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

Background Experimental 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 Findings We 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. Conclusions In 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 Registration University Hospital Medical Information Network Clinical Trials Registry UMIN000004490
In a randomized controlled trial, Koichi Node and colleagues assess the efficacy of sitagliptin in limiting atherosclerosis among patients over 29 years of age living in Japan.
Author Summary Why Was This Study Done? Translational research suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors, which are drugs for type 2 diabetes mellitus (T2DM), may prevent cardiovascular disease to a greater extent than other T2DM drugs. However, recently published large clinical trials showed no additional efficacy for DPP-4 inhibitors beyond that expected for the drugs’ glycemic control. Possibly these studies showed no benefit to cardiovascular health because they assessed cardiovascular mortality and other relatively rare outcomes. Change in carotid intima-media thickness (IMT) is a simple, noninvasive method to assess atherosclerosis, an intermediate and more common condition that can precede cardiovascular disease. What Did the Researchers Do and Find? We conducted a trial to evaluate whether DPP-4 inhibitors affect atherosclerosis in people with T2DM. In all, 463 participants recruited at 48 medical centers were randomly divided into two groups and treated with sitagliptin, a DPP-4 inhibitor, or other conventional drugs for two years. Carotid IMT was evaluated with ultrasonography in a blinded manner. We found that annual changes in carotid IMT were not significantly different between the two groups. On the other hand, the decrease in HbA1c and in the incidence of hypoglycemia with sitagliptin were superior to conventional therapy. The rate of other adverse events was not different between the two groups. What Do These Findings Mean? These findings provide no evidence that sitagliptin slows the progression of carotid intima-media thickening in participants with T2DM to a greater extent than conventional drugs. As some of the conventional anti-T2DM drugs have shown anti-atherosclerotic effects in clinical trials, the present findings do not mean that sitagliptin does not possess anti-atherosclerotic properties in participants with T2DM. Importantly, however, sitagliptin is useful for controlling hyperglycemia for clinical setting.