Ameliorating Glucose Intolerance with BP Control: Azelnidipine or Amlodipine?

Apart from being strong predictors of Coronary Artery Diseases, Hypertension and Diabetes Mellitus (DM) are two well-known interrelated complications of each other.

When insulin resistance induces hyperinsulinemia, the sodium reabsorption from renal tubules is increased and leads to high blood pressure. Systolic blood pressure elevation can be caused by increased circulatory fluid volume which is caused due to hyperglycaemia induced hyperosmolarity. Hyperinsulinemia stimulates sympathetic nervous activity which increases cardiac output and peripheral vascular resistance which in turn elevates blood pressure. During the period from the impaired glucose tolerance to diabetes onset, the main pathologies causing blood pressure elevation are the promotion of sodium reabsorption due to higher insulin levels and excessive body fluid due to hyperglycemia-induced osmolar adjustment (1).

At the same time, Hypertension is associated with impaired glucose tolerance and insulin resistance resulting in the development of DM in hypertensive patients

Arash Derakhshan et al evaluated the impact of different combinations of glucose tolerance and blood pressure status on the development of type 2 diabetes mellitus (T2DM), hypertension (HTN), and chronic kidney disease (CKD) in a total of 12,808 Iranian adults aged ≥20 years. From the study the authors found that Presence of Hypertension was associated with increased risk of T2DM among the PreDM population; however, dysglycemia did not increase the risk of hypertension among individuals with prehypertension (2).

Coexistence of DM and Hypertension increases the risk of cardiovascular disease by 2-3-fold. Hence, medications which prevent new-onset DM and HTN, are important in non- diabetic patients with hypertension

Calcium channel blockers (CCB) are the first-line drugs used to treat hypertension. CCBs lower blood pressure through vasodilation and reduction of peripheral resistance. They usually do not impair glucose metabolism or lipid profile and may even attenuate the development of arteriosclerotic lesions. While Amlodipine has been a popular CCB prescribed by physicians, Azelnidipine is a relatively newly developed and commercially used long-acting calcium antagonist that decreases blood pressure without increasing the heart rate prevents cardiac damage, reduces glucose intolerance, and possesses antioxidant properties (3).

Certain experimental studies have demonstrated that azelnidipine improved glucose intolerance and lowered the risk of hyperglycemia-induced metabolic disorders in diabetic mice [7,8]

To study the impact of CCBs on clinical practice, Kosuke Fukao et al studied the effect of long-acting CCB such as Azelnidipine and Amlodipine on glucose tolerance and insulin resistance [4] in a randomized crossover study titled AGENT Trial. The objective of the study was to examine the levels of blood glucose and insulin, lipids, inflammatory markers, circulating a number of progenitor cells, and endothelial functions after administration of azelnidipine and amlodipine in a prospective randomised cross over study.

Methodology:

Eighteen non-diabetic patients with essential hypertension were enrolled in the study. The subjects were randomised by a non-treating physician using random numbers to match two groups for age, sex, glycated haemoglobin levels (HbA1c). Subjects having a history of secondary hypertension/DM, serum creatinine levels ≥ 2.0 mg/dL, symptomatic heart failure, acute cardiovascular diseases 3 months prior to the examination, history of gastrointestinal surgery, and systemic diseases, such as hepatic disease, collagen disease, and malignancy were excluded from the study.

After randomization, azelnidipine 16 mg once daily or amlodipine 5 mg once daily was administered in a crossover manner each for 12-week. At the beginning of this study and the end of each treatment, a blood sample was taken from an antecubital vein after 12 h of fasting.

The plasma levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and high-sensitivity C-reactive protein (hs-CRP), Low-density lipoprotein cholesterol (LDL-C) levels, HbA1 c, IL-6 were measured, and a standard 75 g OGTT was done. Blood samples for the measurement of glucose and insulin were drawn just before glucose administration, as well as 30, 60 and 120 min later. The morning urine sample was collected for urinalysis at the beginning and the end of each therapy period. Urinary albumin and liver type fatty acid-binding protein (L-FABP) were measured and expressed as ratios to the urinary creatinine concentration. Circulating number of haematopoietic progenitor cells (HPCs) were quantified and Endothelial function as determined by reactive hyperemia in peripheral arteries was measured.

Results:

From the study, the following was found:

• No significant differences were observed in systolic blood pressure (SBP) and diastolic blood pressure (DPB) after administration of azelnidipine and amlodipine
• The heart rate after azelnidipine administration was significantly lower than that after amlodipine administration.
• The levels of blood glucose and immunoreactive insulin (IRI) after the 75 g OGTT at baseline and after administration of the two medications were significantly lower for azelnidipine than after amlodipine administration.
  
• Changes of TC, LDL-C, HDL-C, and HbA1 c showed no significant differences between each drug administration group.
• hs-CRP levels tended to be lower after azelnidipine than after amlodipine administration.
• Circulating numbers of HPC after azelnidipine administration were significantly higher than those after the amlodipine administration.
• No significant differences were observed in the estimated glomerular filtration rate, peripheral arterial tonometry (PAT) ratio, L-FABP levels, or urinary albumin levels after the administration of azelnidipine or amlodipine.
• The anti-sympathetic nervous system effect of azelnidipine may contribute to a favourable effect on glucose tolerance

The authors observed that after azelnidipine administration, the heart rate was significantly reduced and was significantly lower than that after amlodipine administration. They noted that the anti-sympathetic nervous system effect of azelnidipine may contribute to a favourable effect on glucose tolerance.

The researchers further noted that their study demonstrated that azelnidipine administration rather than amlodipine administration significantly ameliorated glucose intolerance and the inflammatory state in non-diabetic patients with essential hypertension. In addition, the number of circulating HPCs was significantly higher after azelnidipine administration than those after amlodipine administration

From the study, the authors concluded that azelnidipine treatment may have beneficial effects against glucose intolerance, insulin sensitivity, the inflammatory state, and circulating numbers of progenitor cells in non-diabetic patients with essential hypertension.

References:

1. Ohishi, M. Hypertension with diabetes mellitus: physiology and pathology. Hypertens Res 2018 41, 389–393.

2. Arash Derakhshan, Farideh Bagherzadeh‐Khiabani, Banafsheh Arshi, Azra Ramezankhani, Fereidoun Azizi, Farzad Hadaegh. "Different Combinations of Glucose Tolerance and Blood Pressure Status and Incident Diabetes, Hypertension, and Chronic Kidney Disease". Journal of the American Heart Association 2016; 5(8):e003917.

3. Kain V, Kumar S, Puranik AS, Sitasawad SL. Azelnidipine protects myocardium in hyperglycemia-induced cardiac damage. Cardiovasc Diabetol. 2010 Dec 1;9:82. doi:10.1186/1475-2840-9-82.

4. Fukao, K., Shimada, K., Hiki, M. et al. Effects of calcium channel blockers on glucose tolerance, inflammatory state, and circulating progenitor cells in non-diabetic patients with essential hypertension: a comparative study between Azelnidipine and amlodipine on Glucose tolerance and ENdothelial function - a crossover Trial (AGENT). Cardiovasc Diabetol 10, 79 (2011). https://doi.org/10.1186/1475-2840-10-79

5. Yu Xiao, Gang Hu: The effects of azelnidipine and amlodipine in the treatment of mild to moderate hypertension: a systematic review. Int J Clin Exp Med 2017;10(7):11273-11281

6. Koike, Y., Kawabe, T., Nishihara, K. et al. Effects of azelnidipine and amlodipine on exercise-induced sympathoexcitation assessed by pupillometry in hypertensive patients. Hypertens Res 2016 39, 863–867

7. Iwai M, Li HS, Chen R, Shiuchi T, Wu L, Min LJ, Li JM, Tsuda M, Suzuki J, Tomono Y, et al: Calcium channel blocker azelnidipine reduces glucose intolerance in diabetic mice via different mechanism than angiotensin receptor blocker olmesartan. J Pharmacol Exp Ther 2006, 319(3):1081-1087.

8. Kain V, Kumar S, Puranik AS, Sitasawad SL: Azelnidipine protects myocardium in hyperglycemia-induced cardiac damage. Cardiovasc Diabetol 2010, 9:82

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