Comparative Effect of Valsartan and Amlodipine on Insulin Resistance in Hypertensive Patients

ypertension is the most widespread cardiovascular disease. Permanently elevated arterial blood pressure damages blood vessels in kidney, heart, and brain and leads to an increased incidence of renal failure, coronary disease, heart failure and stroke. Therefore, pharmacologic treatment of blood pressure has been shown to prevent damage to blood vessels and to substantially reduce morbidity and mortality rates ¹. The most commonly used drugs for the management of hypertension include, β-adrenoceptor blockers, diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and others ².

   Elevated blood pressure tends to impair glucose tolerance and induce a resistance to the actions of insulin rendering hypertensive patients at a risk of developing diabetes mellitus³. Non-treated patients with essential hypertension generally have higher fasting and postprandial insulin levels than normotensive patients. A direct relationship presents between blood pressure and fasting insulin levels in patients with essential hypertension ⁴.

   Many studies have shown that insulin resistance, which is present in more than 50% of the patients with hypertension ^5,6, plays an important role in the development and progression of hyperten­sion and diabetes. In addition to its role in increasing the incidence of diabetes ⁷, insulin resistance is also directly linked with the severity of hypertension ⁵.  Therefore, it is important that antihypertensive drugs are chosen such that they do not adversely affect the metabolic parameters and worsen the already insulin resistant state in hypertensive patients and rather prevent the new onset of diabetes mellitus in hypertensive patients ⁸.

   So the main objective of this study was to study the influence of commonly used first line antihypertensive drugs valsartan and amlodipine on insulin resistance parameters in hypertensive patients free from diabetes mellitus.

METHODS

Thirty two non-diabetic patients with mild to moderate hypertension between 25-55 year age male or female attending private medical clinics in Mosul city were recruited in this study from April 2018 to November 2018. The exclusion criteria includes any patient take other drugs except valsartan and amlodipine, patients with any type of diabetes, patients have secondary hypertension, patients with uncontrolled hypertension, patients with other disease states, and any hypersensitivity to valsartan and amlodipine.

   The study was approved by the Medical Research and Ethics Committee of the Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul (Iraq). Before the beginning of the study, all participants given written informed consent.

   This was a prospective, openlabled, randomized controlled study. The patients participatedy in the study were randomized into two groups to receive the following treatments orally: Group I (Amlodipine no= 17): Amlodipine titrated from 5 mg to 10 mg daily, Group II (Valsartan no= 15):  Valsartan titrated from 80 mg to 160 mg daily. Treatment with this drugs were continued for 8 week period.

   Five milliliters venous blood samples were obtained from both groups of treatment at baseline and after 8 week treatment after overnight fasting.

Fasting serum insulin (FSI) was measured by the LIAISON insulin assay uses chemiluminescencev immunoassay (CLIA) technology for the in vitro  quantitative determination of insulin in human serum specimens. DiaSorin S.p.A Via Crescentino snc-13040 Saluggia (VC) Italy. Fasting serum glucose (FSG) was measured by Trinder method (Trinder  1969) using Human Glucose GOD-PAP kit (BIOLABO SA, Maizy, France) ⁹.

   The homeostasis model assessment for insulin resistance (HOMA-IR) was computed as ¹⁰:

   Body mass index was calculated using the formula:

BMI = Weight in Kg/ (Height in m)²

   Mercury sphygmomanometer was used to record the blood pressure, systolic blood pressure (SBP) and diastolic blood pressure (DBP). Each patient was instructed to sit for at least five minutes in a chair before measuring blood pressure. The auscultatory method of blood pressure measurement was used. Mean of the two recordings was taken. Blood pressure was recorded for each patients both at baseline and after 8 week treatment.

   The data in this study are expressed as mean±SD. P-value equal or less than 0.05 was considered significant in all types of statistical tests. The present study was analyzed using SPSS program (version 15). Unpaired t-test was used for the analyses between valsartan and amlodipine groups for the data at baseline and at 8 week. Paired t-test was used to compare the differences in various parameters of the hypertensive patients before and after therapy in each group.

RESULTS

Thirty two patients were recruited in this study and randomly divided into two groups to receive treatment with amlodipine (n=17) or valsartan (n=15) once daily for 8 weeks. The characteristics and baseline data of the study groups were shown in Table 1, there were no significant differences between the two groups in term of baseline data except for BMI (the difference was significant), and the study subjects were approximately comparable with each other for different demographic and clinical variables.

   The results also showed that after 8 week treatment with amlodipine and valsartan, SBP, DBP, FSI and HOMA-IR for both groups were significantly decreased in comparison with baseline data while FSG where non significantly decreased as shown in Table 2 and 3.

   Table 4 shows that valsartan produce non-significant greater reduction in SBP, FSG, FSI and HOMA-IR than amlodipine in terms of greater difference that its produce.

Table 1: Baseline characteristics for amlodipine and valsartan groups.

Unpaired t-test

^⁎ Significant differences

Table 2: Effect of valsartan on studied parameters after 8 week treatment.

Paired t-test

^⁎ Significant differences

Table 3: Effect of amlodipine on studied parameters after 8 weeks treatment.

Paired t-test

^⁎ Significant differences

Table 4: Difference produce by amlodipine and valsartan.

Unpaired t-test

DISCUSSION

Diabetes occurring concomitantly with hypertension increases the risk of cardiovascular diseases by manifold ¹¹. Several studies showed the insulin sensitizing effects of ARBs especially telmisartan. Telmisartan has an action similar to the thiazolidinedione drugs which  possess agonistic activity at peroxisome proliferator-activated receptor, gamma (PPAR-γ), this explains its effects on glucose- insulin metabolism ¹². But it is not known if this favorable effect on insulin sensitivity is shared by whole ARB class or not.

   Other clinical studies have shown that amlodipine, the long acting calcium channel blockers may improve glucose tolerance and lower insulin resistance¹³. Therefore, this study was conducted to evaluate improvements of insulin resistance and elevated blood pressure in patients with hypertension receive treatment with either amlodipine or valsartan for 8 weeks.

   The results of this study demonstrated that in non-diabetic hypertensive patients, both studied drugs exhibited favorable effects on the glucometabolic variables and blood pressure (significant decrease in  FSI, HOMA-IR, SDP and DBP but non-significant decrease in FSG).

   In a study conducted by Bharati and Singh, 2016 who studied the effects of two antihypertensive drugs losartan (50-100) mg and amlodipine (5-10) mg in 40 nondiabetic hypertensive patients, they concluded that losartan and amlodipine lowered insulin resistance (P<0.05) in patients of mild to moderate hypertension¹⁴.

   Tian et al., 2016 in their meta-analysis about the effect of valsartan on insulin resistance in patients with hypertension found that many clinical studies have reported that valsar­tan was effective at lowering blood pressure and improving insulin resistance in patients with hypertension¹⁵.

   Of the two drugs in this study, valsartan produce greater reduction in HOMA-IR than amlodipine but the difference was not statistically signifi­cant and this was in agreement with the results of the Tian et al., 2016 who stated that "The present meta-analysis suggested that valsartan showed a tendency to be superior to other antihypertensive drugs in the improvement of insulin re­sistance" ¹⁵.

   In two studies, it has been reported that the angiotensin (AT1) receptor blocker telmisartan and the ACE inhibitor ramipril also have antidiabetic effects mediated by stimulation of the peroxisome proliferator-activated receptor-gamma (PPAR-γ) receptor and probable benefits to insulin sensitivity ^16,17.

   Calcium channel blockers (CCBs) may decrease insulin resistance by having vasodilator action especially in the insulin sensitive tissues with negligible increase in sympathetic activity. Calcium channel blockers may help in the translocation of glucose transporters and prevent the inhibition of glycogen synthase by calcium. Improvement in insulin sensitivity by CCBs might be linked through their antioxidant effects¹⁸.

   The possible mechanisms by which ARBs may improve the insulin resistance are hemodynamic effects, increase of glucose transport and improvement of the intracellular signal transduction of insulin^19,20. Furthermore, these effects may be due to blocking the oxidative stress and the reduction of adiponectin level ²¹. Telmisartan and irbesartan have a partial agonist action of PPARγ ²² and are expected to have beneficial effects on insulin resistance by increasing adiponectin levels than the other ARBs without such action.

CONCLUSION

This study showed that the antihypertensive drugs amlodipine and valsartan have favorable effects on insulin resistance mediated by decreasing HOMA-IR in non-diabetic hypertensive patients. Also, this study illustrated that valsartan seems to have a more potent effect of lowering HOMA-IR than amlodipine in the standard dose.