vasodilatation , impaired barrier function , and higher inflammatory and pro - coagulant activity . although pharmacotherapy based on the glp-1 system may provide beneficial effects to the endothelium ( figure 2 ) , there are no studies on the central bp .
however , this study included an invasive method to assess endothelial function , which is not applicable in the clinical practice .
sitagliptin , another dpp-4 inhibitor , demonstrated the same beneficial effects : an increase in endothelial progenitor cells by inhibiting the degradation of the chemokine stromal - derived factor 1-alpha and improved endothelial function in uncontrolled diabetic patients . some studies on this class of drugs have shown effects on no modulation .
liraglutide , a new glp-1 receptor agonist , reduced the plasminogen activator inhibitor 1 and asymmetric dimethylarginine levels and , consequently , improved no availability .
pathophysiological mechanisms that associate hyperglycemia , endothelial dysfunction , arterial stiffness , and cardiovascular disease .
this figure explains how the hyperglycemia causes endothelial damage , which results in arterial stiffness and increased central bp .
the glp-1 system provides beneficial effect on the endothelium in 2 ways , directly in the oxidative stress modulation ( blocked arrow ) or indirectly in the insulin production increase .
the elevated central bp and aix may interfere in the endothelial dysfunction ( dashed arrow ) , and contribute to the arterial stiffness .
aix  =  augmentation index , bp  =  blood pressure , chd  =  coronary heart disease , cvd  =  cardiovascular disease , dpp-4  =  dipeptidyl peptidase-4 , glp-1  =  glucagon - like peptide 1 , tod  =  target organ damage .
firstly , a vasodilator response to acetylcholine was observed in the vascular bed . in second place , vildagliptin is able to control the daily acute glucose fluctuations and delay the progression of atherosclerosis in dm . in this study
, it was demonstrated that the cimt , a surrogate of carotid atherosclerosis , decreased 3 months after the use of both vildagliptin and sitagliptin .
finally , glp-1 has been shown to exert anti - inflammatory effects on different tissues and to decrease daily oxidative stress parameters .
thus , the decrease in the cimt might be mediated by improved vascular inflammation and endothelial dysfunction . in the present study ,
to better differentiate the effect of dpp-4 inhibitors on hemodynamic parameters ( endothelial function , arterial stiffness , peripheral , and central sbp ) , it is important to consider the role played by changes in lifestyle on these benchmarks .
some authors showed that individuals treated with dpp-4 inhibitors presented reductions in peripheral sbp independent of decreases in blood glucose and without reducing bmi . on the contrary , in obese patients with type 2 diabetes , treatment using dpp-4 inhibitors in combination with metformin was associated with improvements in glycemic control and a reduction in body weight .
thus , it remains to be seen whether the reduction in bp with dpp-4 inhibitor treatment is related to the improvements in blood glucose and the drop in body weight or the effects of this therapeutic drug itself or both .
recently , a study showed that weight loss was significantly and independently associated with central bp and brachial bp .
however , the study population included a small number of hypertensive ( 35.8% ) and diabetic ( 15.8% ) patients .
in morbidly obese dysglycemic subjects without hypertension , modest weight loss reduced arterial stiffness . another study demonstrated that 10.6% of weight loss did not influence the vascular stiffness in a nondiabetic population . in obese children and adolescents ,
moreover , low - fat versus low - carbohydrate diet in adults without dm demonstrated significant weight loss in both groups .
however , arterial stiffness improved only in the group following the low - fat diet . in conclusion , with these data , the effect of weight loss on arterial stiffness is not clear , suggesting that more studies are necessary , including a study with a specific population ( hypertensive and dm without coronary disease ) . in relationship to exercise , there is evidence that resistance training has an effect on the central bp ; however , the patient in this case did not do intense exercising . in respect to hba1c ,
some studies demonstrated weight loss in adults with dm managed by low - carbohydrate diet , but the hba1c level decreased only by 0.6% to 1.0% , while the weight loss was between 1.2 and 4.2  kg .
these studies justified that weight loss participated in glycemic control , but it was not enough to decrease the hba1c level .
furthermore , studies have shown solely reduction in peripheral bp with the use of dpp-4 inhibitors , without observing the effects on the central bp .
so , we strongly believe that vildagliptin was the main responsible for the improvement in endothelial function , and peripheral and central sbp . anyway , as we know that one case report is not proof of the effect of dpp-4 inhibitor on central bp , a study that evaluates the endothelial function and glucose - independent beneficial cardiovascular effects of dpp-4 inhibitor is being carried out with this purpose .
vilela - martin , md , phd , unpublished data , february 2015 , https://clinicaltrials.gov/ct2/show/nct02145611?term=vildagliptin&rank=8 ) .
in conclusion , to the best of our knowledge this is the first report that suggests an effect of the dpp-4 inhibitor on arterial stiffness parameter ( central bp ) in a hypertensive and type 2 diabetic individual , using a noninvasive method for evaluating the central bp .
other studies that evaluate the endothelial function and show glucose - independent beneficial cardiovascular effects of dpp-4 inhibitor are expected .
 abstracthypertension and type 2 diabetes mellitus ( dm ) are among the main risk factors for the development of cardiovascular disease . 
 pharmacotherapy for dm should not only improve blood glucose control , but also provide beneficial glucose - independent cardiovascular effects . 
 the central systolic blood pressure ( sbp ) has become more important than the brachial sbp in the assessment of cardiovascular risk.this case report describes the effect of vildagliptin , a dipeptidyl peptidase-4 ( dpp-4 ) inhibitor , on the central sbp in a 54-year - old woman with hypertension and dm . 
 she was submitted to applanation tonometry ( at ) before and after vildagliptin association . at of the radial artery 
 is a non - invasive method that indirectly assesses arterial stiffness by calculating the central sbp and the augmentation index ( aix).after 3 months of follow - up using vildagliptin , central sbp and aix were improved . 
 moreover , she presented better glycemic control.this case suggests an effect of dpp-4 inhibitor on arterial stiffness parameter ( central sbp ) in a hypertensive and diabetic patient , which shows a glucose - independent beneficial cardiovascular effect of this group of drugs . 
INTRODUCTION
CASE REPORT
DISCUSSION
CONCLUSION