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Review

The Role of Angiotensin Receptor Blockers in the Personalized Management of Diabetic Neuropathy

by
Danai-Thomais Kostourou
,
Dimitrios Milonas
,
Georgios Polychronopoulos
,
Areti Sofogianni
and
Konstantinos Tziomalos
*
First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki 54636, Greece
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2022, 12(8), 1253; https://doi.org/10.3390/jpm12081253
Submission received: 27 June 2022 / Revised: 27 July 2022 / Accepted: 29 July 2022 / Published: 30 July 2022
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Abstract

:
Neuropathy is a frequent complication of diabetes mellitus (DM) and is associated with the increased risk ofamputation and vascular events. Tight glycemic control is an important component inthe prevention of diabetic neuropathy. However, accumulating data suggest that angiotensin receptor blockers (ARBs) might also be useful in this setting. We discuss the findings of both experimental and clinical studies that evaluated the effects of ARBs on indices of diabetic neuropathy. We also review the implicated mechanisms of the neuroprotective actions of these agents. Overall, it appears that ARBs might be a helpful tool for preventing and delaying the progression of diabetic neuropathy, but more data are needed to clarify their role in the management of this overlooked complication of DM.

1. Introduction

Type 2 diabetes mellitus (T2DM) is becoming increasingly prevalent and currently affects approximately 14.3% of the adult US population [1]. Moreover, a further 38.0% of the adult US population has prediabetes, i.e., impaired fasting glucose or impaired glucose tolerance [1]. Diabetic neuropathy is a frequent complication of both T2DM and type 1 diabetes mellitus (T1DM), and it is present in approximately 3.5–9.4% of patients who havehad T1DM for 1–5 years and in 28% of patients who havehad T2DM for > 4 –7 years [2,3,4]. The prevalence of diabetic neuropathy increases with age and diabetes duration, and it is higher in patients with poor glycemic control [5,6,7,8,9,10]. Diabetic neuropathy can affect almost all parts of the nervous system, and its most common forms are chronic distal symmetric sensorimotor polyneuropathy and autonomic neuropathy [7]. The former increases the risk for foot ulcer, amputation, and death [7,11,12,13]. On the other hand, cardiovascular autonomic neuropathy is present in approximately one-third of patients with T2DM and in a similar proportion of patients who have had T1DM for approximately 25 years [5,6]. More importantly, cardiovascular autonomic neuropathy is associated with increased vascular morbidity and mortality in patients with either T1DM or T2DM [7,14,15,16,17].
Randomized controlled trials have showed that tight glycemic control prevents and delays the progression of both peripheral and autonomic neuropathy in T1DM [4,5,18,19,20]. In contrast, the effects of tight glycemic control on T2DM-associated neuropathy are more controversial, with some reports showing benefits [21,22,23] and others having no effect [24,25]. Several agents have been used in patients with diabetic neuropathy, including aldose reductase inhibitors, antioxidants, and protein kinase C inhibitors, but their benefit is unclear [7]. Angiotensin receptor blockers (ARBs) are the antihypertensive agents of choice for hypertensive patients with diabetes mellitus (along with angiotensin-converting enzyme inhibitors, ACE-I) [26]. ARBs act by inhibiting the binding of angiotensin II (which is produced by the cleavage of angiotensin I by the angiotensin-converting enzyme) to angiotensin receptor I, thereby promoting vasodilation and inhibiting aldosterone secretion [27] (Figure 1). Accumulating experimental data and some small clinical studies suggest that ARBs might also have a role in the management of diabetic neuropathy. We summarize these data and discuss the implicated mechanisms.

2. Search Strategy

The PubMed database was reviewed for papers using the terms “diabetes”, “neuropathy”, “angiotensin receptor blocker”, “losartan”, “valsartan”, “candesartan”, “olmesartan”, “telmisartan” and “azilsartan”. The references of pertinent articles were also hand-searched for relevant papers.

3. Preclinical Studies

In an early study ofstreptozotocin-diabetic rats, the ARB ZD 8731 was given 1 month after the induction of diabetes and for a duration of 1 month [28]. ZD 8731 ameliorated both motor and sensory nerve conduction velocity (NCV) [28]. An increase in nerve capillary density was observed, which might have contributed to the improvement in NCV [28]. In contrast, ZD 8731 had no effect on these parameters in non-diabetic rats [28]. The same group of investigators assessed the effects of another ARB, ZD 7155, in streptozotocin-diabetic rats [29]. ZD 7155 was given for 1 month, either immediately after the induction of diabetes or after 1 month [29]. The amelioration of motor and sensory NCV and an improvement in nerve regeneration after experimental damage were observed regardless of the timing of treatment initiation [29]. The investigators confirmed an ARB-induced increase in nerve capillary density and also observed an augmentation of endoneurial blood flow [29]. In another study, olmesartan improved nerve regeneration in diabetic rats [29]. There was an increase in the production of the ciliary neurotrophic factor (a nerve growth factor), which might have played a role in this neurotrophic effect [30]. Interestingly, in vitro and animal studies have also reported the neurotrophic effect of olmesartan on spinal motor neurons in non-diabetic animals [31].In an in vitro study ofPC12 cells, both losartan and telmisartan reduced oxidative stress, but only telmisartan prevented glucose-induced apoptosis [32]. In more recent studies, both losartan and telmisartan prevented the development of neuropathy in diabetic rat models [33,34]. The principal findings of major preclinical studies that evaluated the effect of ARBs on diabetic neuropathy are summarized in Table 1.

4. Clinical Studies

In contrast to these promising experimental data, early clinical studies that assessed the effects of ARBs on diabetic neuropathy yielded negative results [35,36]. In normotensive patients with T2DM and microalbuminuria, treatment with losartan for 12 weeks did not improve peripheral or autonomic neuropathy [35]. In another early study onpatients with T1DM or T2DM, treatment with losartan for 12 months did not improve cardiovascular autonomic function or the vibration-perception threshold [36]. However, in another study, treatment with losartan for 12 months improved autonomic nervous function in normotensive patients with autonomic neuropathy due to either T1DM or T2DM [37]. Treatment with quinapril also ameliorated autonomic neuropathy, in accordance with previous findings [38,39]. Interestingly, the losartan/quinapril combination appeared to be more beneficial than either monotherapy [37]. However, the vibration-perception threshold did not change with either losartan or quinapril [37]. These findings, although preliminary, suggest that the beneficial effectsof ARB on diabetic neuropathy become apparent only after long-term treatment, and that autonomic neuropathy improves more with these agents than peripheral neuropathy [37]. However, a study onhypertensive patients with diabetic nephropathy showed an improvement in the low-tohigh-frequency ratio (an index of sympathovagal balance) after only 12 weeks of treatment with losartan or telmisartan [40]. The principal findings of major clinical studies that evaluated the effect of ARBs on diabetic neuropathy are summarized in Table 2.

5. Studies Onnon-Diabetic Patients

Studies onnon-diabetic patients have also suggested an improvement in various indices of cardiovascular autonomic neuropathy with ARB treatment [41]. Several different ARBs improved cardiac baroreceptor sensitivity in different populations, including patients with hypertension [42]. ARBs werealso observed to increase heart rate variability (HRV), another index of cardiovascular autonomic function, in obese prehypertensive patients [43] and in patients with hypertension [44], ischemic cardiomyopathy [45], or idiopathic dilated cardiomyopathy [46]. ARBs also decreased the low-tohigh-frequency ratio in hypertensive patients [44]. However, other reports, mostly in hypertensive patients, did not show any benefit of ARBs with regard tothese parameters [45,46,47,48,49,50,51,52,53]. In addition, some studies reported an improvement in some parameters of cardiovascular autonomic function (i.e., baroreflex sensitivity), but not in others (i.e., HRV) [54]. Regarding the effects of ARBs on cardiovascular autonomic neuropathy as compared with other antihypertensive agents, the existing evidence is also controversial. Compared with beta-blockers in hypertensive patients, atenolol increased HRV and baroreflex sensitivity, whereas irbesartan and fosinopril had no effect [55]. In another study onhypertensive patients, losartan improved baroreflex sensitivity and did not affect HRV, whereas atenolol did not change baroreflex sensitivity and reduced HRV despite a similar BP reduction [56]. Several studies compared the effects of ARBs and ACE-Is on cardiovascular autonomic function, and most reported comparable improvements [57,58,59]. The combination of the two classes yielded greater reductions than monotherapy ineither class [57]. However, in one report onpatients with heart failure, lisinopril increased HRV, whereas valsartan had no effect [60]. Neither valsartan nor lisinopril had any effect on baroreflex sensitivity [60]. A recent observational study also suggested that treatment with either ARBs or ACE-Is protects against platinum-induced sensory neuropathy [61]. These discrepant results are partly due to the small number of patients and differences in patients’ characteristics, duration of treatment, and index of autonomic function. It is also unclear whether these findings in non-diabetic subjects can be extrapolated to diabetic patients. The principal findings of major clinical studies that evaluated the effect of ARBs on neuropathy in non-diabetic patients are summarized in Table 3.

6. ARBs and Erectile Dysfunction

Diabetic neuropathy might also manifest as erectile dysfunction, which is present in approximately 60% of patients who have had T1DM or T2DM for > 10–20 years [62,63]. Studies onstreptozotocin-diabetic rats and aged rats showed an improvement in erectile function with ARB treatment [64,65,66]. ARBs also ameliorated erectile dysfunction in hypertensive patients with [67] or without the metabolic syndrome, which is a prediabetic condition [68,69]. However, it has not been evaluated whether ARBs improve erectile function in diabetic patients.The principal findings of major clinical studies that evaluated the effect of ARBs on erectile dysfunction are summarized in Table 4.

7. Putative Mechanisms of the Effects of ARBs on Diabetic Neuropathy

Several mechanisms appear to account for the beneficial effects of ARBs on diabetic neuropathy. ARBs might confer neuroprotection by improving nerve blood flow through their vasodilating properties [70]. Interestingly, in animal models of diabetic neuropathy, angiotensin II reduced endoneurial blood flow more than in non-diabetic animals [71]. Oxidative stress and advanced glycation end-products also appear to play a role in the pathogenesis of diabetic neuropathy [72,73]. On the other hand, ARBs exert antioxidant effects [74,75] and reduce the production of advanced glycation end-products [76]. Accordingly, it was suggested that these actions might play a role in the neuroprotective effects of ARBs [77]. Several prospective studies showed that hypertension increases the risk ofneuropathy in diabetic patients [8,9]. However, in several randomized controlled trials involving patients with T2DM, more aggressive antihypertensive treatment did not prevent or delay the progression of neuropathy as compared with less tight blood pressure control [78,79,80,81]. Nevertheless, beta-blockers, calcium channel blockers, and ACE-Is were used in the latter trials, and it remains to be established whether ARBs can improve diabetic neuropathy independently of their blood pressure-lowering effects. Regarding erectile function, the beneficial effects of ARBs are partly due to the inhibition of angiotensin II, which is locally produced in the corpus cavernosum and directly terminates erection [82,83,84]. ARBs also improved erectile function through the suppression of oxidative stress and an increase in the expression of endothelial nitric oxide synthase in the corpus cavernosum [64]. Whether the improvement in diabetic neuropathy plays a role in the amelioration of erectile dysfunction during ARB treatment remains to be established.The major mechanisms potentially implicated in the beneficial effects of ARBs on diabetic neuropathy are shown in Figure 2.

8. Indications for ARB Therapy

AllARBs are indicated for the management of hypertension. Losartan and irbesartan are also indicated for the management of chronic kidney disease in hypertensive patients with T2DM. Losartan, valsartan, and candesartan are also indicated for the management of patients with heart failure and reduced ejection fraction (i.e.,≤ 40%) if ACE-Is are contraindicated or not tolerated. Valsartan is also indicated for the treatment ofpatients with a recent myocardial infarction and symptomatic heart failure or asymptomatic left ventricular systolic dysfunction. Losartan is also indicated for the prevention of ischemic stroke in hypertensive patients with left ventricular hypertrophy diagnosed viaelectrocardiogram. Telmisartan is also indicated for the prevention of cardiovascular events in patients with established cardiovascular disease and in patients with T2DM and target organ damage.

9. Conclusions

Emerging experimental and clinical data suggest than ARBs might be a useful tool for preventing and delaying the progression of diabetic neuropathy. It is also possible that the combination of ARBs with other interventions that improve diabetic neuropathy (mainly tight glycemic control) might yield an incremental benefit [85]. Indeed, in the Steno-2 study, intensified multifactorial intervention that included an ACE-I, an ARB, or both, but also lifestyle changes, intensive glucose- and lipid-lowering treatment, and aspirin delayed the progression of autonomic neuropathy in patients with T2DM and microalbuminuria [85]. However, peripheral neuropathy was not affected [85]. Clearly, more data are needed to clarify the potential role of ARBs in the management of this overlooked complication of diabetes.

Author Contributions

D.-T.K., D.M., G.P. and A.S.; writing—original draft preparation; K.T.; writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Menke, A.; Casagrande, S.S.; Geiss, L.S.; Cowie, C.C. Prevalence of and Trends in Diabetes Among Adults in the United States, 1988–2012. JAMA 2015, 314, 1021–1029. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Mizokami-Stout, K.R.; Boyle, C.T.; Shah, V.N.; Aleppo, G.; Mcgill, J.B.; Pratley, R.; Toschi, E.; Ang, L.; Pop-Busui, R. Contemporary Prevalence of Diabetic Neuropathy in Type 1 Diabetes (T1D)—Findings from the T1D Exchange. Diabetes Care 2020, 43, 806–812. [Google Scholar] [CrossRef] [PubMed]
  3. Sun, J.; Wang, Y.; Zhang, X.; Zhu, S.; He, H. Prevalence of peripheral neuropathy in patients with diabetes: A systematic review and meta-analysis. Prim. Care Diabetes 2020, 14, 435–444. [Google Scholar] [CrossRef]
  4. The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann. Intern. Med. 1995, 122, 561–568. [Google Scholar] [CrossRef] [PubMed]
  5. Pop-Busui, R.; Low, P.A.; Waberski, B.H.; Martin, C.L.; Albers, J.W.; Feldman, E.L.; Sommer, C.; Cleary, P.A.; Lachin, J.M.; Herman, W.H.; et al. Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complica-tions study (DCCT/EDIC). Circulation 2009, 119, 2886–2893. [Google Scholar] [CrossRef] [Green Version]
  6. Ko, S.H.; Park, S.A.; Cho, J.H.; Song, K.H.; Yoon, K.H.; Cha, B.Y.; Son, H.Y.; Yoo, K.D.; Moon, K.W.; Park, Y.M.; et al. Progression of car-diovascular autonomic dysfunction in patients with type 2 diabetes: A 7-year follow-up study. Diabetes Care 2008, 31, 1832–1836. [Google Scholar] [CrossRef] [Green Version]
  7. Pop-Busui, R.; Boulton, A.J.; Feldman, E.L.; Bril, V.; Freeman, R.; Malik, R.A.; Sosenko, J.M.; Ziegler, D. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care 2016, 40, 136–154. [Google Scholar] [CrossRef] [Green Version]
  8. Tesfaye, S.; Chaturvedi, N.; Eaton, S.E.; Ward, J.D.; Manes, C.; Ionescu-Tirgoviste, C.; Witte, D.R.; Fuller, J.H.; EURODIAB Prospective Complications Study Group. Vascular risk factors and diabetic neuropathy. N. Engl. J. Med. 2005, 352, 341–350. [Google Scholar] [CrossRef] [Green Version]
  9. Forrest, K.Y.; Maser, R.E.; Pambianco, G.; Becker, D.J.; Orchard, T.J. Hypertension as a risk factor for diabetic neuropathy: A prospective study. Diabetes 1997, 46, 665–670. [Google Scholar] [CrossRef]
  10. Partanen, J.; Niskanen, L.; Lehtinen, J.; Mervaala, E.; Siitonen, O.; Uusitupa, M. Natural History of Peripheral Neuropathy in Patients with Non-Insulin-Dependent Diabetes Mellitus. N. Engl. J. Med. 1995, 333, 89–94. [Google Scholar] [CrossRef]
  11. Abbott, C.A.; Carrington, A.L.; Ashe, H.; Bath, S.; Every, L.C.; Griffiths, J.; Hann, A.W.; Hussein, A.; Jackson, N.; Johnson, K.E.; et al. The North-West Diabetes Foot Care Study: Incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet. Med. 2002, 19, 377–384. [Google Scholar] [CrossRef] [PubMed]
  12. Young, M.J.; Breddy, J.L.; Veves, A.; Boulton, A.J.M. The Prediction of Diabetic Neuropathic Foot Ulceration Using Vibration Perception Thresholds: A prospective study. Diabetes Care 1994, 17, 557–560. [Google Scholar] [CrossRef] [PubMed]
  13. Coppini, D.; Bowtell, P.; Weng, C.; Young, P.; Sönksen, P. Showing neuropathy is related to increased mortality in diabetic patients—A survival analysis using an accelerated failure time model. J. Clin. Epidemiol. 2000, 53, 519–523. [Google Scholar] [CrossRef]
  14. Vinik, A.I.; Ziegler, D. Diabetic Cardiovascular Autonomic Neuropathy. Circulation 2007, 115, 387–397. [Google Scholar] [CrossRef]
  15. Astrup, A.S.; Tarnow, L.; Rossing, P.; Hansen, B.V.; Hilsted, J.; Parving, H.-H. Cardiac Autonomic Neuropathy Predicts Cardiovascular Morbidity and Mortality in Type 1 Diabetic Patients with Diabetic Nephropathy. Diabetes Care 2006, 29, 334–339. [Google Scholar] [CrossRef] [Green Version]
  16. Chowdhury, M.; Nevitt, S.; Eleftheriadou, A.; Kanagala, P.; Esa, H.; Cuthbertson, D.J.; Tahrani, A.; Alam, U. Cardiac autonomic neu-ropathy and risk of cardiovascular disease and mortality in type 1 and type 2 diabetes: A meta-analysis. BMJ Open Diabetes Res. Care 2021, 9, e002480. [Google Scholar] [CrossRef]
  17. Gerritsen, J.; Dekker, J.M.; TenVoorde, B.J.; Kostense, P.J.; Heine, R.J.; Bouter, L.M.; Heethaar, R.M.; Stehouwer, C.D. Impaired Autonomic Function Is Associated with Increased Mortality, Especially in Subjects with Diabetes, Hypertension, or a History of Cardiovascular Disease: The Hoorn Study. Diabetes Care 2001, 24, 1793–1798. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Martin, C.L.; Albers, J.; Herman, W.H.; Cleary, P.; Waberski, B.; Greene, D.A.; Stevens, M.J.; Feldman, E.L.; DCCT/EDIC Research Group. Neuropathy Among the Diabetes Control and Complications Trial Cohort 8 Years After Trial Completion. Diabetes Care 2006, 29, 340–344. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insu-lin-dependent diabetes mellitus. N. Engl. J. Med. 1993, 329, 977–986. [Google Scholar] [CrossRef]
  20. Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT). Diabetologia 1998, 41, 416–423. [Google Scholar] [CrossRef] [Green Version]
  21. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of compli-cations in patients with type 2 diabetes (UKPDS 33). Lancet 1998, 352, 837–853. [Google Scholar] [CrossRef]
  22. Shichiri, M.; Kishikawa, H.; Ohkubo, Y.; Wake, N. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000, 23 (Suppl. S2), B21–B29. [Google Scholar] [PubMed]
  23. Ohkubo, Y.; Kishikawa, H.; Araki, E.; Miyata, T.; Isami, S.; Motoyoshi, S.; Kojima, Y.; Furuyoshi, N.; Shichiri, M. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: A randomized prospective 6-year study. Diabetes Res. Clin. Pr. 1995, 28, 103–117. [Google Scholar] [CrossRef]
  24. Advance Collaborative Group; Patel, A.; MacMahon, S.; Chalmers, J.; Neal, B.; Billot, L.; Woodward, M.; Marre, M.; Cooper, M.; Glasziou, P.; et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 2008, 358, 2560–2572. [Google Scholar]
  25. Duckworth, W.; Abraira, C.; Moritz, T.; Reda, D.; Emanuele, N.; Reaven, P.D.; Zieve, F.J.; Marks, J.; Davis, S.N.; Hayward, R.; et al. Glucose control and vascular complications in veterans with type 2 diabetes. N. Engl. J. Med. 2009, 360, 129–139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. American Diabetes Association Professional Practice Committee. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes 2018. Diabetes Care 2022, 45 (Suppl. S1), S144–S174. [Google Scholar] [CrossRef]
  27. Turner, J.M.; Kodali, R. Should Angiotensin-Converting Enzyme Inhibitors Ever Be Used for the Management of Hypertension? Curr. Cardiol. Rep. 2020, 22, 95. [Google Scholar] [CrossRef]
  28. Maxfield, E.K.; Cameron, N.E.; Cotter, M.A.; Dines, K.C. Angiotensin II receptor blockade improves nerve function, modulates nerve blood flow and stimulates endoneurial angiogenesis in streptozotocin-diabetic rats and nerve function. Diabetologia 1993, 36, 1230–1237. [Google Scholar] [CrossRef]
  29. Maxfield, E.K.; Love, A.; Cotter, M.A.; Cameron, N.E. Nerve function and regeneration in diabetic rats: Effects of ZD-7155, an AT1 receptor antagonist. Am. J. Physiol. Metab. 1995, 269, E530–E537. [Google Scholar] [CrossRef]
  30. Nakamura, H.; Domon, Y.; Inoue, T.; Arakawa, N.; Yokoyama, T. Olmesartan medoxomil ameliorates sciatic nerve regeneration in diabetic rats. NeuroReport 2009, 20, 1481–1485. [Google Scholar] [CrossRef]
  31. Iwasaki, Y.; Ichikawa, Y.; Igarashi, O.; Kinoshita, M.; Ikeda, K. Trophic effect of olmesartan, a novel AT1R antagonist, on spinal motor neurons in vitro and in vivo. Neurol. Res. 2002, 24, 468–472. [Google Scholar] [CrossRef] [PubMed]
  32. Shahveisi, K.; Mousavi, S.H.; Hosseini, M.; Rad, A.K.; Jalali, S.A.; Rajaei, Z.; Sadeghnia, H.R.; Hadjzadeh, M.A. The role of local ren-in-angiotensin system on high glucose-induced cell toxicity, apoptosis and reactive oxygen species production in PC12 cells. Iran. J. Basic Med. Sci. 2014, 17, 613–621. [Google Scholar] [PubMed]
  33. Cavusoglu, T.; Karadeniz, T.; Cagiltay, E.; Karadeniz, M.; Yigitturk, G.; Acikgoz, E.; Uyanikgil, Y.; Ates, U.; Tuglu, M.I.; Erbas, O. The Protective Effect of Losartan on Diabetic Neuropathy in a Diabetic Rat Model. Exp. Clin. Endocrinol. Diabetes 2015, 123, 479–484. [Google Scholar] [CrossRef] [PubMed]
  34. Al-Rejaie, S.S.; Abuohashish, H.M.; Ahmed, M.M.; Arrejaie, A.; Aleisa, A.M.; AlSharari, S.D. Telmisartan inhibits hyperalgesia and inflammatory progression in a diabetic neuropathic pain model of Wistar rats. Neurosciences 2015, 20, 115–123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Kubba, S.; Agarwal, S.K.; Prakash, A.; Puri, V.; Babbar, R.; Anuradha, S. Effect of losartan on albuminuria, peripheral and autonomic neuropathy in normotensive microalbuminuric type 2 diabetics. Neurol. India 2003, 51, 355–358. [Google Scholar]
  36. Maser, R.E.; Lenhard, M. Effect of treatment with losartan on cardiovascular autonomic and large sensory nerve fiber function in individuals with diabetes mellitus: A 1-year randomized, controlled trial. J. Diabetes Complicat. 2003, 17, 286–291. [Google Scholar] [CrossRef]
  37. Didangelos, T.P.; Arsos, G.A.; Karamitsos, D.T.; Athyros, V.G.; Georga, S.D.; Karatzas, N.D. Effect of quinapril or losartan alone and in combination on left ventricular systolic and diastolic functions in asymptomatic patients with diabetic autonomic neuropathy. J. Diabetes Complicat. 2006, 20, 1–7. [Google Scholar] [CrossRef]
  38. Athyros, V.G.; Didangelos, T.P.; Karamitsos, D.T.; Papageorgiou, A.A.; Boudoulas, H.; Kontopoulos, A.G. Long-term effect of conver-ting enzyme inhibition on circadian sympathetic and parasympathetic modulation in patients with diabetic autonomic neuropathy. Acta Cardiol. 1998, 53, 201–209. [Google Scholar]
  39. Kontopoulos, A.G.; Athyros, V.G.; Didangelos, T.P.; Papageorgiou, A.A.; Avramidis, M.J.; Mayroudi, M.C.; Karamitsos, D.T. Effect of Chronic Quinapril Administration on Heart Rate Variability in Patients with Diabetic Autonomic Neuropathy. Diabetes Care 1997, 20, 355–361. [Google Scholar] [CrossRef]
  40. Masuda, S.; Tamura, K.; Wakui, H.; Kanaoka, T.; Ohsawa, M.; Maeda, A.; Dejima, T.; Yanagi, M.; Azuma, K.; Umemura, S. Effects of an-giotensin II type 1 receptor blocker on ambulatory blood pressure variability in hypertensive patients with overt diabetic nephropathy. Hypertens. Res. 2009, 32, 950–955. [Google Scholar] [CrossRef]
  41. Tambara, K.; Fujita, M.; Sumita, Y.; Miyamoto, S.; Sekiguchi, H.; Eiho, S.; Komeda, M. Beneficial effect of candesartan treatment on cardiac autonomic nervous activity in patients with chronic heart failure: Simultaneous recording of ambulatory electro-cardiogram and posture. Clin. Cardiol. 2004, 27, 300–303. [Google Scholar] [CrossRef] [Green Version]
  42. Béchir, M.; Enseleit, F.; Chenevard, R.; Lüscher, T.F.; Noll, G. Effect of losartan on muscle sympathetic activity and baroreceptor function in systemic hypertension. Am. J. Cardiol. 2005, 95, 129–131. [Google Scholar] [CrossRef] [PubMed]
  43. Amador, N.; Encarnación, J.J.; Guízar, J.M.; Rodríguez, L.; Lopez, M. Effect of losartan and spironolactone on left ventricular mass and heart sympathetic activity in prehypertensive obese subjects: A 16-week randomized trial. J. Hum. Hypertens. 2005, 19, 277–283. [Google Scholar] [CrossRef] [PubMed]
  44. Galetta, F.; Franzoni, F.; Fallahi, P.; Tocchini, L.; Graci, F.; Carpi, A.; Antonelli, A.; Santoro, G. Effect of telmisartan on QT interval variability and autonomic control in hypertensive patients with left ventricular hypertrophy. Biomed. Pharmacother. 2010, 64, 516–520. [Google Scholar] [CrossRef]
  45. Özdemir, M.; Arslan, U.; Türkoğlu, S.; Balcioğlu, S.; Çengel, A. Losartan Improves Heart Rate Variability and Heart Rate Turbulence in Heart Failure Due to Ischemic Cardiomyopathy. J. Card. Fail. 2007, 13, 812–817. [Google Scholar] [CrossRef]
  46. Petretta, M.; Spinelli, L.; Marciano, F.; Apicella, C.; Vicario, M.L.E.; Testa, G.; Volpe, M.; Bonaduce, D. Effects of losartan treatment on cardiac autonomic control during volume loading in patients with DCM. Am. J. Physiol. Circ. Physiol. 2000, 279, H86–H92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Karas, M.; Lacourcière, Y.; LeBlanc, A.R.; Nadeau, R.; Dubé, B.; Florescu, M.; Lamarre-Cliche, M.; Poirier, L.; Larochelle, P.; de Champlain, J. Effect of the renin-angiotensin system or calcium channel blockade on the circadian variation of heart rate variability, blood pressure and circulating catecholamines in hypertensive patients. J. Hypertens. 2005, 23, 1251–1260. [Google Scholar] [CrossRef]
  48. Neumann, J.; Ligtenberg, G.; Oey, L.; Koomans, H.A.; Blankestijn, P.J. Moxonidine Normalizes Sympathetic Hyperactivity in Patients with Eprosartan-Treated Chronic Renal Failure. J. Am. Soc. Nephrol. 2004, 15, 2902–2907. [Google Scholar] [CrossRef]
  49. Heusser, K.; Vitkovsky, J.; Schmieder, R.E.; Schobel, H.P. AT1 antagonism by eprosartan lowers heart rate variability and baro-reflex gain. Auton. Neurosci. 2003, 107, 45–51. [Google Scholar] [CrossRef]
  50. Klein, I.H.; Ligtenberg, G.; Oey, P.L.; Koomans, H.A.; Blankestijn, P.J. Enalapril and Losartan Reduce Sympathetic Hyperactivity in Patients with Chronic Renal Failure. J. Am. Soc. Nephrol. 2003, 14, 425–430. [Google Scholar] [CrossRef] [Green Version]
  51. Guasti, L.; Petrozzino, M.R.; Mainardi, L.T.; Grimoldi, P.; Zanotta, D.; Garganico, D.; Diolisi, A.; Simoni, C.; Grandi, A.M.; Gaudio, G.; et al. Autonomic function and baroreflex sensitivity during angiotensin-converting enzyme inhibition or angiotensin II AT-1 receptor blockade in essential hypertensive patients. Acta Cardiol. 2001, 56, 289–295. [Google Scholar] [CrossRef] [PubMed]
  52. Fridman, K.U.; Wysocki, M.; Friberg, P.R.; Andersson, O.K. Candesartan cilexetil in hypertension: Effects of six weeks’ treatment on haemodynamics, baroreceptor sensitivity and the renin-angiotensin-aldosterone system. Blood Press 1999, 8, 242–247. [Google Scholar]
  53. Rongen, G.A.; Brooks, S.; Ando, S.-I.; Dajani, H.R.; Abramson, B.L.; Floras, J.S. Neural and Hypotensive Effects of Angiotensin II Receptor Blockade. Hypertension 1998, 31, 378–383. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Vaile, J.; Chowdhary, S.; Osman, F.; Ross, H.; Fletcher, J.; Littler, W.; Coote, J.; Townend, J. Effects of angiotensin II (AT1) receptor blockade on cardiac vagal control in heart failure. Clin. Sci. 2001, 101, 559. [Google Scholar] [CrossRef]
  55. Rabbia, F.; Silke, B.; Carra, R.; Milan, A.; Del Colle, S.; Pugni, C.; Mulatero, P.; Chiandussi, L.; Veglio, F. Heart Rate Variability and Baroreflex Sensitivity during Fosinopril, Irbesartan and Atenolol Therapy in Hypertension. Clin. Drug Investig. 2004, 24, 651–659. [Google Scholar] [CrossRef] [PubMed]
  56. Chern, C.-M.; Hsu, H.-Y.; Hu, H.-H.; Chen, Y.-Y.; Hsu, L.-C.; Chao, A.-C. Effects of Atenolol and Losartan on Baroreflex Sensitivity and Heart Rate Variability in Uncomplicated Essential Hypertension. J. Cardiovasc. Pharmacol. 2006, 47, 169–174. [Google Scholar] [CrossRef] [PubMed]
  57. Franchi, F.; Lazzeri, C.; Foschi, M.; Tosti-Guerra, C.; Barletta, G. Cardiac autonomic tone during trandolapril-irbesartan low-dose combined therapy in hypertension: A pilot project. J. Hum. Hypertens. 2002, 16, 597–604. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Sakata, K.; Yoshida, H.; Obayashi, K.; Ishikawa, J.; Tamekiyo, H.; Nawada, R.; Doi, O. Effects of losartan and its combination with quinapril on the cardiac sympathetic nervous system and neurohormonal status in essential hypertension. J. Hypertens. 2002, 20, 103–110. [Google Scholar] [CrossRef] [PubMed]
  59. Yee, K.M.; Struthers, A. Endogenous angiotensin II and baroreceptor dysfunction: A comparative study of losartan and enalapril in man. Br. J. Clin. Pharmacol. 1998, 46, 583–588. [Google Scholar] [CrossRef] [Green Version]
  60. De Tommasi, E.; Iacoviello, M.; Romito, R.; Ceconi, C.; Guida, P.; Massari, F.; Francolini, G.; Bertocchi, F.; Ferrari, R.; Rizzon, P.; et al. Comparison of the effect of valsartan and lisinopril on autonomic nervous system activity in chronic heart failure. Am. Heart J. 2003, 146, E17. [Google Scholar] [CrossRef]
  61. Frachet, S.; Danigo, A.; Labriffe, M.; Bessaguet, F.; Quinchard, B.; Deny, N.; Baffert, K.-A.; Deluche, E.; Sturtz, F.; Demiot, C.; et al. Renin-Angiotensin-System Inhibitors for the Prevention of Chemotherapy-Induced Peripheral Neuropathy: OncoToxSRA, a Preliminary Cohort Study. J. Clin. Med. 2022, 11, 2939. [Google Scholar] [CrossRef] [PubMed]
  62. Bacon, C.G.; Hu, F.B.; Giovannucci, E.; Glasser, D.B.; Mittleman, M.A.; Rimm, E.B. Association of Type and Duration of Diabetes with Erectile Dysfunction in a Large Cohort of Men. Diabetes Care 2002, 25, 1458–1463. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. De Berardis, G.; Franciosi, M.; Belfiglio, M.; Di Nardo, B.; Greenfield, S.; Kaplan, S.H.; Pellegrini, F.; Sacco, M.; Tognoni, G.; Valentini, M.; et al. Quality of Care and Outcomes in Type 2 Diabetes (QuED) Study Group. Erectile dysfunction and quality of life in type 2 diabetic patients: A serious problem too often overlooked. Diabetes Care 2002, 25, 284–291. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Chen, Y.; Li, S.X.; Yao, L.S.; Wang, R.; Dai, Y.T. Valsartan treatment reverses erectile dysfunction in diabetic rats. Int. J. Impot. Res. 2006, 19, 366–370. [Google Scholar] [CrossRef] [PubMed]
  65. Yang, R.; Yang, B.; Wen, Y.; Fang, F.; Cui, S.; Lin, G.; Sun, Z.; Wang, R.; Dai, Y. Losartan, an Angiotensin Type I Receptor, Restores Erectile Function by Downregulation of Cavernous Renin-Angiotensin System in Streptozocin-Induced Diabetic Rats. J. Sex. Med. 2009, 6, 696–707. [Google Scholar] [CrossRef] [PubMed]
  66. Park, K.; Shin, J.W.; Oh, J.K.; Ryu, K.S.; Kim, S.W.; Paick, J.-S. Restoration of erectile capacity in normotensive aged rats by modulation of angiotensin receptor type 1. J. Androl. 2004, 26, 123–128. [Google Scholar]
  67. Baumhäkel, M.; Schlimmer, N.; Böhm, M.; on behalf of the DO-IT Investigators. Effect of irbesartan on erectile function in patients with hypertension and metabolic syndrome. Int. J. Impot. Res. 2008, 20, 493–500. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Llisterri, J.L.; Vidal, J.V.L.; Vicente, J.A.; Roca, M.A.; Bravo, C.P.; Zamorano, M.A.S.; Ferrario, C.M. Sexual Dysfunction in Hypertensive Patients Treated with Losartan. Am. J. Med Sci. 2001, 321, 336–341. [Google Scholar] [CrossRef]
  69. Düsing, R. Effect of the angiotensin II antagonist valsartan on sexual function in hypertensive men. Blood Press. Suppl. 2003, 2, 29–34. [Google Scholar] [CrossRef]
  70. Maser, R.E.; Lenhard, M.J. Cardiovascular Autonomic Neuropathy Due to Diabetes Mellitus: Clinical Manifestations, Consequences, and Treatment. J. Clin. Endocrinol. Metab. 2005, 90, 5896–5903. [Google Scholar] [CrossRef] [Green Version]
  71. Kihara, M.; Mitsui, M.K.; Mitsui, Y.; Okuda, K.; Nakasaka, Y.; Takahashi, M.; Schmelzer, J.D. Altered vasoreactivity to angiotensin II in experimental diabetic neuropathy: Role of nitric oxide. Muscle Nerve 1999, 22, 920–925. [Google Scholar] [CrossRef]
  72. Rutkove, S.B. A 52-year-old woman with disabling peripheral neuropathy: Review of diabetic polyneuropathy. JAMA 2009, 302, 1451–1458. [Google Scholar] [CrossRef] [PubMed]
  73. Ziegler, D. Treatment of diabetic neuropathy and neuropathic pain: How far have we come? Diabetes Care 2008, 31 (Suppl. S2), S255–S261. [Google Scholar] [PubMed] [Green Version]
  74. Ceriello, A.; Assaloni, R.; Da Ros, R.; Maier, A.; Piconi, L.; Quagliaro, L.; Esposito, K.; Giugliano, D. Effect of Atorvastatin and Irbesartan, Alone and in Combination, on Postprandial Endothelial Dysfunction, Oxidative Stress, and Inflammation in Type 2 Diabetic Patients. Circulation 2005, 111, 2518–2524. [Google Scholar] [CrossRef] [PubMed]
  75. Ceriello, A.; Assaloni, R.; Da Ros, R.; Maier, A.; Quagliaro, L.; Piconi, L.; Esposito, K.; Giugliano, D. Effect of irbesartan on nitrotyrosine generation in non-hypertensive diabetic patients. Diabetologia 2004, 47, 1535–1540. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Miyata, T.; van Ypersele de Strihou, C.; Ueda, Y.; Ichimori, K.; Inagi, R.; Onogi, H.; Ishikawa, N.; Nangaku, M.; Kurokawa, K. Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation end products: Biochemical mechanisms. J. Am. Soc. Nephrol. 2002, 13, 2478–2487. [Google Scholar] [CrossRef] [Green Version]
  77. Chaturvedi, N. Metabolic memory in the autonomic neuropathy of diabetes: Implications for pathogenesis and patient care. Circulation 2009, 119, 2865–2867. [Google Scholar] [CrossRef] [Green Version]
  78. Patel, A.; MacMahon, S.; Advance Collaborative Group; Chalmers, J.; Neal, B.; Woodward, M.; Billot, L.; Harrap, S.; Poulter, N.; Marre, M.; et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): A randomised controlled trial. Lancet 2007, 370, 829–840. [Google Scholar] [CrossRef] [Green Version]
  79. Schrier, R.W.; Estacio, R.O.; Esler, A.; Mehler, P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int. 2002, 61, 1086–1097. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Estacio, R.O.; Jeffers, B.W.; Gifford, N.; Schrier, R.W. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 2000, 23, B54–B64. [Google Scholar]
  81. Diabetes UKPDS UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2. BMJ 1998, 317, 703–713. [Google Scholar] [CrossRef] [Green Version]
  82. Ferrario, C.M.; Levy, P. Sexual dysfunction in patients with hypertension: Implications for therapy. J. Clin. Hypertens. 2002, 4, 424–432. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Kifor, I.; Williams, G.H.; Vickers, M.A.; Sullivan, M.P.; Jodbert, P.; Dluhy, R.G. Tissue angiotensin II as a modulator of erectile function. I. Angiotensin peptide content, secretion and effects in the corpus cavernosum. J. Urol. 1997, 157, 1920–1925. [Google Scholar] [CrossRef]
  84. Becker, A.J.; Ückert, S.; Stief, C.G.; Truss, M.C.; Machtens, S.; Scheller, F.; Knapp, W.H.; Hartmann, U.; Jonas, U. Possible role of bradykinin and angiotensin II in the regulation of penile erection and detumescence. Urology 2001, 57, 193–198. [Google Scholar] [CrossRef]
  85. Gæde, P.; Vedel, P.; Larsen, N.; Jensen, G.V.; Parving, H.-H.; Pedersen, O. Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes. N. Engl. J. Med. 2003, 348, 383–393. [Google Scholar] [CrossRef] [Green Version]
Jpm 12 01253 g001 550
Figure 1. Mechanism of action of angiotensin receptor blockers.
Figure 1. Mechanism of action of angiotensin receptor blockers.
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Jpm 12 01253 g002 550
Figure 2. Major mechanisms potentially implicated in the beneficial effects of angiotensin receptor blockers on diabetic neuropathy.
Figure 2. Major mechanisms potentially implicated in the beneficial effects of angiotensin receptor blockers on diabetic neuropathy.
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Table
Table 1. Principal findings of preclinical studies that evaluated the effect of angiotensin receptor blockers (ARBs) on diabetic neuropathy.
Table 1. Principal findings of preclinical studies that evaluated the effect of angiotensin receptor blockers (ARBs) on diabetic neuropathy.
Ref.ARBAnimal ModelMajor Findings
[28]ZD 8731Streptozotocin-diabetic ratsZD 8731 ameliorated motor and sensory nerve conduction velocity and increased nerve capillary density
[29]ZD 7155Streptozotocin-diabetic ratsZD 7155 ameliorated motor and sensory nerve conduction velocity, improved nerve regeneration, and increased nerve capillary density and endoneurial blood flow
[30]OlmesartanDiabetic ratsOlmesartan improved nerve regeneration and increased the production of the ciliary neurotrophic factor
Table
Table 2. Principal findings of major clinical studies that evaluated the effect of angiotensin receptor blockers (ARBs) on diabetic neuropathy.
Table 2. Principal findings of major clinical studies that evaluated the effect of angiotensin receptor blockers (ARBs) on diabetic neuropathy.
Ref.nStudy PopulationARBTreatment Duration (Months)Major Findings
[35]25Normotensive patients with T2DM and microalbuminuriaLosartan1Losartan had no effect on peripheral or autonomic neuropathy
[36]44Patients with T1DM or T2DMLosartan12Losartan had no effect on cardiovascular autonomic function or vibration-perception threshold
[37]62Normotensive patients with T1DM or T2DM and autonomic neuropathyLosartan12Losartan improved autonomic nervous function but did not affect vibration-perception threshold
T2DM: type 2 diabetes mellitus; T1DM: type 1 diabetes mellitus.
Table
Table 3. Principal findings of major clinical studies that evaluated the effect of angiotensin receptor blockers (ARBs) on neuropathy in non-diabetic patients.
Table 3. Principal findings of major clinical studies that evaluated the effect of angiotensin receptor blockers (ARBs) on neuropathy in non-diabetic patients.
Ref.nStudy PopulationARBTreatment Duration (Months)Major Findings
[43]50Prehypertensive obese patientsLosartan4Losartan decreased heart sympathetic activity
[47]57Hypertensive patientsTelmisartan2Telmisartan increased heart parasympathetic activity
[49]25Young malesEprosartan7 daysEprosartan lowered heart rate variability and baroreflex gain
Table
Table 4. Principal findings of major clinical studies that evaluated the effect of ARBs on erectile dysfunction.
Table 4. Principal findings of major clinical studies that evaluated the effect of ARBs on erectile dysfunction.
Ref.nStudy
Population		ARBTreatment Duration (Months)Major Findings
[67]1069Hypertensive males with metabolic syndromeIrbesartan6Irbesartan improved erectile function, orgasmic function, and intercourse satisfaction
[68]164Hypertensive malesLosartan3Losartan improved sexual satisfaction and increased the frequency of sexual activity
[69]3502Hypertensive malesValsartan6Valsartan improved erectile function, orgasmic function, and intercourse satisfaction; increased sexual desire
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Kostourou, D.-T.; Milonas, D.; Polychronopoulos, G.; Sofogianni, A.; Tziomalos, K. The Role of Angiotensin Receptor Blockers in the Personalized Management of Diabetic Neuropathy. J. Pers. Med. 2022, 12, 1253. https://doi.org/10.3390/jpm12081253

AMA Style

Kostourou D-T, Milonas D, Polychronopoulos G, Sofogianni A, Tziomalos K. The Role of Angiotensin Receptor Blockers in the Personalized Management of Diabetic Neuropathy. Journal of Personalized Medicine. 2022; 12(8):1253. https://doi.org/10.3390/jpm12081253

Chicago/Turabian Style

Kostourou, Danai-Thomais, Dimitrios Milonas, Georgios Polychronopoulos, Areti Sofogianni, and Konstantinos Tziomalos. 2022. "The Role of Angiotensin Receptor Blockers in the Personalized Management of Diabetic Neuropathy" Journal of Personalized Medicine 12, no. 8: 1253. https://doi.org/10.3390/jpm12081253

APA Style

Kostourou, D. -T., Milonas, D., Polychronopoulos, G., Sofogianni, A., & Tziomalos, K. (2022). The Role of Angiotensin Receptor Blockers in the Personalized Management of Diabetic Neuropathy. Journal of Personalized Medicine, 12(8), 1253. https://doi.org/10.3390/jpm12081253

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