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592 • J Clin Pharmacol 2008;48:592-598
The effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on ambulatory blood pressure was assessed in nondia- betic patients with mild to moderate hypertension in a randomized, double-blind, placebo-controlled, 3-period crossover study. Nineteen patients on stable treatment with antihypertensive agent(s) received sitagliptin 100 mg b.i.d., 50 mg b.i.d., or placebo for 5 days, with at least a 7-day washout interval between periods. Twenty-four–hour ambulatory blood pressure, including systolic blood pres- sure, diastolic blood pressure, and mean arterial pressure, were monitored on days 1 and 5. Relative to placebo on day 1, the mean difference in 24-hour systolic blood pres- sure was –0.9 mm Hg (90% confidence interval: –2.9 to 1.1; P = .46) with sitagliptin 50 mg b.i.d. and –2.8 mm Hg (90% confidence interval: –4.9 to –0.8; P < .05) with 100 mg b.i.d. On day 5, the mean difference in 24-hour systolic blood pressure was –2.0 mm Hg (90% confidence interval: –3.5 to –0.4; P < .05) with 50 mg b.i.d. and –2.2 mm Hg
(90% confidence interval: –3.7 to –0.6; P < .05) with 100 mg b.i.d. relative to placebo. For 24-hour diastolic blood pressure, there were no between-group differences in mean 24-hour diastolic blood pressure on day 1. On day 5, sitagliptin 50 mg and 100 mg b.i.d significantly (P < .05) lowered mean 24-hour diastolic blood pressure by –1.8 mm Hg (90% confidence interval: –2.8 to –0.8) and –1.6 mm Hg (90% confidence interval: –2.6 to –0.7), respec- tively, relative to placebo. Sitagliptin produced small but statistically significant reductions of 2 mm Hg to 3 mm Hg in 24-hour ambulatory blood pressure measurements acutely (day 1) and at steady state (day 5), and was gener- ally well tolerated in nondiabetic patients with mild to moderate hypertension.
Keywords: DPP-4; incretin; sitagliptin; blood pressure Journal of Clinical Pharmacology, 2008;48:592-598
© 2008 the American College of Clinical Pharmacology
Effect of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, on Blood Pressure
in Nondiabetic Patients With Mild to Moderate Hypertension
Goutam C. Mistry, MSc, Andrea L. Maes, MS, Kenneth C. Lasseter, MD, Michael J. Davies, PhD, Keith M. Gottesdiener, MD, FACP, John A. Wagner, MD, PhD,
and Gary A. Herman, MD
Dipeptidyl peptidase-4 (DPP-4) inhibitors, suchas sitagliptin and vildagliptin, represent a new class of antihyperglycemic agents recently approved for the treatment of patients with type 2 diabetes.1
Dipeptidyl peptidase-4 inhibitors are incretin
enhancers that act by inhibiting the inactivation and degradation of the intact (active) incretins, glucagon- like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).2 Following a meal, these incretins regulate glucose by stimulating insulin release (GLP-1 and GIP) and suppressing glucagon release (GLP-1) in a glucose-dependent manner.3
Treatment with native GLP-1 and GLP-1 receptor agonists have been reported to increase blood pres- sure and heart rate in animal models.4,5 Conversely, continuous infusion of GLP-1 produced small, non- significant decreases in blood pressure (BP) in patients with type 2 diabetes.6 Since DPP-4 inhibitors increase fasting and postprandial levels of active
From Merck Research Laboratories, Rahway, New Jersey (Mr Mistry, Ms Maes, Dr Davies, Dr Gottesdiener, Dr Wagner, Dr Herman), and Clinical Pharmacology Associates, Miami, Florida (Dr Lasseter). Submitted for publi- cation November 21, 2007; revised version accepted February 20, 2008. Address for correspondence: Gary A. Herman, MD, Department of Experimental Medicine, Merck Research Laboratories, RY34-A400, 126 East Lincoln Avenue, Rahway, NJ 07065; e-mail: [email protected]. DOI: 10.1177/0091270008316885
EFFECTS OF THE DPP-4 INHIBITOR SITAGLIPTIN ON AMBULATORY BLOOD PRESSURE
PHARMACOKINETICS AND PHARMACODYNAMICS 593
GLP-1,7 and considering that 20% to 60% of patients with diabetes have hypertension,8 it was of interest to assess the effects of sitagliptin on BP in a highly con- trolled study early in the development of sitagliptin, prior to initiating large scale trials in patients with type 2 diabetes. Moreover, the effect of sitagliptin on BP was assessed in the acute state (day 1) and at steady state (day 5). Although it was reasonable to assume that BP might be reduced, it was also impor- tant to assess whether it might be increased given the importance of this comorbid condition.
METHODS
The study was conducted according to the provi- sions of the Declaration of Helsinki, and written informed consent was obtained from each study par- ticipant prior to conducting any protocol-related procedure. The study was approved by the Southern Institutional Review Board in Miami, Florida.
Patients
Men and women aged 18 to 70 years were eligible for participation if they had a documented diagnosis of mild to moderate hypertension on stable antihy- pertensive agent treatment and the following vital sign findings after at least 5 minutes in a sitting posi- tion and confirmed by repeated tests: (1) systolic blood pressure (SBP) >95 or ≤160 mm Hg; (2) dias- tolic blood pressure (DBP) >50 or ≤95 mm Hg; (3) a decrease in SBP of <20 mm Hg or increase in heart rate (HR) of <30 beats per minute (bpm) when stand- ing from the sitting position; and (4) a pulse rate >40 bpm in the sitting position.
As noted, patients were required to be on stable treatment (type of medication, dose, and regimen) with one or more antihypertensive medication(s) for at least 6 weeks prior to the start of the study and to remain on the same regimen throughout the entire study. Patients were restricted to 2 antihypertensive agents, with or without a diuretic, to avoid adverse experiences resulting from polypharmacy. Prior to randomization, on days –7, –4 and –1, patients had to demonstrate a maximum BP of ≤160/95 mm Hg, and the average DBP on days –4 and –1 must not have differed by more than 10 mm Hg using a man- ual sphygmomanometer.
The patients were required to be in generally good health without type 2 diabetes or clinically signifi- cant abnormalities unrelated to hypertension, as determined on the basis of medical history, physical
examination, vital signs, 12-lead electrocardiograms (ECGs), and laboratory safety tests (hematology, blood chemistry, urinalysis), including a creatinine clearance ≥60 mL/min. A history of clinically signif- icant cardiovascular disease (stroke, active angina, myocardial infarction, or claudication) precluded patients from entering the study. With the exception of the medications used to treat hypertension and dyslipidemia, patients were prohibited from taking other prescription or nonprescription medications.
Study Design
This was a randomized, double-blind, placebo- controlled, double-dummy, 3-period, crossover study in 19 nondiabetic patients with mild to moderate hypertension. The patients received either sitagliptin 50 mg b.i.d., sitagliptin 100 mg b.i.d., or placebo b.i.d. at approximately 9 AM and 9 PM for 5 days for 3 periods. Five days of drug administration with sitagliptin was chosen because previous clinical studies have demonstrated that steady-state trough concentrations were generally attained within 3 days after the start of drug administration.9 Ambulatory BP was monitored for 24 hours on days 1 and 5 in each period. All patients had study drug adminis- tered concomitantly with their standard of care ther- apy. There was at least a 7-day washout interval for study drug in between treatment periods to ensure no carryover effect of sitagliptin. During the washout intervals prior to periods 2 and 3, documented tele- phone contact was made daily with patients to ensure compliance with the antihypertensive ther- apy. Patients were domiciled in the clinical research unit (CRU) on day 1 and day 5 of each period when ambulatory BP was being monitored. On days 2 through 4, patients returned to the CRU in the morn- ing for study drug dosing by the medical personnel and adverse experience assessment, and compliance was verified for the previous evening’s dose.
Ambulatory Blood Pressure Measurement
Continuous 24-hour ambulatory BP measurements (ABPM) were obtained on days 1 and 5 of each period with an ABPM unit (model 90207; SPACE- LABS, Issaquah, Washington), which was applied to the nondominant arm immediately prior to the morning dose of study drug. Ambulatory BP measurements were collected every 15 minutes from 8 AM to mid- night, and every 20 minutes from midnight to 8 AM the following day. The ABPM unit was removed
594 • J Clin Pharmacol 2008;48:592-598
after the 8 AM reading on day 2 prior to dosing and on day 6 at 24 hours following the morning dose on day 5.
Ambulatory Blood Pressure Endpoints
The primary endpoint was 24-hour SBP on day 1. Secondary endpoints included 24-hour SBP on day 5, 24-hour DBP on days 1 and 5, and 24-hour MAP on days 1 and 5. In addition, the maximum moving average decrease during 4 hours was determined for the 0 to 4–hour and 4 to 8–hour postdose intervals.
Safety and Tolerability
Safety and tolerability were assessed by the review of safety evaluations, including clinical and labora- tory adverse experiences, laboratory safety tests (hematology, blood chemistry, and urinalysis), rest- ing and orthostatic vital signs, physical examina- tions, and ECGs.
Statistical Analyses
The BP parameters (mean 24-hour SBP, mean 24- hour DBP, and 24-hour MAP) were compared after administration of 50 mg of sitagliptin b.i.d., 100 mg of sitagliptin b.i.d., and placebo for 5 days. For days 1 and 5, between-treatment comparisons were per- formed using an analysis of variance (ANOVA) appropriate for a 3-period, crossover design with fac- tors for subject, period, and treatment. Baseline BP was the predose measurement prior to the start of study drug administration on day 1 in each period. A P value ≤ .05 was considered statistically significant.
For the power calculation, if the true mean differ- ence of 24-hour SBP (sitagliptin—placebo) is 0, then a sample size of 18 patients provides this study with 99% probability of observing the 90% confidence interval (CI) for the difference (sitagliptin—placebo) above the prespecified bound of –14 mm Hg. If the true mean difference of 24-hour SBP is –8 mm Hg, then a sample size of 18 patients provides this study with 90.7% probability of observing the 90% CI for the difference above the prespecified bound of –14 mm Hg. This calculation was based on a within- patient standard deviation for the mean 24-hour ambulatory SBP measurements of 5.9 mm Hg observed in a similarly designed trial.
In exploratory analyses, summary statistics for ambulatory SBP, ambulatory DBP, and MAP during the time intervals of 0 to 4 hours and 4 to 8 hours
postdose were calculated. In order to account for large spurious ambulatory measurements, an analy- sis of moving averages was also performed. Moving averages were calculated during each of the 3 con- secutive 15-minute measurements. For each patient, the maximum moving average decrease (minMA) during 4 hours for SBP or DBP was computed for each of the two 4-hour intervals, 0 to 4 hours (minMA0-4) and 4 to 8 hours (minMA4-8).
RESULTS
Demographics
Nineteen patients (7 men; 12 women) were enrolled, and 18 patients completed the study. Two patients were discontinued from the study, one of which reenrolled (see below). One patient was discontinued on period 1, day 3 because the patient did not report to the CRU for dosing and was replaced. Due to a malfunction of the ambulatory BP monitor, another patient, after receiving the morning 50-mg dose of sitagliptin, was discontinued on day 1 of period 1 but reenrolled with a new randomization number. In the enrolled study population, the mean age was 57.3 years (range, 39-67 y), mean body mass index (BMI) was 28.6 kg/m2 (range, 21.9-35.7 kg/m2), and mean sitting BP on days –7, –4, and –1 was 141/85, 139/85, and 139/86 mm Hg, respectively. Of the 19 patients, 9 patients were on monotherapy with an antihyper- tensive agent (5 on a calcium channel blocker; 3 on an ACE inhibitor; and 1 on a beta-blocker) and 10 received combination therapy (2 on an ACE inhibitor and a diuretic; 2 on an ACE inhibitor, a diuretic, and a calcium channel blocker; and the others on differ- ent combinations of calcium channel blockers, ACE inhibitors, beta-blockers, or diuretics).
Ambulatory Blood Pressure
Administration of sitagliptin 50 mg b.i.d. and 100 mg b.i.d. resulted in small dose-dependent decreases in mean 24-hour SBP on day 1 and day 5 (Table I). The mean reduction in 24-hour SBP with the 50-mg b.i.d. dose relative to placebo was not significant, while the difference (–2.8 mm Hg) between the 100-mg dose and placebo was statistically significant (P < .05) on day 1. On day 5, the 24-hour SBP was significantly (P < .05) reduced up to 2.2 mm Hg with sitagliptin relative to placebo (Table II) (Figure 1). The mean dif- ference in 24-hour SBP between sitagliptin doses was not statistically significant on either day.
MISTRY ET AL
EFFECTS OF THE DPP-4 INHIBITOR SITAGLIPTIN ON AMBULATORY BLOOD PRESSURE
PHARMACOKINETICS AND PHARMACODYNAMICS 595
On day 1, mean 24-hour DBP was not statistically significantly different between the sitagliptin 50 mg b.i.d. and placebo groups, but the small difference (–1.6 mm Hg) between sitagliptin 100 mg b.i.d. and placebo approached statistical significance (P = .055) (Table I). Relative to placebo, both doses of sitagliptin produced small but significant (P < .05) reductions in mean 24-hour DBP on day 5 (Table II) (Figure 2). The mean difference in 24-hour DBP between sitagliptin doses was not statistically signi- ficant on either day.
Consistent with the small changes observed for 24-hour SBP and DBP, sitagliptin 100 mg b.i.d. signifi- cantly (P < .05) reduced 24-hour MAP relative to placebo on days 1 and 5, whereas the change in 24- hour MAP was only statistically significant on day 5 for the 50-mg b.i.d. dose (Tables I and II) (Figure 3). The mean difference in 24-hour MAP between sitagliptin doses was not statistically significant on either day.
Maximum Moving Average Decrease
When the SBP response was evaluated in the first 4 hours following dose administration, the mean dif- ference during this period (minMA0-4) was 0.7 mm
Hg (90% CI: –3.4 to 4.8) and –3.0 mm Hg (90% CI: –7.1 to 1.1) in the sitagliptin 50-mg and 100-mg groups relative to placebo, respectively, on day 1.
Table I 24-hour Ambulatory Blood Pressure Measurements for Day 1
BP Parameter Placebo (n == 18) Sitagliptin 50 mg b.i.d. (n == 18) Sitagliptin 100 mg b.i.d. (n == 18)
24-hr SBP (mm Hg) 124.3 ± 8.9 123.4 ± 10.8 121.4 ± 9.4 Mean difference from placebo (90% CI) — –0.9 (–2.9 to 1.1) –2.8 (–4.9 to –0.8)* 24-hr DBP (mm Hg) 74.8 ± 7.6 74.1 ± 7.9 73.2 ± 7.9 Mean difference from placebo (90% CI) — –0.7 (–2.0 to 0.7) –1.6 (–3.0 to –0.2) 24-hr MAP (mm Hg) 92.0 ± 7.0 91.1 ± 8.0 89.7 ± 7.2 Mean difference from placebo (90% CI) — –0.9 (–2.5 to 0.6) –2.3 (–3.9 to –0.8)*
Data are expressed as mean ± standard deviation or mean difference (90% confidence interval). BP, blood pressure; SBP, systolic blood pressure; CI, con- fidence interval; DBP, diastolic blood pressure; MAP, mean arterial pressure. *P < .05.
Table II 24-hour Ambulatory Blood Pressure Measurements for Day 5
BP Parameter Placebo (n == 18) Sitagliptin 50 mg b.i.d. (n == 18) Sitagliptin 100 mg b.i.d. (n == 18)
24-hr SBP (mm Hg) 124.4 ± 9.7 122.4 ± 9.4 122.2 ± 9.2 Mean difference from placebo (90% CI) — –2.0 (–3.5 to –0.4)* –2.2 (–3.7 to –0.6)* 24-hr DBP (mm Hg) 75.2 ± 7.4 73.5 ± 6.7 73.6 ± 7.9 Mean difference from placebo (90% CI) — –1.8 (–2.8 to –0.8)* –1.6 (–2.6 to –0.7)* 24-hr MAP (mm Hg) 92.0 ± 7.1 90.2 ± 6.4 90.4 ± 7.4 Mean difference from placebo (90% CI) — –1.7 (–2.8 to –0.7)* –1.6 (–2.6 to –0.6)*
Data are expressed as mean ± standard deviation or mean difference (90% confidence interval). BP, blood pressure; SBP, systolic blood pressure; CI, con- fidence interval; DBP, diastolic blood pressure; MAP, mean arterial pressure. *P < .05.
Figure 1. Hourly mean SBP (± standard error) during 24 hours postdose on day 5.
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H g)
100
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596 • J Clin Pharmacol 2008;48:592-598
The mean differences in SBP minMA0-4 on day 5 showed a similar trend between the sitagliptin and placebo groups. The largest reductions in SBP occurred during the 4-hour period at 4 to 8 hours fol- lowing dosing (SBP minMA4-8), a similar pattern and potentially larger reduction relative to baseline occurring after the evening dose (Figure 1). On day 5, SBP minMA4-8 was changed by –4.9 mm Hg (90% CI: –7.8 to –2.0) and –5.5 mm Hg (90% CI: –8.3 to –2.6) with sitagliptin 50 mg b.i.d. and 100 mg b.i.d.
relative to placebo, respectively. On day 1, only the sitagliptin 100 mg b.i.d. group had a greater mean difference in SBP minMA4-8 compared to the placebo group (–6.11 mm Hg [90% CI: –10.9 to –1.4]).
The DBP response was not different between treatment groups in the first 4 hours following dos- ing (DBP minMA0-4) on days 1 and 5 (data not shown). Similarly no between-group differences were found in DBP minMA4-8 on day 1. There were, however, differences in DBP minMA4-8 between groups on day 5 (Figure 2). The mean change in DBP minMA4-8 was –3.5 mm Hg (90% CI: –6.8 to –0.2) and –4.1 mm Hg (90% CI: –7.4 to –0.8) with sitagliptin 50 mg b.i.d. and 100 mg b.i.d. relative to placebo, respectively.
Safety Results
Of the 19 patients, 5 reported a total of 12 clinical adverse experiences, 10 of which were considered possibly drug related by the investigator. Of these adverse experiences, 3 were reported in patients while they were receiving placebo. The most common nonserious adverse experience was headache (9 episodes). All of the clinical adverse experiences were transient and mild in intensity. No serious clin- ical adverse experiences were reported, and no patient discontinued the study because of a clinical adverse experience.
Although hypotension was not reported as an adverse experience, one subject had lightheaded- ness that started 2.75 hours after receiving a 50-mg dose of sitagliptin on the morning of period 3, day 5 with a duration of approximately 2 minutes; this was considered possibly drug related by the investi- gator. For this subject, further inspection of the data showed that there was a slight reduction in BP at 2 and 4 hours postdose. Compared to a baseline BP of 128/88 mm Hg, the BP readings at 2 and 4 hours postdose were 127/81 and 122/83 mm Hg, respec- tively. In addition, compared to a baseline value of 74 bpm, pulse rate remained relatively unchanged at 2 hours postdose (71 bpm) and was slightly higher at 4 hours postdose (85 bpm). No vital signs were obtained at the time of the adverse experience. This subject also received the 100-mg dose of sitagliptin without the occurrence of lightheadedness.
Serial BP (sphygmomanometer) and HR measure- ments in the seated position on days 1 and 5 at 2 and 4 hours postdose were generally consistent with the ambulatory BP readings. The maximum mean reduc- tion in manual SBP and DBP was no more than approximately 6.5 mm Hg compared to baseline and
MISTRY ET AL
Figure 2. Hourly mean DBP (±standard error) during 24 hours postdose on day 5.
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ic B
lo od
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ss ur
e (m
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g)
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60
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90
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Sitigliptin 100 mg b.i.d.Sitigliptin 50 mg b.i.d.Placebo
Figure 3. Hourly MAP (mean ± standard error) during 24 hours postdose on day 5.
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Sitigliptin 100 mg b.i.d.Sitigliptin 50 mg b.i.d.Placebo
EFFECTS OF THE DPP-4 INHIBITOR SITAGLIPTIN ON AMBULATORY BLOOD PRESSURE
PHARMACOKINETICS AND PHARMACODYNAMICS 597
3 bpm for HR compared to baseline. Furthermore, no clinically significant deviations were found in the orthostatic vital sign measurements.
No consistent, clinically meaningful, treatment- related effects were observed in mean change (or percent change) from baseline for any laboratory parameter.
DISCUSSION
Sitagliptin is the first approved antihyperglycemic agent from the DPP-4 inhibitor class.10 Dipeptidyl peptidase-4 inhibitors prevent the degradation and inactivation of incretins, specifically GLP-1 and GIP.7 In addition to their effects on glucose home- ostasis, incretins and incretin-based therapies have been shown to have differential effects on BP.4-6,11
Because many patients with type 2 diabetes have hypertension and may receive concomitant therapy with one or more antihypertensive agents and anti- hyperglycemic therapies that may impact BP con- trol, the effects of sitagliptin on BP (positive or negative) was assessed in a highly controlled setting in patients with mild to moderate hypertension who take one or more antihypertensive agents. This study was conducted prior to initiating chronic studies with sitagliptin in patients with type 2 diabetes and to provide additional reassurance around its safety in these longer-term trials. In this study, sitagliptin was generally well tolerated with no adverse events of hypotension observed. Sitagliptin produced small and mostly significant reductions in ambulatory SBP and DBP on the order of 2 to 3 mm Hg in the acute state (day 1) and at steady state (day 5). These reductions are not considered to represent a poten- tial safety issue and may even be a potential thera- peutic benefit in diabetic patients with elevated BP.
For the primary endpoint—24-hour mean ambu- latory SBP on day 1—a small statistically significant mean reduction of ~3 mm Hg was observed in the sitagliptin 100-mg b.i.d group. Since the manage- ment of type 2 diabetes requires chronic treatments, it was of interest to study the effects of sitagliptin on blood pressures responses following multiple daily dosing. Steady-state sitagliptin trough concentra- tions are generally observed on day 3 of multiple daily dosing.9 A noteworthy and possibly more clin- ically relevant observation was the statistically sig- nificant sustained mean reductions in SBP of up to 2.2 mm Hg observed on day 5.
The greatest reductions in SBP and DBP occurred 4 to 8 hours following dose administration. There
were reductions in 4-hour maximum moving aver- age in SBP of up to 6 mm Hg relative to placebo on the morning of day 1 and after 5 days of treatment. For DBP, average reductions of nearly 4 mm Hg were observed during this 4-hour period after 5 days of sitagliptin treatment. The maximum reduction in ambulatory SBP and DBP observed between 4 and 8 hours postdose was presumably because the highest plasma concentrations of sitagliptin exerting maxi- mal DPP-4 inhibition occurs between 2 and 4 hours postdose.12 Although not an endpoint, a similar pat- tern and potentially larger reductions in SBP and DBP relative to baseline were observed in the same time period following the evening dose of study medication.
Incretins regulate glucose homeostasis by increas- ing insulin release and decreasing glucagon release following a meal or oral glucose challenge.3 Insulin has been shown to have vasodilatory effects, which may help explain the reductions in BP in this study.13,14 Previous studies in healthy volunteers with normoglycemia (or without type 2 diabetes) showed that sitagliptin produced ~2-fold increases in active GLP-1 levels without affecting fasting and postprandial glucose and insulin responses com- pared with placebo.9,12 Although insulin, glucose, and incretins were not measured in the present study, based on the previous findings in nondiabetic volunteers,9,12 the reductions in BP in the present study may have been caused by the increased active GLP-1 levels that would have resulted with sitagliptin treatment in these hypertensive patients with normoglycemia. The small reductions in SBP with sitagliptin are consistent with the changes in SBP noted with continuous infusion of GLP-1 dur- ing 48 hours in patients with type 2 diabetes6 and with another DPP-4 inhibitor.11
Cardiovascular outcome studies have shown that lowering BP with antihypertensive agents reduces the risk of stroke and myocardial infarction.15
Therefore, diabetic patients with hypertension may receive additional vascular benefits with their anti- hypertensive drugs combined with an antihyper- glycemic agent that improves glycemic control and also lowers BP. The significance of the current study is that sitagliptin produced small reductions in BP in nondiabetic patients with mild to moderate hypertension and that the coadministration of sitagliptin with antihypertensive drugs is generally well tolerated. The clinical benefit of sitagliptin on BP now needs to be established in a larger clinical trial in hypertensive patients with type 2 diabetes.
598 • J Clin Pharmacol 2008;48:592-598
MISTRY ET AL
In summary, sitagliptin has a modest effect on BP in nondiabetic patients with hypertension on stable antihypertensive therapy, with decreased ambulatory BP measurements acutely and following steady state.
Financial disclosure: This study was sponsored by Merck & Co Inc, the manufacturer of sitagliptin. Mr Mistry, Ms Maes, Dr Davies, Dr Gottesdiener, Dr Wagner, and Dr Herman are employees of Merck & Co Inc and may hold stocks or stock options in the company.
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1. Barnett A. DPP-4 inhibitors and their potential role in the man- agement of type 2 diabetes. Int J Clin Pract. 2006;60:1454-1470. 2. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929-2940. 3. Drucker DJ. The role of gut hormones in glucose homeostasis. J Clin Invest. 2007;117:24-32. 4. Barragan JM, Rodriguez RE, Blazquez E. Changes in arterial blood pressure and heart rate induced by glucagon-like peptide- 1-(7-36) amide in rats. Am J Physiol. 1994;266:E459-E466. 5. Yamamoto H, Lee CE, Marcus JN, et al. Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and acti- vates autonomic regulatory neurons. J Clin Invest. 2002;110:43-52. 6. Toft-Nielsen MB, Madsbad S, Holst JJ. Continuous subcuta- neous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients. Diabetes Care. 1999;22:1137-1143.
7. Drucker DJ, Nauck MA. GLP-1R agonists (incretin mimetics) and DPP-4 inhibitors (incretin enhancers) for the treatment of type 2 diabetes. Lancet. 2006;368:1696-1705. 8. Arauz-Pacheco C, Parrott MA, Raskin P. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003;26(Suppl 1):S80-S82. 9. Bergman AJ, Stevens C, Zhou YY, et al. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther. 2006;28:55-72. 10. JANUVIA (sitagliptin) [package insert]. Whitehouse Station, NJ: Merck & Co Inc; 2007. 11. Nathwani A, LeBeaut A, Byiers S, Gimpelewicz C, Chang I. Reduction in blood pressure in patients treated with vildagliptin as monotherapy or in combination with metformin for type 2 dia- betes. Diabetes. 2006;55(Suppl 1):A113. 12. Herman GA, Stevens C, Van Dyck K, et al. Pharmacokinetics and pharmacodynamics of single doses of sitagliptin, an inhibitor of dipeptidyl peptidase-IV, in healthy subjects. Clin Pharm Therap. 2005;78:675-688. 13. Anderson EA, Balon TW, Hoffman RP, Sinkey CA, Mark AL. Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans. Hypertension. 1992;19:621-627. 14. Anderson EA, Hoffman RP, Balon TW, Sinkey CA, Mark AL. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest. 1991;87: 2246-2252. 15. Wang JG, Staessen JA, Franklin SS, Fagard R, Gueyffier F. Systolic and diastolic blood pressure lowering as determinants of cardiovascular outcome. Hypertension. 2005;45:907-913.
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<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> /ENU (Use these settings for creating PDF files for submission to The Sheridan Press. These settings configured for Acrobat v6.0 08/06/03.) >> >> setdistillerparams << /HWResolution [2400 2400] /PageSize [612.000 792.000] >> setpagedevice
