Azelnidipine versus Amlodipine in hypertensive diabetics with albuminuria: Review

The recent 2017 American College of Cardiology/American Heart Association guidelines for the treatment of hypertension defines hypertension as having a Blood pressure of >130/80mm hg (1). Recent Japanese guidelines for hypertension indicate that target blood pressure in hypertensive diabetics should be <130/80mm hg (1). In diabetics with hypertension, who have urinary protein levels of >1g/day, the target blood pressure is further reduced to <125/75mm hg (2).

Aldosterone is the effector molecule of the Renin-angiotensin-aldosterone system (RAAS). Aldosterone induced damage is characterized by proteinuria, collagen accumulation, and glomerular structural lesions. Damage to highly differentiated podocytes, which are pericyte‐like cells is a key initiating factor in the pathogenesis of glomerulosclerosis and proteinuria. Podocytes cause activation of the local RAAS. Various in-vitro studies in the past have found that Increased extracellular glucose stimulated the production of intracellular reactive oxygen species (ROS) through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to podocyte apoptosis (3). Increased NADPH oxidase activity increases oxidative stress (4).

Research done in the past has also found that sustained renal damage is due to the release of reactive oxygen species (5) causing oxidative stress contributing to the progression of tubulointerstitial injury in diabetic nephropathy (6) which in turn causes inflammation leading to diabetic hypertensive organ damages. However, it was found that glomerular and tubular damage due to Diabetes occurs over the years and excretion of proteins precedes the development of microalbuminuria (7). Any functional and structural changes in the proximal tubules and cortical interstitium correlates with the progression of diabetic nephropathy (8).

Tubulointerstitial changes are marked by altered levels of urinary liver type fatty acid-binding protein (L-FABP) and also altered levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) when there is oxidative stress causing nephropathy. L-FABP and 8-OHdG were reported to serve as markers for underlying diabetic complications.

Recent studies have found that certain calcium channel blockers (CCBs) have shown an organo-protective effect.

Azelnidipine which is a novel calcium channel blocker has been found to have profound renoprotective effects. Apart from inhibiting calcium channels, it is also reported to have an antioxidant effect. It suppresses oxidative stress induced by RAAS and has a beneficial effect on renal injury. It also reduces urinary protein excretion and the urinary levels of 8-OHdG and liver-type fatty acid-binding protein. Combination therapy of azelnidipine with any RAS inhibitor was found to have a potent renoprotective effect (9). However, the dosage and kinds of RAS inhibitors were not fixed and the relationship between the changes in those urinary markers and the changes in plasma aldosterone levels are not well known.

With this background, Masanori Abe et al (10) conducted a study to determine the effects of additional therapy from the CCBs azelnidipine or amlodipine using the maximum recommended dose of 40 mg olmesartan (an ARB), on BP control and renoprotection in hypertensive diabetic patients with CKD.

The study was an open-label, randomized, parallel-controlled study conducted at the Nihon University Nerima Hikarigaoka Hospital, Japan. Participants who had type 2 diabetes with nephropathy with stable glycemic control of <7% under medication or insulin were included. Other criteria like having urinary albumin/Cr ratio of 430 mg/g, estimated glomerular filtration rate (eGFR) between 90 and 30 ml/min per 1.73 m 2 , blood pressure at ≥ 130/80 mm Hg, and in treatment with 40 mg olmesartan once daily for at least 8 weeks before the study were included. Patients who were less than 20 and more than 80 yrs of age, having more than second-degree hypertension (>160/100 mm Hg), urinary albumin/Cr ratio of >2000 mg/g, eGFR which is >90 ml/min per 1.73 m 2 or <30 ml/min per 1.73 m 2 , and having HbA1c >7.0% after administration of antidiabetic agents, or having any other conditions like heart failure, angina, myocardial infarction or stroke occurring within 6 months from the start of the trial were excluded from the study.

Patients were randomly assigned to the two treatment arms by an independent investigator who did not have any knowledge of the subject. Necessary modifications to the randomization were done by a dynamic balancing of the serum creatinine (sCr), estimated glomerular filtration rate (eGFR), and urinary albumin/creatinine (Cr) ratio values recorded at the time of patient registration. Maintaining the doses of other antihypertensive agents and statins and measuring the blood pressure to maintain a target of <130/80 mm hg, one patient group having 34 participants were given 8 mg per day azelnidipine, which was increased up to 16 mg per day. The other group having 33 participants were given 2.5 mg per day amlodipine, which was increased up to 5 mg per day.

Laboratory tests like sCr, fasting plasma glucose, HbA1c, haemoglobin, aspartate aminotransferase, alanine aminotransferase, total cholesterol, low-density lipoprotein-cholesterol, triglyceride, sodium, potassium, and uric acid levels, were performed. High-sensitivity C-reactive protein (CRP), Urinary 8-OHdG, L-FABP were measured at baseline before treatment and at week 24 by a specific enzyme-linked immunosorbent assay in the first-morning urine sample and the values were expressed as a ratio to the urinary Cr concentration. Urinary albumin excretion was assessed by measuring urinary concentrations of albumin and Cr (albumin/Cr ratio) in the first-morning urine sample. Plasma renin activity and aldosterone concentrations were measured by radioimmunoassay at baseline and the end of the study.

A modified equation was used to measure the glomerular filtration rate:

eGFR (ml/min per 1.73m 2 ) = 194 x sCr -1.094 x age -0.287 (x0.739 for women). Statistical analysis was done and P<0.05 was set as statistically significant.

The researchers observed the following results

• There were 67 participants in the trial.

• No significant differences were noted between the two groups regarding baseline characteristics.

• The final doses of azelnidipine and amlodipine were 13.9 ± 0.6 and 4.0±0.2 mg per day, respectively.

• In both groups, systolic and diastolic BP values were significantly lower than baseline values 1 month after the initiation of CCB therapy and did not differ significantly till the last of the treatment.

• The heart rate of participants at the end of the study was significantly reduced in the azelnidipine group compared with baseline but did not reach statistical significance.

• sCr levels and eGFR levels were not significantly different between the two groups by the end of the study.

• There were significant differences in the urinary albumin/Cr ratio between the two groups at the end of the study. The baseline value of urinary albumin/Cr ratio was significantly lower from the 4-week time point to the last week of Azelnidipine compared with the amlodipine group.

• Urinary 8-OHdG and Urinary L-FABP levels significantly decreased after 24 weeks in the azelnidipine group. There were significant differences in urinary 8-OHdG levels and Urinary L-FABP between the two groups at the end of the study.

• Plasma renin activity was not significantly changed in either group after 24 weeks of treatment.

• Plasma aldosterone levels were not significantly changed in the amlodipine group but decreased in the azelnidipine group. There was a significant correlation between the percent reduction in plasma aldosterone and percent changes in urinary L-FABP levels in the azelnidipine group.

• Other biochemical parameters like fasting plasma glucose levels, HbA1c levels, total cholesterol, low-density lipoprotein cholesterol, triglyceride, electrolyte, or uric acid levels did not differ significantly between the two groups.

• High-sensitivity CRP levels were significantly reduced in the azelnidipine group.

• No adverse events were reported between the two groups in the trial period.

The researchers also found that there was a significant correlation between the changes in plasma aldosterone levels, urinary 8-OHdG, and L-FABP levels. They added that this could be due to azelnidipine treatment which improved not only glomerular hemodynamics but also tubulointerstitial injury. They recommended further research to clarify whether azelnidipine treatment mediates the reduction of the production of clinical biomarkers of tubulointerstitial damage i.e. urinary 8-OHdG and L-FABP, via prevention of aldosterone-induced NADPH oxidase activation and subsequent superoxide.

Another interesting finding which the authors found was the reduction in heart rate due to azelnidipine action on T-type calcium channels in the cardiac sinus node.

The significant additive effect of azelnidipine found by the researchers was a beneficial effect on urinary 8-OHdG and L-FABP excretion. They reasoned that though all the subjects were treated with the maximal recommended dose of the ARB olmesartan, and statins at baseline between the two groups but still further reduction in high-sensitivity CRP, urinary 8-OHdG and L-FABP levels was obtained due to azelnidipine.

"In conclusion, the present study showed that azelnidipine results in a greater reduction of albuminuria, plasma aldosterone, urinary 8- OHdG and L-FABP levels than amlodipine in patients with diabetic nephropathy. These effects of azelnidipine would appear to make the drug more advantageous in terms of the progression of renal dysfunction and preventing cardiovascular tissue and organ injuries in patients with hypertensive patients with diabetic nephropathy. We propose that azelnidipine therapy should be considered as an additive therapeutic modality for hypertensive diabetic patients whose BP is not sufficiently controlled by RAS-inhibition therapy with the maximal recommended dose of ARBs. Azelnidipine may ameliorate tubulointerstitial injury in diabetic hypertensive patients with CKD, " stated the authors

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10. Abe, M., Maruyama, N., Okada, K. et al. Additive antioxidative effects of azelnidipine on angiotensin receptor blocker olmesartan treatment for type 2 diabetic patients with albuminuria. Hypertens Res 34, 935–941 (2011).