VANCOUVER, B.C. – Alogliptin, an oral inhibitor of dipeptidyl peptidase 4 (DPP-4) having hypoglycemic activity, promoted regression of preclinical carotid atherosclerosis in patients with type 2 diabetes, judging from the findings of the randomized Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A).
Among the 341 patients studied, all of whom were free of known cardiovascular disease at baseline, those in the alogliptin group had significant reductions in echocardiographic carotid intima-media thickness (IMT) at 2 years when compared with peers in a usual care group, according to data reported at the World Diabetes Congress.
Dr. Tomoya Mita
“Our data may suggest … efficacy and benefit of alogliptin when used at an early stage of disease in preventing the progression of atherosclerosis,” commented first author Dr. Tomoya Mita, assistant professor in the department of metabolism and endocrinology at Juntendo University Graduate School of Medicine, Tokyo.
Three other trials – SAVOR TIMI 53, EXAMINE, and TECOS – have not found changes in cardiovascular outcomes with DPP-4 inhibitors among diabetic patients, he noted. Patients in those trials, however, had established cardiovascular disease or were at high risk.
“I’m not sure whether our data will translate into clinical outcome. But the magnitude of IMT reduction was identical to that of pioglitazone, [which] may reduce CV events,” Dr. Mita commented. “We are conducting a follow-up study that focuses on clinical outcome and safety, so we will find more detailed information in that study.”
“The importance of this study is really showing the limitations to cardiovascular outcome trials that have been going on,” commented Dr. Robert E. Ratner, professor of medicine at Georgetown University and senior research scientist at the MedStar Health Research Institute, both in Washington, as well as chief scientific and medical officer of the American Diabetes Association in Alexandria, Va., who was session comoderator.
Those studies have been limited by selection bias, he agreed in an interview. “Taking patients who are so far advanced in their disease really isn’t the practical solution. We need to be thinking earlier, we need to be thinking in terms of prevention.”
Dr. Robert E. Ratner
Patients were recruited to SPEAD-A from diabetes outpatient clinics at 11 centers in Japan. They had to be 30 years of age or older and to have diabetes inadequately controlled by diet and lifestyle measures, or agents other than DPP-4 inhibitors, but with a glycated hemoglobin level of less than 9.4%.
Trial results, reported at the meeting and simultaneously published (Diabetes Care. 2016;39:18-27. doi: 10.2337/dc15-0781), showed that, relative to peers given usual care, patients given alogliptin (U.S. brand name Nesina) had greater reductions at 2 years in levels of glycated hemoglobin (−0.3% vs. −0.1%, P = .004) without a higher incidence of hypoglycemia.
Echocardiographic data revealed differences between the alogliptin group and the usual-care group in favor of the former with respect to changes in common carotid IMT (−0.026 mm vs. +0.005 mm, P = .022), right carotid maximum IMT (−0.045 mm vs. +0.011 mm, P = .025), and left carotid maximum IMT (−0.079 mm vs. −0.015 mm, P = .013).
Body mass index increased in the alogliptin group but decreased in the usual-care group (+0.3 kg/m2 vs. –0.3 kg/m2, P = .003), Dr. Mita reported.
The groups were statistically indistinguishable with respect to insulin and fasting glucose levels, lipid profiles, blood pressure, markers of inflammation, and estimated glomerular filtration rate.
Rates of adverse events and serious adverse events were similar with alogliptin and usual care. There was no significant difference between groups in cardiovascular events, but only five patients experienced these events.
“I’m not sure how the DPP-4 inhibitor reduces the carotid intima-media thickness in this study,” Dr. Mita commented, but other research has suggested that drugs in this class decrease smooth muscle cell proliferation and inflammation and improve endothelial function.
Dr. Mita disclosed that he receives research funds from MSD and Takeda Pharma and that he receives lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Ono Pharmaceutical, and Takeda Pharmaceutical.
Financial support for the study was provided by Astellas Pharma, AstraZeneca, Bayer Holding, Daiichi Sankyo, Sumitomo Dainippon Pharma, Eli Lilly Japan, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Novo Nordisk Pharma, Pfizer Japan, Sanofi, Sanwa Kagaku Kenkyusho, Shionogi, and Takeda