Sitagliptin Attenuates the Progression of Carotid Intima-Media Thickening in Insulin-Treated Patients With Type 2 Diabetes: The Sitagliptin Preventive Study of Intima-Media Thickness Evaluation (SPIKE)
A Randomized Controlled Trial

Mita T, Katakami N, Shiraiwa T, et al.
Diabetes Care 2016; published online ahead of print

Background

In patients with type 2 diabetes mellitus and established atherosclerosis, intensive glucose control was shown to have no significant effect on the rates of major cardiovascular events, and according to some data, it even increased mortality [1,2]. These results have been partially explained by frequent hypoglycaemic episodes and weight gain, caused by the intensive insulin treatment [3]. It is postulated that the combination therapy of reduced insulin doses and oral hypoglycaemic agents may be of benefit for these patients [4,5].
Sitagliptin is a dipeptidyl peptidase 4 (DPP-4) inhibitor that increases insulin secretion and suppresses glucagon release [6,7]. The addition of DPP-4 inhibitors to insulin therapy has been reported to have specific advantages, like reducing the frequency of hypoglycemia and weight gain [8]. Preclinical data suggest that DPP-4 inhibitors could have beneficial effects on atherosclerosis [9].
In this multicenter, randomised study, the effects of sitagliptin compared with conventional treatment on carotid intima-media thickness (IMT) was investigated, in insulin-treated type 2 diabetes mellitus patients.

Main results

• Sitagliptin significantly reduced the mean IMT and the left maximum IMT of common carotid arteries, compared with conventional treatment:
- Mean IMT change: -0.029 (SE: 0.013) vs. 0.024 (SE: 0.013) mm, P = 0.005
- Left maximum IMT change: -0.065 SE: 0.027) vs. 0.022 (SE: 0.026) mm, P = 0.021
- Right maximum IMT change: -0.007 (SE: 0.031) vs. 0.027 (SE: 0.031) mm, P = 0.45
 The findings were similar after adjustment for several confounders (grouped in models).
• Sitagliptin, compared to conventional treatment was associated with significant improvements of
- HbA_1C %: -0.5 ± 1.0% vs. -0.2 ± 0.9%; P = 0.004
- C-peptide (ng/mL): 0.3 ± 0.8 vs. 0.0 ± 0.6; P = 0.02
• There were no significant differences between treatment groups in regard to
- fasting blood glucose concentrations,
- other risk factors for atherosclerosis, such as BMI, blood pressure, and lipid parameters
- the use of antihypertensive drugs and lipid-lowering agents
- the levels of various markers of inflammation and endothelial damage

Conclusion

In insulin-treated type 2 diabetes mellitus patients without cardiovascular disease, sitagliptin decelerated the progression of carotid IMT compared with conventional treatment. The results of this study support the hypothesis according to which early and effective intervention with DPP-4 inhibitors before the development of advanced atherosclerosis may be beneficial for the prevention of carotid IMT progression in these patients.

Find this article online at Diabetes Care

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