Impact of Azelnidipine in reducing urinary albumin excretion and carotid atherosclerosis in type 2 diabetes patients: BOAT 2 study Review
Hypertension and Diabetes Mellitus are the global health burden and strong risk factors for coronary artery disease (1). Impaired glucose tolerance and insulin resistance are associated with hypertension which in turn leads to the development of diabetes in hypertensive patients. This causes inflammation which leads to atherosclerosis and thus leading to an increased risk of cerebrovascular and cardiovascular diseases. Coexistence of both hypertension and diabetes increases the risk of cardiovascular diseases by 2-3fold (2). The risk of these life- threatening diseases escalates with the presence of other complications like diabetic nephropathy.
There is a wide variety of anti-hypertensive drugs that are used to control blood pressure including calcium channel blockers, renin-angiotensin system inhibitors (angiotensin II receptor blockers [ARBs] and angiotensin-converting enzyme [ACE] inhibitors), diuretics and β-blockers. α-blockers and central sympathetic nerve inhibitors are also administered additionally (3). Various studies in the past have shown that renin-angiotensin system blockers delay the progression of diabetic nephropathy and hence are recommended as the primary antihypertensive drugs (4,5). But as monotherapy may not be sufficient for effective blood pressure control, Combination therapy with other drugs is used.
Studies have also pointed out that in the presence of proteinuria, renin-angiotensin system inhibitors are the first choice of drugs. If proteinuria and diabetes are absent, RAS inhibitors or calcium channel blockers or thiazide-type diuretics should be used (3).
Amlodipine:
Amlodipine is a synthetic dihydropyridine calcium channel blocker with antihypertensive and antianginal properties. It inhibits the influx of extracellular calcium ions into myocardial and peripheral vascular smooth muscle cells, thereby preventing vascular and myocardial contraction. This causes a dilatation of the main coronary and systemic arteries, decreased myocardial contractility, increased blood flow and oxygen delivery to the myocardial tissue, and a decreased total peripheral resistance (6).
Azelnidipine:
Azelnidipine is a dihydropyridine calcium channel blocker. It is 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 (7). Azelnidipine has profound renoprotective effects and antioxidant effects. It suppresses oxidative stress induced by Renin-Angiotensin-Aldosterone-System (RAAS) and has a beneficial effect on renal injury by reducing urinary protein excretion Combination therapy of azelnidipine with any RAAS inhibitor was found to have a potent renoprotective effect (8).
Considering the unique properties of azelnidipine like the antioxidant and anti-inflammatory effects, Kazuhito Tawaramoto et al conducted a study with a hypothesis that azelnidipine is more effective to delay the progression of atherosclerosis and/or diabetic nephropathy (9). The study was published as the letter to the editor in the journal "Diabetology & Metabolic Syndrome"
Methodology:
The study was a prospective, two-arm, randomized controlled clinical study with azelnidipine and amlodipine and was conducted in the division of Diabetes, Endocrinology and Metabolism in Kawasaki Medical School. A total of 38 patients with type 2 diabetes whose blood pressure was not sufficiently controlled by treatment with 20 mg/day of olmesartan for over 2 months were considered for the study. Insufficient blood pressure control was defined as having systolic blood pressure >130 mmHg and/or diastolic blood pressure >80 mmHg according to the guidelines by the Japanese Society of Hypertension.
Inclusion criteria were patients with type 2 diabetes and without well-controlled blood pressure by treatment with olmesartan, aged between 40-75 years old and having an HbA1c below 9.4 %. Patients with suspiciously secondary hypertension or non-diabetic kidney disease, with congenital dyslipidemia or extremely high LDL-cholesterol (>200 mg/dl), with advanced hepatic disease (AST >75 IU/ml) or advanced renal failure (Crn >2.0 mg/dl for male, Crn >1.5 mg/dl for female), pregnancy, or with a current history of any malignant neoplasm, using steroids or any medications like hormonal, diuretics, immune-suppressing medications and/or potassium drug or those with a past history of stroke or myocardial infarction occurring within past 6 months from the start of the trial were excluded from the study. There was no dropout during the follow-up period.
Patients were randomly divided into 2 groups where they were prescribed 16mg/day of azelnidipine and 5mg/day of amlodipine. The effects of both the drugs were evaluated after 32 weeks. Carotid IMT was measured and images of the carotid artery were scanned by computer and then analyzed. Various parameters like Plasma MCP-1, TNF-α, HMW adiponectin, leptin, soluble vascular cell adhesion molecule-1 (VCAM-1), soluble intercellular adhesion molecule-1 (ICAM-1) were measured using enzyme-linked immunosorbent assay kits. Statistical analysis was done.
Results:
The following results were noted
• There was no difference between the two groups in any clinical background including age, BMI, duration of diabetes, blood pressure and biochemical laboratory data except for heart rate.
• There was no difference between the two groups about the treatment of any anti- diabetic or anti-dyslipidemic medication.
• In both groups, systolic and diastolic blood pressure were significantly reduced during the trial (p >0.05), but the efficacy of lowering blood pressure was similar.
• Heart rate was significantly decreased only in azelnidipine group (p >0.05) and there was no statistically significant difference in heart rate between the two groups at the follow-up point.
• At baseline, there was no difference in glucose and lipid metabolism between the two groups.
• HbA1c, fasting plasma glucose and fasting plasma insulin levels were not altered during the treatment with azelnidipine or amlodipine.
• Plasma triglyceride, LDL-cholesterol and HDL-cholesterol levels were not altered.
• Max IMT was significantly decreased only in azelnidipine group at 32 weeks (p >0.05), although average IMT was not altered in both groups.
• Urinary albumin: At baseline, there was no difference in urinary albumin excretion between the two groups. Urinary albumin excretion was significantly reduced after azelnidipine treatment (p >0.05), but not after amlodipine treatment. Urinary albumin excretion in azelnidipine group was significantly lowered compared to the amlodipine group (p > 0.05).
Thus, the authors observed that Azelnidipine causes reduction of urinary albumin excretion and carotid atherosclerosis. In the present study, the authors found that Azelnidipine reduced inflammatory factors like plasma MCP-1 and TNF-α which are key factors secreted by injured vascular cells in atherosclerosis.
The researchers also found from the study that azelnidipine does not affect theadipocytokines which are the key molecules for the improvement of urinary albumin excretion. By affecting the inflammatory axis rather than the adhesion molecules or adipocytokines, azelnidipine leads to the reduction of urinary albumin excretion and carotid atherosclerosis.
The authors suggested a further study with larger sample size, using a placebo, and evaluating the patients for habits like smoking.
" In summary, both azelnidipine (16 mg/day) and amlodipine (5 mg/day) have a similar ability to decrease blood pressure in hypertensive patients complicated with type 2 diabetes. However, azelnidipine delayed the progression of urinary albumin excretion and carotid atherosclerosis, which was not observed with amlodipine. We assume that the reduction of inflammation by azelnidipine explains, at least in part, its beneficial effects on urinary albumin excretion and carotid atherosclerosis," the authors concluded
The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Azelnidipine, click here
References:
1. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ. 2006;332(7533):73–78.
2. Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: an update. Hypertension. 2001;37(4):1053–1059.
3. Umemura, S., Arima, H., Arima, S. et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019). Hypertens Res 42, 1235–1481 (2019).
4. Abe, H., Mita, T., Yamamoto, R., Komiya, K., Kawaguchi, M., Sakurai, Y., Shimizu, T., Ohmura, C., Ikeda, F., Kawamori, R., Fujitani, Y., & Watada, H. (2013). Comparison of effects of cilnidipine and azelnidipine on blood pressure, heart rate and albuminuria in type 2 diabetics with hypertension: A pilot studyJournal of Diabetes Investigation, 4(2), 202-205.
5. Ogihara T, Kikuchi K, Matsuoka H, et al. The Japanese Society of Hypertension Committee for Guidelines for the Management of Hypertension. Hypertens Res 2009; 32: 4–5.
6. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004-. PubChem Compound Summary for CID 2162, Amlodipine; [cited 2020 Sept. 14]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Amlodipine
7. PubChem [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004-. PubChem Compound Summary for CID 65948, Azelnidipine; [cited 2020 Sept. 14]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Azelnidipine
8. Ogawa S, Mori T, Nako K, Ito S. Combination therapy with renin-angiotensin system inhibitors and the calcium channel blocker azelnidipine decreases plasma inflammatory markers and urinary oxidative stress markers in patients with diabetic nephropathy. Hypertens Res 2008; 31: 1147–1155.
9. Tawaramoto, K., Kaneto, H., Hashiramoto, M., Kawasaki, F., Tatsumi, F., Shimoda, M., Kamei, S., Matsuki, M., Mune, T., & Kaku, K. (2015). Azelnidipine, but not amlodipine, reduces urinary albumin excretion and carotid atherosclerosis in subjects with type 2 diabetes: Blood pressure control with olmesartan and azelnidipine in Type 2 diabetes (BOAT2 study)Diabetology & metabolic syndrome, 7, 80.
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