DPP-4 inhibitor attenuates progression and predicts regression of carotid IMT in T2DM

The Effect of Sitagliptin on the Regression of Carotid Intima-Media Thickening in Patients with Type 2 Diabetes Mellitus: A Post Hoc Analysis of the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation

Literature - Mita T, Katakami N, Shiraiwa T, et al. - SPIKE trial

In two separate publications, Mita and colleagues report on analyses of data from the SPIKE trial on the effect of the DPP-4 inhibitor sitagliptin on cIMT in T2DM patients receiving insulin therapy.

Int J Endocrinol. 2017;2017:1925305. doi: 10.1155/2017/1925305

A drawback of strict glycaemic control in CVD patients with advanced atherosclerosis or longstanding T2DM is that the higher risk of hypoglycaemia and weight gain might diminish its benefit [1,2]. Use of oral hypoglycaemic agents (OHA) may reduce these adverse effects of insulin therapy, due to stimulation of endogenous glucose responsive insulin secretion and increased insulin sensitivity.

Add-on therapy of metformin [3] or pioglitazone [4] to insulin therapy was shown not to slow down progression of carotid IMT in patients with T2DM compared with controls. However, it was reported that sitagliptin, a DPP-4 inhibitor, attenuated progression of carotid IMT in insulin-treated patients with T2DM as compared with conventional treatment without increasing risk of hypoglycaemia, in the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation (SPIKE). [5]. The effect of DPP-4 inhibition on regression of carotid IMT is largely unknow.

This study therefore examined whether sitagliptin has a beneficial effect on regressing carotid IMT in a post hoc analysis of the SPIKE trial [5], as the original article focussed on IMT progression. 282 Insulin-treated Japanese T2DM patients without a history of apparent CVD were randomised to sitagliptin or conventional treatment, and 137 patients in each group were included in the full analysis set. Ultrasonography of the carotid arteries was performed at the start of the study, and after 52 and 104 weeks.

  • The percentage of patients who achieved a decrease of ≥0.10mm in mean-IMT-CCA at the end of the study was 28.9% in the sitagliptin group, as compared with 16.4% in the conventional group (P=0.022). For left max-IMT-CCA the percentages were 43.0% and 26.2% respectively (P=0.007), and right max-IMT-CCA tended to be higher in the sitagliptin groups as compared to the conventional group (38.3% vs. 27.9%, P=0.10).
  • In multiple logistic regression analysis (treatment, age, gender, baseline IMT), sitagliptin significantly achieved higher target attainment of mean-IMT ≥0.10mm (adjOR: 2.29, 95%CI: 1.17-4.47, P=0.015) and left max-IMT-CCA ≥0.10mm (adjOR: 2.22, 95%CI: 1.25-3.92, P=0.006) as compared to controls.
  • Similar findings were seen in models further adjusted for BMI and current smoking, and with additional correction for HbA1c, total cholesterol, HDL-c, triglycerides, SBP, and another model that also included correction for eGFR and ACE/ARB use, statin and antiplatelets, and one including OHA.
  • Factors predictive of regression of IMT ≥0.10mm from baseline were examined in multivariate logistic regression models. Baseline cIMT and treatment group were the only factors significantly associated with regression in each of the three IMT measures, with adjusted ORs ranging from 1.02 to 1.05 for baseline cIMT, and a stronger effect of treatment group in the range of 2.02 (right max IMT) to 3.58 (mean IMT).

This analysis suggests that the DPP-4 inhibitor sitagliptin is associated with regression of carotid atherosclerosis in insulin-treated patients with T2DM, but free from apparent CVD. Sitagliptin treatment was an independent predictor of carotid IMT, irrespective of several possible risk factors for atherosclerosis, background therapies that might have antiatherosclerotic effects and/or changes in metabolic parameters.


Changes in carotid intima-media thickening in patients with type 2 diabetes mellitus: Subanalysis of the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation

J Diabetes Investig. 2017 Mar;8(2):254-255. doi: 10.1111/jdi.12559

In a letter to the editor in the Journal of Diabetes Investigation, the same group reported on a comparison of the efficacy of treatment with sitagliptin with that of other modalities on the progression of carotid IMT in prespecified subgroups of the SPIKE trial, with the aim to identify characteristics of patients who benefited most from sitagliptin treatment in terms of decrease in IMT.

  • Among 243 patients whose IMT data were available at baseline and 104 weeks, consistent reductions in mean IMT-CCA and left max IMT-CCA but not right max IMT-CCA were seen in the sitagliptin group.
  • A greater reduction in carotid IMT was most striking after treatment with sitagliptin in patients with risk factors for CVD, such as higher HbA1c, higher BMI, longer duration of T2DM, use of ACEi/ARBs, use of statins, worse hypertension and/or hyperlipidaemia at baseline, as compared with conventional treatment.

Thus, these data suggest that treatment with DPP-4 inhibitors may prevent progression of carotid atherosclerosis regardless of disease burden. Previously, it had been shown that treatment with statins and ACE-inhibitors reduced the progression of carotid atherosclerosis in patients with T2DM. Sitagliptin was now shown to further attenuate carotid IMT progression in patients already receiving these therapies.


1. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group,” The New England Journal of Medicine, vol. 329, no. 14, Article ID 8366922,pp. 977–986, 1993.

2.A. N. Jacob, K. Salinas, B. Adams-Huet, and P. Raskin, “Weight gain in type 2 diabetes mellitus,” Diabetes, Obesity &Metabolism, vol. 9, no. 3, Article ID 17391167, pp. 386–393, 2007.

3. L. Lundby-Christensen, L. Tarnow, T. W. Boesgaard et al., “Metformin versus placebo in combination with insulin analogues in patients with type 2 diabetes mellitus-the randomised, blinded Copenhagen Insulin and Metformin Therapy (CIMT) Trial,” British Medical Journal Open,vol. 6, no. 2, Article ID 26916684, 2016.

4. E. Yasunari, K. Takeno, H. Funayama et al., “Efficacy of pioglitazone on glycemic control and carotid intima-media thickness in type 2 diabetes patients with inadequate insulin therapy,” Journal of Diabetes Investigation, vol. 2, no. 1, Article ID 24843462, pp. 56–62, 2011.

5. T. Mita, N. Katakami, T. Shiraiwa et al., “Sitagliptin attenuates the progression of carotid intima-media thickening in insulintreated patients with type 2 diabetes: the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation (SPIKE): a randomized controlled trial,” Diabetes Care, vol. 39, no. 3, Article ID 26822324, pp. 455–464, 2016.

Find the article in Int J Endocrinol online Find the letter to the editor in J Diabetes Investig. online

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