The Effect of Sitagliptin on Carotid Artery Atherosclerosis in Type 2 Diabetes: The PROLOGUE Randomized Controlled Trial

Abstract

BackgroundExperimental studies have suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors provide cardiovascular protective effects. We performed a randomized study to evaluate the effects of sitagliptin added on to the conventional therapy compared with conventional therapy alone (diet, exercise, and/or drugs, except for incretin-related agents) on the intima-media thickness (IMT) of the carotid artery, a surrogate marker for the evaluation of atherosclerotic cardiovascular disease, in people with type 2 diabetes mellitus (T2DM).Methods and FindingsWe used a multicenter PROBE (prospective, randomized, open label, blinded endpoint) design. Individuals aged ≥30 y with T2DM (6.2% ≤ HbA1c < 9.4%) were randomly allocated to receive either sitagliptin (25 to 100 mg/d) or conventional therapy. Carotid ultrasound was performed at participating medical centers, and all parameters were measured in a core laboratory. Of the 463 enrolled participants with T2DM, 442 were included in the primary analysis (sitagliptin group, 222; conventional therapy group, 220). Estimated mean (± standard error) common carotid artery IMT at 24 mo of follow-up in the sitagliptin and conventional therapy groups was 0.827 ± 0.007 mm and 0.837 ± 0.007 mm, respectively, with a mean difference of −0.009 mm (97.2% CI −0.028 to 0.011, p = 0.309). HbA1c level at 24 mo was significantly lower with sitagliptin than with conventional therapy (6.56% ± 0.05% versus 6.72% ± 0.05%, p = 0.008; group mean difference −0.159, 95% CI −0.278 to −0.041). Episodes of serious hypoglycemia were recorded only in the conventional therapy group, and the rate of other adverse events was not different between the two groups. As it was not a placebo-controlled trial and carotid IMT was measured as a surrogate marker of atherosclerosis, there were some limitations of interpretation.ConclusionsIn the PROLOGUE study, there was no evidence that treatment with sitagliptin had an additional effect on the progression of carotid IMT in participants with T2DM beyond that achieved with conventional treatment.Trial RegistrationUniversity Hospital Medical Information Network Clinical Trials Registry UMIN000004490

Impact of glycemic control with sitagliptin on the 2-year progression of arterial stiffness: a sub-analysis of the PROLOGUE study

“…The rationale and design of the PROLOGUE study (University hospital Medical Information Network Center: ID 000004490) have been described previously [12, 13]. In brief, it was a multicenter, prospective, randomized, open-label, blinded-endpoint trial carried out with the participation of 48 Japanese institutions.…”

“…We enrolled 463 patients with T2DM between June 2011 and September 2012. The inclusion criteria and exclusion criteria are described elsewhere [12, 13]. The patients were randomized to either add-on sitagliptin treatment (sitagliptin group) or to continued treatment with conventional anti-diabetic agents (conventional antidiabetic treatment group).…”

“…In both groups, the target glycemic control level was “maintenance of the HbA1c value at <6.2% or of the fasting blood glucose at <110 mg/dl throughout the study period”. The treatment randomization was conducted based on the age, gender, use of statins, pre-treatment diabetes type (non-pharmacological or pharmacological treatment), HbA1c (<7 or ≥7%), office systolic blood pressure (<135 or ≥135 mmHg) and maximum IMT (<1.0 or ≥1.0 mm) [12, 13]. All the patients were followed up annually for 2 years until September 2014.…”

“…The PROLOGUE study was a prospective multicenter study carried out to examine the effect of add-on DPP4 inhibitor therapy on the progression of the carotid intima-media thickness (IMT) over a 2-year follow-up period [12, 13]. In this study, the PWV was also measured in some of the study participants.…”

Dipeptidyl Peptidase-4 Inhibitors and Cardiovascular Risk in Patients with Diabetes: Fact or Fiction?

“…In addition, there were no differences in term of hospitalization for heart failure or angina ( HR 1.00, 95% CI 0.83-1.20).Adding sitagliptin to other therapies didn't cause an increase of cardiovascular adverse events. The second trial (PROLOGUE) published in 2016 aimed to examine the effect of sitagliptin on cardiovascular safety by using the intima-media thickness of the carotid artery as a surrogate marker for the cardiac health (21). The study is a prospective, randomized, open-labeled, blinded controlled trial.…”