Role of Azelnidipine on management of BP in hypertensive Diabetics: Review

Aldosterone is the effector molecule of the Renin-angiotensin-aldosterone system (RAAS) (2). Aldosterone induced damage is characterized by proteinuria, collagen accumulation, and glomerular structural lesions (3,4). The sustained renal damage is due to the release of reactive oxygen species. Aldosterone can also induce fibrosis and target organ damage by plasminogen activator inhibitor stimulation, TGF-β1, and reactive oxygen species (5). Hypertension in diabetes is characterized by reduced nitric oxide (NO)-mediated vasorelaxation, reduced baroreflex sensitivity, enhanced sympathetic activity, and abnormalities that are promoted by aldosterone (6).

There are multiple drug regimens to treat hypertension in diabetics including β-blockers, ACE inhibitors, Angiotensin receptor blockers (ARBs), diuretics, and calcium channel blockers (7). Various studies in the past have shown that combination therapy showed more beneficial effects than monotherapies. Aldosterone antagonists also appear to have considerable potential in treating diabetic patients with hypertension. For patients having hypertension and diabetes, CDA guidelines recommend any combination of ACEIs/ARBs, dihydropyridine CCBs, or thiazide/thiazide-like diuretics (1).

Azelnidipine is a novel calcium channel blocker which has several beneficial effects. It is a dihydropyridine calcium channel blocker marketed by Daiichi-Sankyo pharmaceuticals, Inc. in Japan. It has a gradual onset of action and produces a long-lasting decrease in blood pressure, with only a small increase in heart rate, and does not induce reflex tachycardia unlike some other calcium channel blockers (8). It has reno-protective, cardioprotective, cerebroprotective, insulin resistance improving features, and anti-atherosclerotic effects (9) and also can suppress the sympathetic nerve activity.

As the beneficial effects of Calcium channel blockers to treat hypertensive diabetics, remains to be elucidated, Tsuyoshi Isaka et al designed a study to evaluate the effects of Azelnidipine in hypertensive patients with type 2 diabetes mellitus compared with other CCBs. The study was shortly named as Jikei Azelnidipine study in patients with Hypertension and Diabetes Mellitus (JAz-HDM) (10).

The study was an open-labeled prospective study. Patients aged above 20 years with hypertension and T2 diabetes who received one CCB other than Azelnidipine were included in the study. Concomitant use of other anti-hypertensive drugs like ARBs, angiotensin- converting enzyme inhibitor (ACE-I), β-blockers, and diuretics were also allowed. Patients in whom Azelnidipine was contraindicated or who are on more than 2 kinds of CCBs were excluded from the study. As per the study protocol, all the participants were given Azelnidipine 16 mg after the initial examination of the physical and laboratory blood data. 24 weeks later, a final examination was done.

Efficacy assessments were done by measuring body mass index (BMI), blood pressure (BP), mean arterial pressure, pulse pressure, HbA1c, serum creatinine, estimated glomerular filtration rate, highly sensitive C reactive protein, plasma renin activity (PRA), plasma aldosterone concentration (PAC), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, vascular cell adhesion molecule (VCAM-1), plasminogen activator inhibitor type 1 (PAI1), urinary albumin excretion, urinary 8-hydroxydeoxyguanosine excretion before and 6 months after prescription of Azelnidipine. Blood pressure was regularly measured, and Blood sampling and spot urine collection were also performed at the follow-up visit. The estimated glomerular filtration ratio was also measured. Statistical analysis was performed using GraphPad Prism 5 for windows.

35 patients between 45 – 84 years of age were enrolled in the study. The mean age ±SD was 64.9±9.4 yrs. Finally, 33 patients participated in the study which had 18 male and 15 female patients. There were no recognized adverse events. The duration of CCBs usage other than azelnidipine was more than 4 months. ARBs/ACEIs were also prescribed. Other antihypertensives were also prescribed. 28 Patients were treated with glucose-lowering drugs and insulin. 15 patients were also treated for dyslipidemia.

The authors observed the following results

 The change of CCB resulted in a significant decrease in BMI but did not reach statistically significant values.

 PAC or plasma aldosterone concentration was significantly decreased after the prescription of azelnidipine. PRA increased but not statistically significant. PAC was reduced in the patients treated with amlodipine before azelnidipine (p<0.01).

 PAI 1 decreased in Azelnidipine patients but not statistically significant.

 Δ PAC and ΔPAI 1 did not correlate with ΔBMI. ΔPAI 1 did not correlate with ΔPAC.

 Change of CCB resulted in a significant increase in serum creatinine and a decrease in eGFR.

 Prescription of azelnidipine increased urinary albumin excretion, but the increase of urinary albumin excretion did not reach statistical significance.

 Other parameters, such as HbA1c, hsCRP, PRA, HDL-C, LDL-C, VCAM-1, and urinary 8-OHdG were not significantly changed after the prescription of azelnidipine.

Thus, the authors observed that there was a significant decrease of PAC and PAI-1 concentration after prescription of azelnidipine despite significant changes of systolic blood pressure, mean arterial pressure, diastolic blood pressure, and pulse pressure compared with formerly prescribed calcium channel blockers. They also added that azelnidipine may contribute to avoid the "aldosterone breakthrough" by its suppressive effects on aldosterone synthesis and secretion.

The authors also put forth an interesting finding on PAC. They found statistical differences in the decrease of PAC by the prescription of azelnidipine, especially in the patients who received amlodipine. The authors attributed this discrepancy to the basal value of PAC in patients who received amlodipine earlier. But the same was not found in patients who switched from benidipine to azelnidipine which was attributed to the suppressive effects of benidipine on PAC production.

The researchers gave another important finding on PAI-1. They found that azelnidipine caused a significant decrease in PAI-1. It could be due to inhibition of the effects of angiotensin II by ACE-I which resulted in decreased PAI-1 expression. Thus, azelnidipine contributed to the improvements of the fibrinolytic balance by direct suppression of PAI-1. They also added that in their study they did not find a significant decrease of urinary 8-OHdG excretion which is a biomarker of oxidative stress.

An increase in serum creatinine and decrease of eGFR was found in the present study to which the researchers reasoned that azelnidipine caused dilation of efferent arterioles of the kidney and progressed disease state of diabetic nephropathy in the present study population. They also added that there was no improvement in albuminuria despite that azelnidipine improved excretion. This could be due to the underlying diabetic condition of the study population.

The Jaz-HDM study revealed that the usage of azelnidipine in the treatment of hypertension may lead to a decrease of PAC and PAI-1, which may be involved in the pathogenesis of cardiovascular diseases and metabolic syndrome, compared with other CCBs.

"Azelnidipine may decrease PAC independent to PRA in patients with type-2 diabetes mellitus and hypertension. Based on the results, azelnidipine exert additional beneficial actions beyond the anti-hypertensive action and maybe one of the suitable CCBs in the treatment of hypertension in patients with type 2 diabetes mellitus," the authors concluded

1. Passarella P, Kiseleva TA, Valeeva FV, Gosmanov AR. Hypertension Management in Diabetes: 2018 Update. Diabetes Spectr. 2018;31(3):218-224.

2. Muñoz-Durango, N., Fuentes, C. A., Castillo, A. E., González-Gómez, L. M., Vecchiola, A., Fardella, C. E., & Kalergis, A. M. (2016). Role of the Renin- Angiotensin-Aldosterone System beyond Blood Pressure Regulation: Molecular and Cellular Mechanisms Involved in End-Organ Damage during Arterial Hypertension. International journal of molecular sciences, 17(7), 797.

3. Calo L.A., Zaghetto F., Pagnin E., Davis P.A., de Mozzi P., Sartorato P., Martire G., Fiore C., Armanini D. Effect of aldosterone and glycyrrhetinic acid on the protein expression of PAI-1 and p22(phox) in human mononuclear leukocytes. J. Clin. Endocrinol. Metab. 2004;89:1973–1976.

4. Walczak C., Gaignier F., Gilet A., Zou F., Thornton S.N., Ropars A. Aldosterone increases VEGF-α production in human neutrophils through PI3K, ERK1/2 and p38 pathways. Biochim. Biophys. Acta. 2011;1813:2125–2132.

5. Sowers J.R. Metabolic risk factors and renal disease. Kidney Int. 2007;71:719–720. doi: 10.1038/sj.ki.5002006.

6. McFarlane, S. I., & Sowers, J. R. (2003). Cardiovascular endocrinology 1: aldosterone function in diabetes mellitus: effects on cardiovascular and renal disease. The Journal of clinical endocrinology and metabolism, 88(2), 516–523.

7. Whalen, K. L., & Stewart, R. D. (2008). Pharmacologic management of hypertension in patients with diabetes. American family physician, 78(11), 1277–1282.

8. National Center for Biotechnology Information. PubChem Database. Azelnidipine, CID=65948, https://pubchem.ncbi.nlm.nih.gov/compound/Azelnidipine (accessed on July 18, 2020)

9. Shewale VU, Aher SS, Saudagar RB, Azelnidipine: A Review on Therapeutic Role in Hypertension, Journal of Drug Delivery and Therapeutics. 2019; 9(3-s):1002-1005 h

10. T, I, T, H, Sakamoto, M, N, S, Ikeda, K, Tojo, K. "Azelnidipine decreased plasma aldosterone and plasminogen activator inhibitor type 1 levels in the hypertensive patients with type 2 diabetes mellitus -the Jikei Azelnidipine study in the patients with Hypertension and Diabetes Mellitus (JAz-HDM)-". Therapeutic Research 2011; 32:371-381.