Clinical and preclinical evidence that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers prevent diabetic peripheral neuropathy

Abstract

Given possible involvement of the central and peripheral angiotensin system in pain processing, we conducted clinical and preclinical studies to test whether pharmacological inhibition of the angiotensin system would prevent diabetic peripheral neuropathy (DPN) accompanying type 2 diabetes mellitus (T2DM). In the preclinical study, the nociceptive sensitivity was determined in leptin-deficient ob/ob mice, a T2DM model. A clinical retrospective cohort study was conducted, using the medical records of T2DM patients receiving antihypertensives at three hospitals for nearly a decade. In the ob/ob mice, daily treatment with perindopril, an angiotensin-converting enzyme inhibitor (ACEI), or telmisartan, an angiotensin receptor blocker (ARB), but not amlodipine, an L-type calcium channel blocker (CaB), significantly inhibited DPN development without affecting the hyperglycemia. In the clinical study, the enrolled 7464 patients were divided into three groups receiving ACEIs, ARBs and the others (non-ACEI, non-ARB antihypertensives). Bonferroni's test indicated significantly later DPN development in the ARB and ACEI groups than the others group. The multivariate Cox proportional analysis detected significant negative association of the prescription of ACEIs or ARBs and β-blockers, but not CaBs or diuretics, with DPN development. Thus, our study suggests that pharmacological inhibition of the angiotensin system is beneficial to prevent DPN accompanying T2DM.

Figure 1

Effects of daily treatment with representative ARB, ACEI and CaB on the development of DPN in leptin-deficient ob/ob mice. Tactile (A and B) and thermal (C and D) nociceptive sensitivities and blood glucose levels (E) were determined in ob/ob mice and the control age-matched lean mice between 5 and 12 weeks of age. Telmisartan at 5 mg/kg, perindopril at 2 mg/kg or amlodipine at 3 mg/kg was administered i.p. to ob/ob mice once daily for 6 weeks (i.e. until the age of 12 weeks), starting at the age of 6 weeks. AUC values between 9 and 12 weeks of age, (B) and (D), were calculated from the time-related changes in paw-withdrawal threshold (A) and paw-withdrawal latency (C). Values represent the means ± SEM for 8 mice per group.

Figure 2

Kaplan–Meier curves for the development of DPN in T2DM patients undergoing different antihypertensive pharmacotherapies at the three hospitals. The patients were divided into 3 groups according to the prescribed antihypertensives, i.e. (1) ACEI, (2) ARB and (3) Others (non-ACEI, non-ARB antihypertensives). In this analysis, 25 patients receiving both ACEI and ARB were not included. Statistical significance was analyzed by Log-rank test, followed by Bonferroni’s test for multiple comparisons.

Figure 3

Sub-analysis of the association of the prescribed antihypertensives with the development of DPN in T2DM patients at each of the three hospitals. Kaplan–Meier curves of the three patient groups receiving ACEI, ARB and the others (non-ACEI, non ARB antihypertensives) were drawn for each of Kansai Medical (Med) University (Univ) Hospital (Hosp) (A), Kindai Univ Nara Hosp (B) or Seichokai Fuchu Hosp (C). Statistical significance was analyzed by Log-rank test, followed by Bonferroni’s test for multiple comparisons.