dihydropyridines and Diabetes-Mellitus--Type-2

In patients with hypertension and diabetes, atherothrombosis is a leading cause of morbidity and mortality, and there is now compelling evidence demonstrating that lowering elevated blood pressure (BP) is one of the most beneficial aims of therapy in this high-risk population. Indeed, major international guidelines have set a target BP goal of 130/80 mmHg in high-risk patients and recommend combination treatment with two or more drug classes to help achieve this objective. Manidipine plus delapril is a fixed-dose combination of a third-generation dihydropyridine calcium antagonist and an angiotensin-converting enzyme inhibitor, which is effective in mild-to-moderately hypertensive patients with an inadequate response to monotherapy. It is also effective in the long-term (50 weeks) management of essential hypertension. Comparative studies have demonstrated that manidipine plus delapril is as effective as enalapril plus hydrochlorothiazide (HCTZ) in patients with hypertension that is unresponsive to monotherapy, and as effective as ramipril plus HCTZ, valsartan plus HCTZ, irbesartan plus HCTZ and olmesartan plus HCTZ in patients with essential hypertension and Type 2 diabetes. In addition, manidipine plus delapril exhibited renoprotective effects in normotensive Type 2 diabetic patients, and improved fibrinolytic function (significantly more than irbesartan plus HCTZ) in hypertensive patients with Type 2 diabetes. Manidipine 10 mg plus delapril 30 mg once daily was generally well tolerated, with no unexpected adverse effects and evidence of a low incidence of ankle edema. Thus, manidipine plus delapril is a fixed-dose combination treatment that significantly reduces elevated BP with once-daily administration. It is well tolerated and has ancillary properties, such as nephroprotective activity and improvement of fibrinolytic balance, which may help reduce cardiovascular morbidity and mortality, particularly in high-risk patients, such as those with Type 2 diabetes mellitus.

Topics: Blood Pressure Determination; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypertension; Indans; Male; Nitrobenzenes; Piperazines; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Survival Analysis

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Humans; Hypertension; Stroke

Manidipine is a lipophilic, third-generation, highly vasoselective, dihydropyridine (DHP) calcium channel antagonist, which, when given on a once-daily basis, effectively reduces blood pressure (BP) in patients with mild-to-moderate essential hypertension. Manidipine has a gradual onset and a long duration of action, effectively maintaining reduced BP levels throughout the 24-hour dosing period, and is effective in the long term with no evidence of intolerance. The BP-lowering capacity of manidipine is similar to that of other established DHPs and of angiotensin-converting enzyme inhibitors. Diabetic patients and very elderly patients with mild-to-moderate hypertension also respond favourably to treatment with manidipine. Manidipine has neutral effects on glucose and lipid metabolism and is generally well tolerated. Manidipine thus represents a first-line option for lowering BP in patients with mild-to-moderate hypertension.

Topics: Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Humans; Hypertension; Kidney Diseases; Male; Nitrobenzenes; Piperazines; Randomized Controlled Trials as Topic; Syndrome

Manidipine is a lipophilic, third-generation dihydropyridine calcium channel antagonist with a high degree of selectivity for the vasculature, thereby inducing marked peripheral vasodilation with negligible cardiodepression. In addition, manidipine does not significantly affect norepinephrine levels, suggesting a lack of sympathetic activation. It has a gradual onset of action and a long duration of action enabling once daily administration. Furthermore, manidipine dilates both the efferent and the afferent renal arterioles and appears to have beneficial renal effects unrelated to its antihypertensive effect. Once-daily oral manidipine is an effective and generally well tolerated antihypertensive agent for younger and elderly adult patients with mild-to-moderate hypertension. In particular, in a large double-blind trial, the incidence of ankle oedema was significantly lower in manidipine than in amlodipine recipients. Manidipine is also effective in hypertensive patients with comorbidities, such as type 2 diabetes mellitus and/or renal impairment, and appears to improve insulin sensitivity without affecting metabolic function. Thus, manidipine represents a first-line treatment option for patients with essential mild-to-moderate hypertension.

Topics: Adult; Aged; Antihypertensive Agents; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dihydropyridines; Humans; Hypertension; Middle Aged; Nitrobenzenes; Piperazines; Renal Insufficiency

It has been suggested that renoprotection with calcium channel blockers (CCBs) may differ. This study aimed to compare the anti-proteinuric effect of different CCBs in patients with type 2 diabetes (T2D).. A multicentre, randomized, open-label, active-controlled study was performed in seven centres in Korea. A total of 74 patients with T2D and microalbuminuria treated with renin-angiotensin system (RAS) blockers were randomized to a cilnidipine 10 mg treatment (n=38) or amlodipine 5 mg treatment (n=36).. Urine albumin to creatinine ratio (ACR) reduction was similar between the two groups at 12 weeks (-53.0±123.2 mg/g in cilnidipine group and -35.7±83.6 mg/g in amlodipine group, P=.29) or 24 weeks (-57.3±106.9 mg/g in cilnidipine group and -20.0±110.4 mg/g in amlodipine group, P=.24). In a subgroup analysis, cilnidipine treatment showed a larger ACR reduction than amlodipine treatment at 12 weeks (-84.7±106.8 mg/g in cilnidipine group and -9.5±79.2 mg/g in amlodipine group, P=.01) and 24 weeks (-84.0±111.7 mg/g in cilnidipine group and 14.6±119.4 mg/g in amlodipine group, P=.008), particularly in patients with a longer duration of diabetes more than 10 years.. Cilnidipine did not show any additional anti-albuminuric effect compared with amlodipine in patients with T2D and microalbuminuria treated with an RAS blocker. However, the anti-albuminuric effect of cilnidipine might differ according to the duration of diabetes.

Topics: Adult; Aged; Albuminuria; Amlodipine; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Administration Schedule; Female; Humans; Hypertension; Male; Middle Aged; Treatment Outcome

In AMANDHA trial, the addition of manidipine, but not amlodipine, in diabetic patients with uncontrolled hypertension, microalbuminuria and preserved renal function resulted in a large decrease of urinary albumin excretion (UAE) despite similar blood pressure (BP) reductions. Factors associated with the reduction of UAE were analyzed.. For this purpose, a multivariable analysis was performed.. Although after 6 months of treatment, manidipine and amlodipine decreased BP to a similar extent, reductions of UAE were higher with manidipine. The assigned treatment, changes in mean BP, sympathetic tone and glycemic control were associated with changes in UAE.. The assigned treatment, changes in mean BP, sympathetic tone and glycemic control were independently associated with changes in UAE. Compared with amlodipine, manidipine reduced UAE to a higher extent, independently of BP reduction.

Topics: Adult; Aged; Albumins; Albuminuria; Amlodipine; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Multivariate Analysis; Nitrobenzenes; Piperazines

Essential hypertension has been extensively reported to cause endothelial dysfunction. The aim of this study was to evaluate the effects of barnidipine or lercanidipine, in addition to losartan, on some parameters indicative of endothelial damage and oxidative stress in hypertensive, type 2 diabetic patients.. One hundred and fifty one patients were randomised to barnidipine, 20 mg/day, or lercanidipine, 20 mg/day, both in addition to losartan, 100 mg/day, for 6 months. We assessed BP every month, in addition, patients underwent ambulatory blood pressure monitoring (ABPM). We also assessed: fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), some markers such as high-sensitivity C-reactive protein (Hs-CRP), tumor necrosis factor-α (TNF-α), metalloproteinase-2 (MMP-2) and -9 (MMP-9), soluble vascular adhesion protein-1 (sVCAM-1), soluble intercellular adhesion protein-1 (sICAM-1), isoprostanes and paraoxonase-1 (PON-1).. Both barnidipine and lercanidipine resulted in a significant reduction in blood pressure, even if the reduction obtained with barnidipine + losartan was greater than that obtained with lercanidipine + losartan. Data recorded with ABPM also showed a similar trend. Barnidipine + losartan reduced the levels of Hs-CRP, TNF-α, sVCAM-1, sICAM-1, and isoprostanes both compared to baseline and to lercanidipine + losartan.. Barnidipine + losartan gave an improvement of some parameters indicative of endothelial damage and oxidative stress in diabetic and hypertensive patients.. NCT02064218 , ClinicalTrials.gov.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Biomarkers; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Endothelium, Vascular; Female; Humans; Hypertension; Italy; Losartan; Male; Middle Aged; Nifedipine; Oxidative Stress; Time Factors; Treatment Outcome

This study compared the efficacy and safety of azelnidipine with that of trichlormethiazide in Japanese type 2 diabetic patients with hypertension.. In a multicenter, open-label trial, 240 patients with adequately controlled diabetes (HbA1c ≤ 7.0%) under lifestyle modification and/or administration of hypoglycemic agents and inadequately controlled hypertension (systolic blood pressure [sBP] ≥ 130 mmHg or diastolic blood pressure [dBP] ≥ 80 mmHg) who were being treated with olmesartan were enrolled. Participants were randomly assigned to an azelnidipine group or a trichlormethiazide group and were followed up for 48 weeks. Main outcome measure was the difference in the change in HbA1c levels from the baseline values at 48 weeks between these two groups.. Of the 240 subjects that were enrolled, 209 subjects (azelnidipine group: 103 patients, trichlormethiazide group: 106 patients) completed this trial. At 48 weeks, the following changes were observed in the azelnidipine and trichlormethiazide groups, respectively: HbA1c levels, 0.19 ± 0.52% and 0.19 ± 0.54%; sBP/dBP, -10.7 ± 9.6/-6.6 ± 6.6 mmHg and -7.1 ± 7.7/-3.3 ± 6.1 mmHg (P < 0.001 for both sBP and dBP). In both groups, dizziness (12 patients [11.7%] and 16 patients [15.1%]) and edema (16 patients [15.5%] and 7 patients [6.6%], P = 0.047) were observed during the 48-week follow-up period.. Azelnidipine was more effective for controlling blood pressure than trichlormethiazide in Japanese type 2 diabetes patients, whereas trichlormethiazide was more effective for reducing albuminuria than azelnidipine. Both of these agents, however, similarly exacerbated glycemic control in type 2 diabetic patients with hypertension.. UMIN 000006081.

Topics: Aged; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Diuretics; Female; Humans; Hypertension; Japan; Male; Middle Aged; Risk Factors; Treatment Outcome; Trichlormethiazide

The aim of this study was to evaluate the effects of lercanidipine or barnidipine on echocardiographic parameters, in hypertensive, type 2 diabetics with left ventricular hypertrophy. One hundred and forty-four patients were randomized to lercanidipine, 20 mg/day, or barnidipine, 20 mg/day, in addition to losartan, 100 mg/day, for 6 months. We evaluated: blood pressure, fasting plasma glucose (FPG), glycated hemoglobin (HbA(1c)), lipid profile, creatinine, estimated glomerular filtration rate (eGFR), sodium, potassium, and acid uric. Echocardiography was performed at baseline and after 6 months. Both lercanidipine and barnidipine decreased blood pressure. Left ventricular mass index was reduced to a greater extent with barnidipine + losartan. Interventricular septal thickness in diastole was reduced by barnidipine + losartan. Posterior wall thickness in diastole was decreased by both treatments, even if barnidipine + losartan were more effective. Ratio of peak early diastolic filling velocity to peak filling velocity at atrial contraction was increased by barnidipine + losartan, but not by lercanidipine + losartan. Finally, isovolumetric relaxation and time and left atrial volume index were reduced by barnidipine + losartan, while lercanidipine + losartan did not affect them. In conclusion, barnidipine + losartan provided a greater improvement of echocardiographic parameters compared to lercanidipine + losartan.

Topics: Aged; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Echocardiography; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Losartan; Male; Middle Aged; Nifedipine; Treatment Outcome

The objective of the present analysis was to determine the effects of a fixed combination of perindopril and indapamide in combination with calcium channel blockers (CCBs) in patients with type 2 diabetes mellitus. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Controlled Evaluation (ADVANCE) trial was a factorial randomized controlled trial. A total of 11 140 patients with type 2 diabetes mellitus were randomly assigned to fixed combination of perindopril-indapamide (4/1.25 mg) or placebo. Effects of randomized treatment on mortality and major cardiovascular outcomes were examined in subgroups defined by baseline use of CCBs. Patients on CCB at baseline (n=3427) constituted a higher risk group compared with those not on CCB (n=7713), with more extensive use of antihypertensive and other protective therapies. Active treatment reduced the relative risk of death by 28% (95% confidence interval, 10%-43%) among patients with CCB at baseline compared with 5% (-12% to 20%) among those without CCB (P homogeneity=0.02) and 14% (2%-25%) for the whole population. Similarly, the relative risk reduction for major cardiovascular events was 12% (-8% to 28%) versus 6% (-10% to 19%) for those with and without CCB at baseline although the difference was not statistically significant (P homogeneity=0.38). There was no detectable increase in adverse effects in those receiving CCB. The combination of perindopril and indapamide with CCBs seems to provide further protection against mortality in patients with type 2 diabetes mellitus.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Combinations; Drug Therapy, Combination; Female; Gliclazide; Humans; Hypertension; Hypoglycemic Agents; Indapamide; Male; Middle Aged; Perindopril; Proportional Hazards Models

A thiazide diuretic used in combination with benazepril is superior to amlodipine plus benazepril in reducing albuminuria in hypertensive patients with diabetes. However, calcium channel blockers have diverse characteristics. Thus, we investigated whether combining an angiotensin receptor blocker with either azelnidipine or a thiazide diuretic produced similar reductions in albuminuria in hypertensive diabetic patients for the same levels of blood pressure achieved.. Hypertensive patients with type 2 diabetes and albuminuria (30-600 mg/g creatinine) under antihypertensive treatment (mean age 67.0±7.6 years) were instructed to stop all antihypertensive treatment and take a combination of olmesartan (20 mg/day) and amlodipine (5 mg/day) for 3 months (run-in period). Then, patients were randomly assigned to receive either olmesartan plus azelnidipine (16 mg/day; n=71) or olmesartan plus trichlormethiazide (1 mg/day; n=72) for an additional 6 months. The primary end point was urinary excretion of albumin at 6 months after randomization.. At the time of randomization, urinary albumin was 116.0 and 107.8 mg/g creatinine (geometric mean) in the azelnidipine and diuretic arms, respectively, and was reduced to a similar extent [79.8 (95% confidence interval 66.4-96.0) and 89.7 (74.6-107.7) mg/g creatinine, respectively, after adjustment for baseline values]. Blood pressure did not differ between the two groups throughout the study period.. Azelnidipine is equally effective as a thiazide diuretic in reducing urinary albumin when used in combination with olmesartan.

Topics: Adult; Aged; Albuminuria; Antihypertensive Agents; Azetidinecarboxylic Acid; Calcium Channel Blockers; Diabetes Complications; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Imidazoles; Kidney Diseases; Male; Middle Aged; Prognosis; Prospective Studies; Risk Factors; Tetrazoles; Young Adult

To clarify whether the L-/N-type calcium channel blocker (CCB) cilnidipine is more renoprotective than the L-type CCB amlodipine in patients with early-stage diabetic nephropathy.. In this prospective, multicenter, open-labeled, randomized trial, the antialbuminuric effects of cilnidipine and amlodipine were examined in renin-angiotensin system (RAS) inhibitor-treated patients with hypertension (blood pressure [BP]: 130-180/80-110 mmHg), type 2 diabetes, and microalbuminuria (urinary albumin to creatinine [Cr] ratio [UACR]: 30-300 mg/g).. Patients received cilnidipine (n = 179, final dose: 10.27 ± 4.13 mg/day) or amlodipine (n = 186, 4.87 ± 2.08 mg/day) for 12 months. Cilnidipine and amlodipine equally decreased BP. The UACR values for the cilnidipine and amlodipine groups were 111.50 ± 138.97 and 88.29 ± 63.45 mg/g, respectively, before treatment and 107.93 ± 130.23 and 89.07 ± 97.55 mg/g, respectively, after treatment. The groups showed similar changes for the natural logarithm of the UACR, serum Cr, and estimated glomerular filtration rate.. Cilnidipine did not offer greater renoprotection than amlodipine in RAS inhibitor-treated hypertensive patients with type 2 diabetes and microalbuminuria.

Topics: Aged; Albuminuria; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Renin-Angiotensin System

It is unknown whether high-dose angiotensin II receptor blocker therapy or angiotensin II receptor blocker + calcium channel blocker combination therapy is better in elderly hypertensive patients with high cardiovascular risk. The objective of the study was to compare the efficacy of these treatments in elderly, high-risk Japanese hypertensive patients.. The OlmeSartan and Calcium Antagonists Randomized (OSCAR) study was a multicenter, prospective, randomized, open-label, blinded-end point study of 1164 hypertensive patients aged 65 to 84 years with type 2 diabetes or cardiovascular disease. Patients with uncontrolled hypertension during treatment with olmesartan 20 mg/d were randomly assigned to receive 40 mg/d olmesartan (high-dose angiotensin II receptor blocker) or a calcium channel blocker + 20 mg/d olmesartan (angiotensin II receptor blocker + calcium channel blocker). The primary end point was a composite of cardiovascular events and noncardiovascular death.. During a 3-year follow-up, blood pressure was significantly lower in the angiotensin II receptor blocker + calcium channel blocker group than in the high-dose angiotensin II receptor blocker group. Mean blood pressure at 36 months was 135.0/74.3 mm Hg in the high-dose angiotensin II receptor blocker group and 132.6/72.6 mm Hg in the angiotensin II receptor blocker + calcium channel blocker group. More primary end points occurred in the high-dose angiotensin II receptor blocker group than in the angiotensin II receptor blocker + calcium channel blocker group (58 vs 48 events, hazard ratio [HR], 1.31, 95% confidence interval, 0.89-1.92; P=.17). In patients with cardiovascular disease at baseline, more primary events occurred in the high-dose angiotensin II receptor blocker group (HR, 1.63, P=.03); in contrast, fewer events were observed in the subgroup without cardiovascular disease (HR, 0.52, P=.14). This treatment-by-subgroup interaction was significant (P=.02).. The angiotensin II receptor blocker and calcium channel blocker combination lowered blood pressure more than the high-dose angiotensin II receptor blocker and reduced the incidence of primary end points more than the high-dose angiotensin II receptor blocker in patients with cardiovascular disease. The addition of a second antihypertensive agent is more effective at lowering blood pressure than simply doubling the dose of an existing agent.

Topics: Aged; Aged, 80 and over; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Azetidinecarboxylic Acid; Calcium Channel Blockers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypertension; Imidazoles; Japan; Male; Prospective Studies; Single-Blind Method; Survival Analysis; Tetrazoles; Treatment Outcome

Angiotensin II receptor blockers (ARB) are often co-administered with a calcium channel blocker (CCB) for treating hypertension. In this open-label randomised study, untreated diabetic hypertensive patients were randomised to receive either olmesartan 20 mg/day or candesartan 8 mg/day for 12 weeks. Patients with blood pressure exceeding 130/80 mm Hg received add-on 16 mg/day azelnidipine to ongoing olmesartan (OL group) or 5 mg/day amlodipine to ongoing candesartan (CA group) for 24 weeks. Home-measured and clinic-measured blood pressure decreased in both groups. Fasting blood glucose, haemoglobin A1c (HbA1c) and urinary albumin levels decreased significantly in the OL group but not in the CA group. In conclusion, this study revealed clinically relevant differences between two combinations of an ARB+CCB in diabetic hypertensive patients. Olmesartan and azelnidipine had a more persistent early morning antihypertensive effect and produced greater decreases in heart rate, fasting blood glucose and HbA1c (National Glycohemoglobin Standardization Program values) levels, and microalbuminuria than did candesartan and amlodipine.

Topics: Aged; Albuminuria; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Azetidinecarboxylic Acid; Benzimidazoles; Biomarkers; Biphenyl Compounds; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Chi-Square Distribution; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Female; Glycated Hemoglobin; Heart Rate; Humans; Hypertension; Imidazoles; Japan; Male; Middle Aged; Tetrazoles; Time Factors; Treatment Outcome

Recently, it has been demonstrated that L-/N-type calcium channel blockers (CCBs), cilnidipine, but not L-type CCB, decreased urinary protein in renin-angiotensin system (RAS), inhibitor-treated hypertensive patients with macroproteinuria. However, the antiproteinuric effect of cilnidipine was weaker in diabetic patients than in nondiabetic patients with macroproteinuria. This may be due to the fact that diabetic neuropathy was also developed in patients with advanced diabetic nephropathy because L-/N-type CCB has been considered to exert its renoprotetive effects through sympatholytic action. If so, the antiproteinuric effect of cilnidipine may be potent in patients with early stages of diabetic nephropathy. To elucidate our hypothesis, we designed a multi-center, open-labeled, randomized trial to compare the antialbuminuric effect between cilnidipine and amlodipine in RAS inhibitor-treated hypertensive (blood pressure [BP]: 130-180/80-110 mmHg) patients with type 2 diabetes and microalbuminuria (urinary albumin/creatinine [Cr] ratio: 30-300 mg/g). The primary study endpoint is the change in the urinary albumin/Cr ratio after a 1-year treatment. Enrollment began in April 2008 and was completed in March 2010. A total of 367 patients were randomly allocated to receive cilnidipine or amlodipine. At baseline, study subjects had 63.3± 8.5 years of age, 145.9 ± 12.2/80.8 ± 10.0 mmHg of BP, 101.0 ± 111.6 mg/g of urinary albumin/Cr. The trial is expected to show whether cilnidipine can exert an antialbuminuric effect in RAS inhibitor-treated hypertensive patients with early stages of diabetic nephropathy.

Topics: Aged; Albuminuria; Amlodipine; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Clinical Protocols; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Humans; Hypertension; Kidney Function Tests; Male; Middle Aged; Renin-Angiotensin System

The present study aimed to determine whether either of two calcium channel blockers affected urinary albumin excretion or urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and liver-type fatty acid-binding protein (L-FABP) in hypertensive diabetic patients with chronic kidney disease (CKD) who were already being treated with maximum doses of the angiotensin II receptor blocker olmesartan. We conducted an open-label, randomized, parallel-controlled study on type 2 diabetic patients with stable glycemic control who were receiving fixed doses of antidiabetic agents. The patients received either 8 mg per day azelnidipine, which was increased up to 16 mg per day (azelnidipine group; n=34), or 2.5 mg per day amlodipine, which was increased up to 5 mg per day (amlodipine group; n=33), over a 24-week period. Mean systolic and diastolic blood pressure decreased significantly in both groups, but there was no significant difference between the two groups at the end of the study. Serum creatinine levels and estimated glomerular filtration rate did not differ significantly between the two groups, whereas the urinary albumin/creatinine ratio and 8-OHdG and L-FABP levels decreased significantly in the azelnidipine group compared with the amlodipine group. Plasma aldosterone level was significantly decreased in the azelnidipine group, and its changes correlated significantly with those of urinary 8-OHdG and L-FABP. Our results suggest that the addition of azelnidipine to the maximal recommended dose of olmesartan was more effective in reducing albuminuria and oxidant stress in hypertensive diabetic patients with CKD than the addition of amlodipine.

Topics: Aged; Albuminuria; Aldosterone; Angiotensin II Type 1 Receptor Blockers; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Imidazoles; Male; Middle Aged; Tetrazoles

To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria <200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [Delapril and Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; n=126), delapril (30 mg/d; n=127), or placebo (n=127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range [IQR]) was 0.32 mL/min per 1.73 m(2) (IQR: 0.16-0.50 mL/min per 1.73 m(2)) on combined therapy, 0.36 mL/min per 1.73 m(2) (IQR: 0.18-0.53 mL/min per 1.73 m(2)) on delapril, and 0.30 mL/min per 1.73 m(2) (IQR: 0.12-0.50 mL/min per 1.73 m(2)) on placebo (P=0.87 and P=0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04-0.78; P=0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07-0.99; P=0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24-0.87; P=0.017) and 0.52 (0.27-0.99; P=0.048), respectively. Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo (P=0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Body Mass Index; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypertension; Indans; Kidney Function Tests; Male; Middle Aged; Nitrobenzenes; Piperazines; Prognosis; Risk Assessment; Severity of Illness Index; Survival Rate; Treatment Outcome

Patients with diabetes complicated by hypertension and microalbuminuria have elevated cardiovascular risk, and controlling blood pressure in these patients is an urgent clinical priority. The present study aimed to examine the effects of a fixed-dose combination of antihypertensives on blood pressure and microalbuminuria.. Patients with type 2 diabetes, mild-to-moderate hypertension (diastolic blood pressure 85-105 mmHg, systolic blood pressure <160 mmHg, and 24-hour mean systolic blood pressure >130 mmHg), and microalbuminuria were randomized to 1 year of doubleblind treatment with fixed-dose manidipine/delapril (n=54) or losartan/hydrochlorothiazide (HCTZ) (n=56).. Blood pressure was significantly reduced at 1 year in both groups (-22.2/-14.6 mmHg and -19.5/-14.3 mmHg, for systolic and diastolic blood pressure respectively, P<0.001 for each), with no significant between-group difference. Reductions in microalbuminuria occurred in both groups, with mean changes at 1 year of -3.9 mg/mmol creatinine (95% CI -5.3, -2.5) for manidipine/delapril (P<0.001 vs. baseline) and -2.7 mg/mmol creatinine (95% CI -4.0, -1.3) for losartan/HCTZ (P<0.001 vs. baseline and P=0.199 between groups). Glycemia over the 1-year study was largely unaffected; the blood glucose concentration was reduced from baseline with manidipine/delapril, although not statistically significant (mean change -0.2 mmol/L, P=0.064). Both treatments were well tolerated, with discontinuation for adverse events for one (1.9%) patient in the manidipine/delapril group and two (3.6%) in the losartan/HCTZ group.. A fixed-dose manidipine/delapril combination represents a useful addition to the treatment options available to control hypertension complicated by diabetes and microalbuminuria.

Topics: Aged; Aged, 80 and over; Albuminuria; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Combinations; Female; Humans; Hydrochlorothiazide; Hypertension; Indans; Losartan; Male; Middle Aged; Nitrobenzenes; Piperazines

The three types of calcium channel blocker (CCB), L-, T- and N-type, possess heterogeneous actions on endothelial function and renal microvascular function. In the present study, we evaluated the effects of two CCBs, efonidipine and amlodipine, on renal function and arterial stiffness.. Forty type 2 diabetic patients with hypertension and nephropathy receiving angiotensin receptor II blockers were enrolled and randomly divided into two groups: the efonidipine group was administered efonidipine hydrochloride ethanolate 40 mg/day and the amlodipine group was admin-istered amlodipine besilate 5 mg/day for 12 months. Arterial stiffness was evaluated by the cardio-ankle vascular index (CAVI).. Changes in blood pressure during the study were almost the same in the two groups. Sig-nificant increases in serum creatinine and urinary albumin and a significant decrease in the esti-mated glomerular filtration rate were observed in the amlodipine group, but not in the efonidipine group. On the other hand, significant decreases in plasma aldosterone, urinary 8-hydroxy-2'-deoxy-guanosine and CAVI were observed after 12 months in the efonidipine group, but not in the amlo-dipine group.. These results suggest that efonidipine, which is both a T-type and L-type calcium chan-nel blocker, has more favorable effects on renal function, oxidative stress and arterial stiffness than amlodipine, an L-type calcium channel blocker.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aldosterone; Amlodipine; Arteries; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Glycated Hemoglobin; Humans; Hypertension; Kidney; Lipids; Male; Middle Aged; Nitrophenols; Organophosphorus Compounds

We conducted a multicenter, randomized, open-label, ascending dose study to investigate the efficacy and safety of combination therapy using the calcium channel blocker azelnidipine and angiotensin-converting enzyme (ACE) inhibitor temocapril in hypertensive diabetics. Patients received monotherapy with 8 mg azelnidipine (group A, n=112) or 2 mg temocapril (group T, n=111) for 4 weeks. If the target blood pressure (<130/80 mmHg) was not achieved, doses were doubled. If it was still not achieved, both drugs were coadministered at week 8, and, if needed, another antihypertensive drug was added after week 16. The treatment period was 52 weeks. Blood pressure was decreased significantly beginning at week 8 (p<0.0001 in both groups), and the systolic and diastolic blood pressure at the end of the treatment period was 128.2+/-11.1/76.4+/-8.1 mmHg. Overall, 53.8% (113/210) of patients achieved the target blood pressure by the end of the study. The effect during the monotherapy period (through week 8) was greater in group A than in group T (systolic, p=0.0475; diastolic, p=0.0001). Laboratory tests showed significant decreases in the urine albumin:creatinine ratio (p=0.0006), high-sensitivity C-reactive protein concentration (p=0.0073), and urine 8-isoprostane concentration (p=0.0215) at the end of the treatment period, as compared with baseline values. No adverse events caused safety problems. In conclusion, combination therapy using azelnidipine and temocapril is an effective treatment for hypertensive diabetics.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Azetidinecarboxylic Acid; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Drug Therapy, Combination; Female; Heart Rate; Humans; Hypertension, Renal; Kidney Function Tests; Lipids; Male; Middle Aged; Thiazepines; Treatment Outcome

The aim of this study was to compare the efficacy and safety of adding manidipine 20 mg versus amlodipine 10 mg to the treatment of diabetic patients with uncontrolled hypertension and microalbuminuria despite full-dose treatment with a renin-angiotensin system blocker for at least 6 months. Patients were randomized to receive manidipine (n = 61) or amlodipine (n = 30) in a 2:1 ratio for 6 months and monitored for microalbuminuria for an additional extension phase of 18 months. Manidipine and amlodipine decreased blood pressure values to a similar extent. Urinary albumin excretion was reduced by 65.5% with manidipine versus 20% with amlodipine (p < 0.01) at 6 months and 62.7 versus 16.6% (p < 0.01) at the end of the extension phase. Manidipine was better tolerated than amlodipine. Thus, the addition of manidipine, but not amlodipine, resulted in a large reduction in the urinary albumin excretion rate despite similar blood pressure reductions.

Topics: Adult; Aged; Albuminuria; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Prospective Studies; Renin-Angiotensin System

Hypertension markedly increases the already high risk for cardiovascular complications in patients with diabetes mellitus. Less than one in eight patients with hypertension and type 2 diabetes have adequately controlled blood pressure. As a result, antihypertensive combinations are now widely used in management of hypertension associated with diabetes.. This double-blind study investigated efficacy of a new fixed dose combination of a calcium antagonist, manidipine 10 mg, and an angiotensin-converting enzyme inhibitor, delapril 30 mg, compared with a combination of an angiotensin receptor blocker, losartan 50 mg, and a diuretic, hydrochlorothiazide 12.5 mg. Patients with hypertension (blood pressure > or = 130/80 mmHg) with controlled type 2 diabetes (HbA1c < or = 7.5%) were randomized to manidipine/delapril (n = 153) or losartan/hydrochlorothiazide (n = 161), administered once daily for 12 weeks. Patients underwent ambulatory blood pressure monitor evaluation at baseline and end of treatment.. Mean decreases in 24-h systolic blood pressure were seen with both manidipine/delapril (-9.3 mmHg) and losartan/hydrochlorothiazide (-10.7 mmHg) combinations. The mean (95% confidence interval) treatment difference was -1.4 (-4.5/1.8) mmHg, demonstrating noninferiority of the manidipine/delapril combination. Reduction in 24-h diastolic blood pressure (-4.6 versus -4.5 mmHg) and daytime (systolic blood pressure -10.5 versus -11.1 mmHg) and night-time (systolic blood pressure -7.1 versus -9.3 mmHg) blood pressure were also not significantly different between treatments. Compliance and adverse events were comparable for both groups.. The study demonstrated that the combination of manidipine and delapril is as effective as losartan and hydrochlorothiazide in treatment of hypertension in type 2 diabetes.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Diabetes Complications; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Indans; Losartan; Male; Middle Aged; Nitrobenzenes; Piperazines; Treatment Outcome

The purpose of this study was to compare the combination treatments of manidipine/delapril and olmesartan/hydrochlorothiazide (HCTZ) in elderly diabetic hypertensives. After a 4-week placebo period, 158 hypertensive patients with type 2 diabetes (age range: 66 to 74 years) were randomized to receive combination treatment of 10 mg manidipine plus 30 mg delapril or 20 mg olmesartan plus 12.5 mg HCTZ for 48 weeks in a prospective, parallel arm trial. After 12 weeks, manidipine or HCTZ was doubled in nonresponders (systolic blood pressure [SBP] > or =130 mmHg and/or diastolic blood pressure [DBP] > or =80 mmHg). Patients were checked at the end of the placebo period and every 12 weeks thereafter. At each visit, lying, sitting and standing BP as well as fasting glycemia, glycosylated hemoglobin (HbA1c), electrolytes, uric acid, total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG) were evaluated. Both combinations reduced sitting SBP (-27.7 and -28.3 mmHg, respectively; both p<0.001) and DBP (-15.1 and -14.8 mmHg, respectively; both p<0.01) with no difference between the two treatments. Standing DBP was more markedly reduced by olmesartan/HCTZ (-19.5 mmHg; p<0.001) than by manidipine/delapril (-14.7 mmHg; p<0.05 vs. olmesartan/HCTZ). No changes in metabolic parameters were observed with manidipine/delapril, whereas an increase in HbA1c (+0.7%; p<0.05), uric acid (+0.4 mg/dL; p<0.05) and TG (+41.3 mg/dL; p<0.05), and a decrease in serum potassium (-0.3 mmol/L; p<0.05) and HDL-C (-3.4 mg/dL; p<0.05) were found in the olmesartan/HCTZ group. In conclusion, both combinations were similarly effective in reducing BP in elderly hypertensive diabetic patients. However, manidipine/delapril offered some advantages in terms of the less-pronounced BP orthostatic changes and absence of metabolic adverse effects.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Complications; Diabetes Mellitus, Type 2; Dihydropyridines; Diuretics; Drug Combinations; Endpoint Determination; Female; Humans; Hydrochlorothiazide; Hypertension; Hypotension, Orthostatic; Imidazoles; Indans; Male; Nitrobenzenes; Piperazines; Posture; Prospective Studies; Tetrazoles

Anti-hypertensive agents with antioxidative effects are potentially useful for diabetic patients with hypertension to prevent the onset and progression of their complication. While dihydropyridine-type calcium antagonists are among the frequently used anti-hypertensive drugs, azelnidipine, a novel calcium antagonist, has been reported to have a unique anti-oxidative effect in vitro and in animals. In this study, we measured lipid hydroperoxides in human sample using diphenyl-1-pyrenylphosphine for the first time, and used the value of lipid hydroperoxides as an index of oxidative stress. Then, we compared the antioxidative properties of azelnidipine and amlodipine, a frequently used calcium antagonist in hypertensive diabetic patients. Administration of vitamin C and E for 8 weeks significantly reduced lipid hydroperoxides in erythrocyte membrane in normal subjects. In hypertensive diabetic patients, azelnidipine treatment for 12 weeks induced a more significant fall in erythrocyte lipid hydroperoxide level than amlodipine, though blood pressure during each treatment was comparable. Our data confirm the usefulness of lipid hydroperoxides in erythrocyte membrane as a marker of oxidative stress in vivo, and indicate that azelnidipine has a unique antioxidative property in human.

Topics: Adult; Aged; Amlodipine; Antihypertensive Agents; Ascorbic Acid; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Erythrocytes; Female; Humans; Hypertension; Lipid Peroxides; Male; Middle Aged; Organophosphorus Compounds; Pyrenes; Vitamin E

We sought to compare the effect of manidipine versus hydrochlorothiazide (HCTZ) in addition to candesartan on the urinary albumin excretion rate (UAER) in hypertensive patients with type II diabetes and microalbuminuria.. After a 2-week washout and run-in period, and 8-week monotherapy with candesartan 16 mg every day, 174 microalbuminuric diabetic hypertensive patients with uncontrolled blood pressure (BP) (>130/80 mm Hg) were randomized to addition of manidipine 10 mg every day (n = 87) or HCTZ 12.5 mg every day (n = 87) for 24 weeks, with a titration after 4 weeks (manidipine or HCTZ dose-doubling) in nonresponder patients. Blood pressure, UAER, creatinine clearance, serum electrolytes, fasting plasma glycemia, and glycosylated hemoglobin were evaluated at baseline (end of run-in period), after candesartan monotherapy, and at the end of the combination treatment period.. Both combinations produced greater systolic BP/diastolic BP reduction than candesartan monotherapy (-28/21 mm Hg versus -16/11 mm Hg and -28/20 mm Hg versus -15/11 mm Hg, respectively; all P < .05 versus monotherapy), with no significant difference between the two combinations. The addition of manidipine produced a greater reduction in UAER than candesartan monotherapy (-55.4 mg/24 h v -36.1 mg/24 h, P < .05), whereas the addition of HCTZ did not significantly modify UAER; the difference between the two combinations was statistically significant (P < .05). Similarly, the percentage of patients moving to a normoalbuminuric state (UAER <30 mg/24 h) was increased by the addition of manidipine to candesartan (from 35% to 64%, P < .05), but not by the addition of HCTZ (from 34% to 39%, NS), with a statistical difference between the two combinations (P < .05).. These findings show that, despite equivalent reduction in BP, the addition of manidipine to candesartan further reduced the UAER, whereas the addition of HCTZ did not modify the UAER. This suggests that the antiproteinuric effect of manidipine is partially independent of BP reduction, and is attributable to mechanisms different from those mediated by angiotensin receptor blockade.

Topics: Adult; Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Diuretics; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Prospective Studies; Proteinuria; Single-Blind Method; Tetrazoles

Topics: Adult; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Hypercholesterolemia; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Nifedipine; Obesity; Treatment Outcome; Verapamil

Angiotensin-converting enzyme inhibitors plus dihydropyridine calcium channel blockers or low-dose thiazide diuretics are considered first-line therapies in hypertensive diabetic patients as glucose metabolism is not relevantly affected. Most diabetic patients require at least two different drug classes to achieve the recommended target blood pressure of 130/85 mmHg. This controlled clinical trial investigated the calcium channel blocker lercanidipine versus hydrochlorothiazide (HCTZ) as add-on in diabetic patients with uncontrolled hypertension on enalapril monotherapy.. Overall, 174 patients (18-80 years old, well-controlled diabetes type 1 or 2, mild to moderate hypertension) were included in a 2-week placebo run-in followed by 4 weeks on enalapril 20 mg. Subsequently, 135 non-responders (90 mmHg < or = mean sitting diastolic blood pressure < or = 109 mmHg) were randomized to 20 weeks of double-blind add-on therapy to enalapril with either lercanidipine 10 mg (n = 69) or HCTZ 12.5 mg (n = 66). The primary study objective was to prove non-inferiority of lercanidipine add-on versus HCTZ add-on in reducing sitting diastolic blood pressure; response rates and tolerability data were also observed.. Both add-on treatments clearly decreased diastolic blood pressure to a greater extent than enalapril monotherapy (mean +/- SD changes at study end: lercanidipine, -9.3 mmHg; HCTZ, -7.4 mmHg); non-inferiority of lercanidipine versus HCTZ was formally proven. Blood pressure response rates reached 69.6% on enalapril plus lercanidipine as compared with 53.6% on enalapril plus HCTZ (difference between treatments, P > 0.05). Blood pressure of 130/85 mmHg or less was achieved in 30.4% of patients on lercanidipine add-on and in 23.2% of those randomized to HCTZ add-on (P > 0.05). Both treatment regimens were well tolerated.. Lercanidipine add-on showed comparable efficacy to HCTZ add-on in diabetic patients with hypertension badly controlled on angiotensin-converting enzyme inhibitor monotherapy. The blood pressure response rates seemed to be somewhat higher following enalapril plus lercanidipine than enalapril plus HCTZ.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Single-Blind Method

Cilnidipine, an L-/N-type calcium channel blocker, dilates the efferent glomerular arterioles in an experimental model and shows a renoprotective effect, but its clinical benefits and safety have not yet been assessed in type II diabetics with albuminuria. The objective of this trial was to evaluate the effect of reducing albuminuria in type II diabetic patients with a combination therapy consisting of valsartan plus cilnidipine versus monotherapy with valsartan. An open-label, randomized controlled trial was conducted from April 2002 to October 2003 in 87 Japanese patients aged 31-90 years with type II diabetes showing albuminuria (urinary albumin/creatinine ratio: 10-300 mg/g). The patients were randomized to receive either valsartan (n=41) or valsartan plus cilnidipine (n=46) once daily for 1 year. The primary end point was the percent change in the albumin/creatinine ratio. The secondary end points were the progression/regression of albuminuria, blood pressure (BP), renal function, and safety. After 1 year, the albumin/creatinine ratio was found to have decreased more markedly in the valsartan plus cilnidipine group than in the valsartan group (reduction rate -44+/-11% (s.e.) versus -9+/-7% (s.e.); P=0.014 by analysis of covariance). Although a significant reduction was observed in the systolic and diastolic BP of both groups from baseline to 1 year (P<0.0001, respectively), there was no significant difference in the change in the BP between the two groups (systolic BP, P=0.066; diastolic BP, P=0.391). There were also no significant differences in the side effects between the two groups. Cilnidipine was thus found to show an additive effect with valsartan and thereby caused a reduction in albuminuria in type II diabetics.

Topics: Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Tetrazoles; Treatment Outcome; Valine; Valsartan

The effects of combination therapy of angiotensin II receptor blockers (ARBs) and a calcium antagonist, benidipine hydrochloride, on glucose and lipid metabolism and pulse pressure were studied in elderly hypertensive patients with type 2 diabetes mellitus. Twenty-five hypertensive diabetic patients aged 65 years or older, who had been receiving candesartan cilexetil, were administered benidipine hydrochloride (4 mg/day) and followed for 4 months. After 4 months, systolic and diastolic blood pressure decreased significantly from 154/91 mmHg to 139/78 mmHg (p<0.01 versus before benidipine hydrochloride administration). Body mass index (BMI) and glycosylated hemoglobin (HbA1c) were apparently reduced but the changes were not statistically significant. The serum lipid profile showed no significant changes in serum total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). Serum lipoprotein lipase mass levels (preheparin LPL mass) increased significantly from 51 to 59 ng/dl (p<0.01 versus before benidipine hydrochloride administration), and the LDL/HDL motility ratio calculated from PAG disc electrophoresis decreased significantly (p<0.05 versus before benidipine hydrochloride administration). When patients were divided into a systolic hypertension group (systolic blood pressure > or =140 mmHg and diastolic blood pressure <90 mmHg) and non-systolic hypertension group (others), preheparin LPL mass was significantly lower in the systolic hypertension group, and the decrease in pulse pressure and increase in preheparin LPL mass were significantly greater in the systolic hypertension group. Stepwise regression analysis showed that low preheparin LPL mass at baseline was associated with a decrease in pulse pressure. Add-on benidipine hydrochloride therapy in elderly hypertensive patients with type 2 diabetes mellitus significantly decreases the LDL/HDL motility ratio and pulse pressure, and significantly increases preheparin LPL mass, in addition to improving blood pressure control. These findings suggest that combination therapy with benidipine hydrochloride and candesartan cilexetil may contribute to the suppression of arteriosclerosis and may be useful for elderly hypertensive patients with diabetes mellitus.

Topics: Aged; Aged, 80 and over; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Diabetes Mellitus, Type 2; Diastole; Dihydropyridines; Drug Therapy, Combination; Female; Heparin; Humans; Hypertension; Lipid Metabolism; Lipids; Lipoprotein Lipase; Male; Systole; Tetrazoles

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Creatinine; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypertension; Indoles; Treatment Outcome; Verapamil

This study was done to evaluate the effect of treatment with manidipine as compared with atenolol on thrombin-mediated platelet aggregation in elderly patients with isolated systolic hypertension and type II diabetes mellitus. After a 2-week washout placebo period, 60 elderly patients (aged 65-80 years) with isolated systolic hypertension (SBP > 140 mm Hg and DBP < 90 mm Hg) were randomly assigned to manidipine 10 mg or atenolol 50 mg 6-week treatment according to a double-blind, crossover design. Thirty patients had a concomitant well-controlled type 2 diabetes mellitus (HbA1c < or = 6.5%). At the end of the washout and of each treatment period, blood pressure (BP) (by mercury sphygmomanometer) and platelet aggregation (by Born-type aggregometer) were evaluated. Blood samples were collected using sodium citrate as anticoagulant, and platelet aggregation was induced by 2 different concentrations of ADP and collagen. Manidipine and atenolol produced a significant BP reduction in both diabetic and nondiabetic patients, with no difference between treatments. Despite the similar BP effect, in diabetic patients manidipine produced a significant reduction in platelet aggregation induced by both doses of either ADP or collagen. In nondiabetic hypertensives, manidipine inhibited platelet aggregation only at the highest doses of both inducers. The difference in the platelet inhibitory effect of manidipine between diabetic and nondiabetic subjects was statistically significant (P < 0.05) at both inducer concentrations. No changes in platelet aggregation were observed in the atenolol group. These data indicate that, unlike atenolol, manidipine inhibits platelet aggregation in elderly hypertensive patients, expecially in those with associated type II diabetes mellitus. The clinical impact of this positive effect in terms of prevention of cardiovascular complications in these high-risk patients remains to be clarified.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Atenolol; Cross-Over Studies; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Female; Humans; Hypertension; Male; Nitrobenzenes; Piperazines; Platelet Aggregation

Blood pressure reduction is associated with a reduced risk for cardiovascular events and death, particularly in patients with both hypertension and type 2 diabetes mellitus.. The aim of this study was to compare the antihypertensive efficacy, tolerability, and effect on metabolic risk factors of manidipine, a new dihydropyridine calcium channel antagonist, and enalapril, a widely used angiotensin-converting enzyme inhibitor, in patients with mild to moderate essential hypertension and type 2 diabetes.. This multicenter, double-blind trial compared manidipine and enalapril in patients with type 2 diabetes and hypertension (diastolic blood pressure [DBP] 90-104 mm Hg, systolic blood pressure [SBP] < or =190 mm Hg). Following a 3-week, single-blind placebo run-in period, eligible patients were randomized to receive either manidipine 10 mg or enalapril 10 mg once daily for 24 weeks. The dose was doubled after 3 weeks in patients who had not responded to treatment (DBP > or =90 mm Hg). The primary efficacy end point was change in DBP from baseline to the end of the study. Secondary outcomes were the responder rate (DBP <90 mm Hg and/or a DBP reduction of > or =10 mm Hg) at the end of the study. Other secondary measures were changes from baseline to the end of the study in heart rate and in the following measures obtained by ambulatory blood pressure monitoring (ABPM): 24-hour, daytime, and nighttime mean DBP and SBP, and the trough:peak ratio. Blood glucose, glycosylated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, uric acid, and creatinine were measured at the end of the placebo run-in period and the end of treatment. The study had 80% power to detect a between-treatment difference in mean sitting DBP of >3 mm Hg.. One hundred twenty-four patients were enrolled in the study. After the placebo run-in period, 13 patients were excluded from the study: 4 for DBP values outside the specified limits, 7 at their request, and 2 for adverse events. Thus, 111 patients met the eligibility criteria and were randomized to treatment (53 manidipine, 58 enalapril). The population consisted of 61 men and 50 women with a mean (SD) age of 62 (11) years and a body mass index of 28.2 (2.4) kg/m2. Among patients who completed the study, drug doses were doubled in 67.6% (25/37) of patients in the manidipine group and 60.0% (24/40) of patients in the enalapril group (P = NS). Similar reductions in blood pressure were observed in both groups, from a mean (SD) of 164 (12)/97.5 (5) mm Hg at baseline to 141 (12)/84.5 (6) mm Hg at the end of the study in the manidipine group (P < 0.01), and from 159 (12)/98 (4) mm Hg to 139 (12)/86 (8) mm Hg in the enalapril group (P < 0.01). The proportion of responders was 66.7% (32/48) in the manidipine group and 60.0% (30/50) in the enalapril group; the difference between groups was not significant. Twenty-four-hour ABPM revealed significant (P < 0.01) and similar reductions in blood pressure in both groups, with a trough:peak ratio of approximately -50%. Neither drug affected heart rate. Among the statistically significant changes in metabolic parameters, significant reductions in HbA(1c) (from 6.7% [1.4%] to 6.2% [1.1%]) and blood glucose concentrations (from 152 [44] to 143 [44] mg/dL) were observed only in the manidipine group (P < 0.05). The incidence of adverse events was similar between groups.. In the present study, manidipine was as metabolically neutral and as effective as enalapril in reducing blood pressure in hypertensive patients with type 2 diabetes, providing a sustained 24-hour antihypertensive effect.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Enalapril; Female; Heart Rate; Humans; Hypertension; Lipoproteins; Male; Middle Aged; Nitrobenzenes; Piperazines

The aim of this open-labelled, randomised, parallel-group study was to evaluate the effect of long-term monotherapy with manidipine or lisinopril on albumin excretion rate (AER) and left ventricular mass index (LVMI) in hypertensive patients with type-2 diabetes and microalbuminuria.. After a 4-week wash-out period, 174 patients with essential hypertension [diastolic blood pressure (DBP) >80 mmHg and <100 mmHg], type-2 diabetes and microalbuminuria were randomised to manidipine 10 mg o.d. or lisinopril 10 mg o.d.; after 8 weeks, the dose was doubled in non-responders (DBP >80 mmHg); after 3 months, treatment was discontinued in the non-responder patients and in those complaining of side effects; the remaining 121 patients continued their therapy with manidipine or lisinopril, and 99 completed the 2-year study. At the end of the wash-out period, of the titration period and after 6, 12, 18 and 24 months of treatment, BP was measured, AER, creatinine clearance, glycosylated haemoglobin (HbA1c) and body mass index (BMI) were evaluated and an echocardiographic evaluation was performed.. The 99 patients who completed the study were statistically analysed according to a per-protocol evaluation. Manidipine and lisinopril significantly reduced systolic blood pressure (SBP) and DBP levels (at 24 months, --22.3/15.5 mmHg, P<0.001 versus baseline and --21.4/15.7 mmHg, P<0.01 versus baseline, respectively). Both drugs provided a significant decrease in AER, but it was significantly more pronounced with lisinopril (at 24 weeks, --37.2 mg/24 h, P<0.001 versus baseline) than with manidipine (--29.9 mg/24 h, P<0.05 versus baseline) and became evident earlier in the lisinopril group (after 3 months versus 6 months of treatment). Manidipine produced a greater reduction of LVMI than lisinopril (--14.9 g/m(2) versus --10.8 g/m(2) at 24 months). The effect was more pronounced in patients with left ventricular hypertrophy at baseline (--19.8 g/m(2) versus --12.8 g/m(2), P<0.05).. These data suggest that, despite similar BP lowering, non-haemodynamic factors play an important role in the pharmacological reduction of AER and LVMI in diabetic hypertensive patients.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Heart Ventricles; Humans; Hypertension; Lisinopril; Male; Middle Aged; Nitrobenzenes; Piperazines

The aim of this double-blind, double-dummy, parallel group study was to compare the effects of delapril-manidipine combination vs a irbesartan-hydrochlorothiazide combination on plasma tissue plasminogen activator (t-PA) and plasmogen activator inhibitor type I (PAI-l) activities in hypertensive patients with type II diabetes mellitus. After a 4-week run-in placebo period, 80 patients (37 male and 43 female), aged 41-65 years, were randomly allocated to an 8-week treatment with delapril 30 mg once daily or irbesartan 150 mg once daily. Thereafter, manidipine l0 mg once daily was added to delapril treatment and hydrochlorothiazide 12.5 mg to irbesartan treatment for a further 8 weeks. Blood pressure (BP), plasma t-PA and PAI-l activities were evaluated at the end of the run-in period, after 4-week monotherapy treatments, and at the end of the combination treatment periods. Both combination treatments, delapril-manidipine and irbesartan-hydrochlorothiazide, produced a greater reduction in systolic BP/diastolic BP (SBP/DBP) values (-27.6/21.8 mmHg and -26.4/20.2 mmHg, respectively) than the respective monotherapies (-15.2/11.7 mmHg with delapril and -16.3/11.3 mmHg with irbesartan). Delapril monotherapy significantly decreased plasma PAI-l activity (-10.4 IU/mI; P<0.05). The addition of manidipine produced a significant increase in t-PA activity (+0.27 IU/mI); P<0.05). Irbesartan monotherapy did not significantly affect the fibrinolytic balance, whereas the addition of hydrochlorothiazide worsened it, producing a significant increase in PAI-l activity (+9.5 IU/ml; P<0.05). In hypertensive patients with type II diabetes mellitus, the combination delapril-manidipine may determine a greater improvement of the fibrinolytic function than the respective monotherapy, while the association irbesartan-hydrochlorothiazide may worsen it.

Topics: Adult; Aged; Antihypertensive Agents; Biphenyl Compounds; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Female; Fibrinolysis; Humans; Hydrochlorothiazide; Hypertension; Indans; Irbesartan; Male; Middle Aged; Nitrobenzenes; Piperazines; Plasminogen Activator Inhibitor 1; Tetrazoles; Tissue Plasminogen Activator; Treatment Outcome

To evaluate the safe use of a new calcium channel blocker, lercanidipine, in diabetic chronic renal failure (CRF) patients.. The study recruited 42 diabetic CRF patients (creatinine > 1.4 mg/dl for males, creatinine > 1.2 mg/dl for females, or creatinine clearance < 70 ml/min). Mean age was 68.2 +/- 9.1 years. 53.8% were males and 46.2% females. Three patients were type 1 diabetics and 39 ones were type II. All patients were receiving ACE inhibitors (67.4%) or angiotensin II antagonist (32.6%) therapy but they had higher blood pressure than recommended for CRF patients (130/85 mmHg). No patients were under diuretic treatment. Patients were clinically evaluated 1, 3 and 6 months after starting treatment with lercanidipine. Samples for urine and blood examination were taken during the examination. When needed, a third drug was added to treatment, excluding diuretics. Creatinine clearance was measured using 24 h urine collection.. BP significantly decrease from 163 +/- 18/90 +/- 8 mmHg to 134 +/- 12/77 +/- 9 mmHg. One half of patients showed significant reduction of blood pressure, 26.7% reached the target blood pressure (< 130/85 mmHg) and 20.0% gets optimal BP control (< 130/85 mmHg). No one patient showed untoward effects. No edema was detected nor adverse effects related to vasodilatation were found. Plasmatic creatinine did not change (1.9 +/- 0.5 baseline vs 1.8 +/- 0.5 mg/dl) and creatinine clearance increased at the end visit (40.1 +/- 14.5 baseline vs 45.4 +/- 18.2 ml/min) but the difference was not significant. Proteinuria was unchanged.. Lercanidipine showed a good antihypertensive effect in diabetics CRF patients. It has a good tolerability profile and showed neutral effect on plasmatic lipids. Neither impairment of renal function nor increment in proteinuria were detected.

Topics: Aged; Antihypertensive Agents; Calcium Channel Blockers; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Edema; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria; Treatment Outcome

Microalbuminuria and hypertension are risk factors for diabetic nephropathy in Type 2 diabetic patients. Recent data suggest that blockade of the renin-angiotensin system slows the progression of diabetic nephropathy; in contrast, the results on the renoprotective effect of calcium channel antagonists are conflicting. We evaluated the effectiveness of lercanidipine, in comparison with ramipril, on the reduction in albumin excretion rate (AER) and blood pressure in mild-to-moderate hypertensive patients with Type 2 diabetes and persistent microalbuminuria. A total of 277 patients were enrolled in a multicentric, randomized, double-blind, active-controlled, parallel-group trial; 180 were randomized to receive 10-20 mg/day of lercanidipine or 5-10 mg/day of ramipril and followed up for 9-12 months. The primary outcome was the change in AER from baseline. After 9-12 months of follow-up, a reduction in AER of -17.4+/-65 microg/min (p<0.05) and -19.7+/-52.5 (p<0.05) in the lercanidipine and ramipril group, respectively, was observed, without differences between the groups. A significant reduction in systolic and diastolic blood pressure was observed in both the lercanidipine and ramipril-based treatment groups (p<0.0001 for both). This study demonstrated that treatment with lercanidipine 10-20 mg/day does not worsen albuminuria in microalbuminuric Type 2 diabetic patients with hypertension. Indeed, both lercanidipine and ramipril treatments resulted in a significant reduction in AER without a statistically significant difference between the two groups.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Ramipril; Treatment Outcome

The importance of measuring microalbuminuria is well established. However, only scanty data are available concerning the biological variability of albumin excretion in type 2 diabetic subjects. We report our experience from a large clinical trial of a new antihypertensive drug (Lercanidipine) designed to reduce albumin excretion and blood pressure in type 2 diabetic patients with hypertension and microalbuminuria. Eighty seven patients with persistent microalbuminuria were studied within 1 year of the clinical trial. The measurements were performed on blood and timed urine samples frozen at -80 degrees C and shipped to a central laboratory unit. Preliminary experiments were performed to assess albumin stability in urine under various conditions (4 degrees C, -20 degrees C and -80 degrees C), particularly with regard to the albumin/creatinine ratio. Urine samples can be stored up to 3 weeks at 4 degrees C or up to 2 months at -80 degrees C. The biological variability of the albumin excretion rate was 25.7%, while that of the albumin/creatinine ratio was 13.4%. These data are useful in defining the analytical goals of imprecision for microalbuminuria (CV = 13% for albumin, and CV = 6% for albumin/creatinine ratio). No correlation between albumin/creatinine ratio and HbA1c was found in the cohort of 61 microalbuminuric patients who completed the trial. The results of this study confirm that the albumin/ creatinine ratio is much more suitable for monitoring albumin excretion in longitudinal studies than the albumin excretion rate.

Topics: Albuminuria; Calcium Channel Blockers; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Humans; Hypertension; Protein Denaturation; Sensitivity and Specificity; Serum Albumin; Temperature

We compared the levels of microparticles, platelet activation markers, soluble cell adhesion molecules, and soluble selectins between hypertensive patients with and without type 2 diabetes and control subjects. Binding of anti-glycoprotein IIb/IIIa and anti-glycoprotein Ib monoclonal antibodies to platelets did not differ significantly between the hypertensive patients and controls, but platelet expression of activation markers (CD62P, CD63, PAC-1, and annexin V) was higher in the hypertensive patients. Platelet-derived microparticle (PDMP) and monocyte-derived microparticle (MDMP) levels were significantly higher in the hypertensive patients than in the controls. Soluble ICAM-1, VCAM-1, P-selectin, and E-selectin levels were also higher in the hypertensive patients, and they were significantly higher in the hypertensive patients with diabetes. After treatment with efonidipine, the levels of PDMPs, CD62P-, CD63-, PAC-1-, and annexin V-positive platelets, sICAM-1, sVCAM-1, sP-selectin, and sE-selectin all decreased significantly. The MDMP levels decreased, and the decrease was significant in the hypertensive patients with diabetes. These findings suggest that administration of efonidipine to hypertension patients with diabetes may prevent the development of cardiovascular complications caused by cell adhesion molecules or activated platelets and monocytes.

Topics: Aged; Antihypertensive Agents; Blood Cell Count; Cell Adhesion Molecules; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Monocytes; Nitrophenols; Organophosphorus Compounds; Platelet Activation; Vascular Diseases

Lipoprotein oxidation, dyslipidemia, and hypertension are important underlying causes of accelerated atherosclerosis in patients with diabetes mellitus. The potential of antihypertensive medications to reduce lipid oxidation is, therefore, an important determinant in the choice of agents for patients with diabetes mellitus. The aim of this study was to compare the lowering effect of a new dihydropyridine calcium antagonist, lercanidipine, with that of the first angiotensin-receptor blocker, losartan, on low-density lipoprotein (LDL) oxidation.. Forty patients in metabolically stable condition who had type 2 diabetes mellitus with hypertension were studied in this single-blind, randomized, prospective crossover study, comprising 2 treatment periods of 16 weeks each, separated by a 4-week washout period. LDL oxidation was evaluated by dialdehyde analysis by means of the thiobarbituric acid-reactive substances assay with and without cupric sulfate, as well as determination of conjugated dienes in the LDL lipid extract.. Lercanidipine and losartan both significantly reduced the propensity of the serum to oxidize LDL (P =.001). With one method of estimation (conjugated dienes), the effect of lercanidipine was superior to that of losartan (P =.04). Losartan lowered urinary albumin excretion but lercanidipine did not.. Both lercanidipine and losartan attenuate LDL oxidation in patients with type 2 diabetes mellitus and hypertension. This observation may offer insight into the mechanisms of the therapeutic effects of these agents in patients with diabetes mellitus.

Topics: Adult; Aged; Analysis of Variance; Antihypertensive Agents; Antioxidants; Cross-Over Studies; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Humans; Hypertension; Lipoproteins, LDL; Losartan; Male; Middle Aged; Oxidation-Reduction; Prospective Studies; Single-Blind Method

This study was carried out to assess whether with a similar degree of blood pressure reduction, Lisinopril compares favorably or otherwise with lacidipine in respect of effects on urinary albumin excretion and renal function as assessed by creatinine clearance, plasma creatinine, urea and electrolytes. Thirty hypertensive diabetic nephropathy patients with moderate hypertension were studied. After a 2-week washout period, they were allocated into two groups matched at baseline for age, sex, weight, blood pressure, and urinary albumin excretion rate as well as creatinine clearance. There were 8 males and 7 females in each group. One group received lisinopril (with furosemide if needed to control BP) and the other group received lacidipine. Staged increases in doses of antihypertensives were used until BP was controlled or maximum dose of 40 mg/day lisinopril or 8 mg/day lacidipine was reached. Furosemide was added to lisinopril if BP was not controlled at 40 mg/day. These medications were given for 12 weeks at the end of which measurements done at baseline were repeated. Comparison of baseline and end of study values of these parameters within the groups and between the two groups were made. Lisinopril group and lacidipine group achieved similar and highly significant reduction in blood pressure levels P < 0.001. There was reduction in urinary albumin excretion rate in both groups but this only reached statistical significance in the lisinopril group [480] [269] mg/day vs. 315 [202] mg/day P < 0.05] while for the lacidipine group it was not significant [491] [257] mg/day vs. 335 [182] mg/day P > 0.05]. However, comparison of albumin excretion rate between both groups at baseline and at end of the study did not show any significant difference, P > 0.1. With both drugs there is a tendency for creatinine clearance to increase and plasma creatinine to drop while plasma potassium tended to rise more with lisinopril than lacidipine but differences within and between both groups, did not reach statistical significance P > 0.05. In conclusion, blood pressure reduction was comparable in both drugs; both drugs reduced albuminuria but lisinopril appeared superior. Treatment with both drugs tended to increase creatinine clearance but both had no significant effects on blood sugar.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Disease Progression; Female; Humans; Hypertension; Lisinopril; Male; Metabolic Clearance Rate; Middle Aged; Potassium; Prospective Studies; Treatment Outcome; Urea

Microalbuminuria (MA) is associated with increased cardiovascular risk and lipid abnormalities in people with type 2 diabetes. ACE inhibitors and calcium channel blockers (CCBs) reduce MA and are neutral on total cholesterol and triglycerides. The effect of ACE inhibitors and CCBs on lipid subfractions such as Lp(a), apolipoprotein (apo) A1, apo B, and others, however, is unclear. The current study tests the hypothesis that a fixed-dose combination of an ACE inhibitor, benazepril (B) with the dihydropyridine CCB, amlodipine (A), will further reduce arterial pressure and reduce atherogenic lipid fractions compared to either agent alone.. A multicentre, randomised, open-label, parallel group design was used to study 27 participants with type 2 diabetes. Measurements for total cholesterol, high- and low-density lipoprotein (HDL and LDL), triglycerides, apo A1, apo B, Lp(a), MA, arterial pressure and creatinine clearance were obtained at baseline and at 12-week intervals during the 36 week study.. Arterial pressure was significantly reduced at 36 weeks in all three groups (P = 0.0078 for A, P = 0.0039 for B, and P = 0.0313 for A+B). MA was lowered in all groups with relatively greater reductions in the B (P < 0.05) and A+B groups (P < 0.03) vs A. An increase in mean HDL-cholesterol from baseline was noted in the B and A+B groups; P < 0.05), but not in the A group. A trend was also observed between the rise in HDL-cholesterol and the reduction in MA in the B and A+B groups. Additionally, only the B group exhibited a decrease in the median value of Lp(a) (P < 0.05).. These data support the concept that ACE inhibition with B reduces the atherogenic profile by decreasing Lp(a) and increasing HDL-cholesterol, the latter being correlated with reductions in MA. While A+B exhibited similar trends in lipid subfractions and MA as B, this group had the greatest reduction in systolic blood pressure of the three groups. Thus, use of A+B offers the benefits of a decreased atherogenic profile with a higher probably of achieving goal blood pressure as recommended by national guidelines.

Topics: Aged; Albuminuria; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Apolipoproteins; Apoprotein(a); Benzazepines; Calcium Channel Blockers; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Humans; Lipoprotein(a); Male; Middle Aged; Pilot Projects; Triglycerides

This study evaluates the effects of lercanidipine antihypertensive treatment on glucose homeostasis in patients with type II diabetes mellitus with mild to moderate hypertension. Forty patients were enrolled. After a 2-week wash-out period, they were randomly allocated to receive in double-blind manner either 10 mg or 20 mg in single daily administration for 8 weeks. Nonresponding patients after the initial 4 weeks, were titrated up to 20 mg and 30 mg lercanidipine, respectively. At the end of the double-blind treatment, all patients entered in single-blind 4 weeks placebo follow-up. Systolic and diastolic blood pressure significantly decreased in both groups of patients after 4 weeks of treatment, and decreased further during the following 4 weeks. In both groups, progressive and significant decrease in fasting blood glucose, glycosylated hemoglobin and area under the curve of the oral glucose tolerance test were detected during lercanidipine treatment. Similarly, a decrease in serum fructosamine values were also observed. All variables returned to towards baseline values during the placebo follow-up period. Adverse events (headache and mild asthenia) were limited to two patients and resolved spontaneously. These data indicate that lercanidipine is effective in lowering high blood pressure in hypertensive patients with type II diabetes mellitus and does not exert negative effects on glucose homeostasis.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Area Under Curve; Blood Glucose; Chi-Square Distribution; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Single-Blind Method

If hypertension in patients with diabetes mellitus type II is not adequately controlled by angiotensin-converting enzyme inhibitors (ACE-i), a beta-blocker is frequently added as second-line therapy. Recently, large randomized trials demonstrated the beneficial effect of second-generation dihydropyridine calcium-channel blockers in these patients. These compounds are increasingly being used to replace beta-blockers. Withdrawal of beta-blockers may influence diabetic control and may cause rebound hypertension. Any rebound hypertension from beta-blocker withdrawal may not occur if the beta-blocker is replaced with a calcium-channel blocker. A calcium-channel blocker will influence vascular resistance (VR) and blood pressure differently than a beta-blocker. Thirty-four patients with diabetes mellitus type II and a resting diastolic blood pressure above 90 mm Hg despite enalapril 10 mg daily (or equipotent dosages of other ACE-i) for at least 3 months were treated in an open label sequential comparison with the same ACE-i in combination with the beta-blocker metoprolol 100 mg for 3 months, and, subsequently for 3 more months with the same ACE-i in combination with the dihydropyridine calcium-channel blocker lercanidipine 10 mg once daily. After 6 weeks, patients with a diastolic blood pressure above 90 mm Hg were titrated up to 200 mg metoprolol or 20 mg lercanidipine once daily. Patients were examined every 6 weeks during the trial, and after 2 weeks while receiving lercanidipine. In addition to blood pressure measurements, VR was measured by iridium strain gauge plethysmography and expressed in units (1 unit = 1 mm Hg/mL blood/100 mL tissue per minute). Two of 34 patients did not complete the protocol because of non-compliance with the lercanidipine treatment in the first 2 weeks of treatment. Their data are included in the analysis. No rebound hypertension 14 days after the change-over of therapies was observed. (Mean arterial pressures [MAPs] were not significantly different from the point of withdrawal of the beta-blockers.) However, heart rate rose from 69+/-7 to 94+/-10 beats/min (p < 0.001). After 3 months on lercanidipine, MAP fell by 6+/-10 mm Hg (p = 0.002) compared to the point of withdrawal of the beta-blocker. Vascular resistance fell by 6.28+/-11.91 units (p<0.01), while glucosylated hemoglobin (HbA1c) rose by 0.4+/-0.5% (p<0.001) and body weight rose by 0.6+/-0.6 kg (p < 0.01). Multiple regression analysis revealed significant associations bet

Topics: Adrenergic beta-Antagonists; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Enalapril; Female; Glycated Hemoglobin; Humans; Hypertension; Male; Metoprolol; Middle Aged; Regression Analysis; Vascular Resistance

Thirty-nine hypertensive patients with type 2 diabetes mellitus were followed under long-term treatment (mean, 20.7 months) with manidipine hydrochloride, a Ca antagonist, or delapril hydrochloride, an ACE inhibitor, at nine institutions. Both the treatments showed similar antihypertensive effects, although slight but significantly larger decreases were observed in systolic and mean blood pressures at months 12 and 24 in the patients treated with manidipine (P < 0.02). The urinary albumin excretion index (AEI) tended to increase throughout the study in both treatment groups, but no significant difference in AEI was observed between the two treatment groups at any time point. Overt albuminuria developed in four patients on manidipine but did not appear in any of the patients on delapril. The risk of progression to overt albuminuria was significantly different between manidipine and delapril groups (P = 0.011). No increase in serum creatinine (Cr) was observed with delapril. The average excretion indexes of tubular markers such as beta2-microglobulin, alpha1-microglobulin, and NAG tended to be higher in the patients on manidipine than in those on delapril. Taken in sum, these findings suggest that the ACE inhibitor delapril is more beneficial than the Ca antagonist manidipine in the treatment of diabetic renal diseases via mechanisms other than the blood pressure regulation, partly through their different effects on tubular function. In conclusion, delapril was significantly more effective than manidipine in inhibiting progression to overt albuminuria in hypertensive type 2 diabetes mellitus patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Humans; Hypertension; Indans; Male; Middle Aged; Nitrobenzenes; Piperazines

Recent studies showed that in diabetic hypertensive patients, administration of angiotensin-converting enzyme (ACE)-inhibitors or calcium antagonists can effectively lower blood pressure (BP) and prevent diabetes-related cardiovascular complications with no adverse metabolic effects. We sought to assess the antihypertensive and metabolic effects of the new dihydropyridine calcium antagonist manidipine (M) in patients with diabetes mellitus and essential hypertension as compared with the ACE inhibitor enalapril (E). After 3 weeks of placebo, 101 (62 men; age range, 34-72 years) hypertensives with type II diabetes mellitus were randomized to M 10-20 mg or E 10-20 mg, od, for 24 weeks. At the end of the placebo period and the active-treatment phase, BP was measured with a mercury sphygmomanometer (office, O) and over the 24 h by ambulatory (A) monitoring. ABP recordings were analyzed to obtain 24-h, day (6 a.m. to midnight), and night (midnight to 6 a.m.) average systolic (S) and diastolic (D) BP and heart rate (HR) values. Homogeneity of the antihypertensive effect over the 24 h was assessed by the smoothness index [SI: i.e., the ratio between the average of the 24 hourly BP changes after treatment and the corresponding standard deviation (the higher the SI, the more uniform is the BP control by treatment over the 24 h]. The O SBP and DBP were significantly (p < 0.01) and similarly reduced by M (16 +/- 10 and 13 +/- 6 mm Hg, n = 49) and E (15 +/- 10 and 13 +/- 6 mm Hg, n = 45). The percentage of patients whose O DBP was reduced < or = 85 mm Hg (i.e., the value indicated to be the optimal DBP goal in diabetic hypertensives) was similar for M (37%) and E (40%). The reduction of 24-h BP also was similar between M (n = 38) and E (n = 38) for both drugs (systolic, 6 +/- 11 and 8 +/- 10 mm Hg; diastolic, 5 +/- 8 and 5 +/- 7; NS, M vs. E). The antihypertensive effect was distributed in a similar homogeneous fashion throughout the dosing interval, as shown by the similar SI values (M, 0.6 +/- 1.2 for SBP and 0.6 +/- 0.9 for DBP; E, 0.6 +/- 0.8 for SBP and 0.5 +/- 0.7 for DBP; NS, M vs. E). O and A HR were unchanged by either treatment. Markers of glucose and lipid metabolism and renal function were not significantly modified by treatment both with M and with E. In the diabetic hypertensives, M was as effective and metabolically neutral as the ACE-inhibitor E.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cholesterol; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diastole; Dihydropyridines; Double-Blind Method; Enalapril; Glycated Hemoglobin; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Systole; Treatment Outcome; Triglycerides; Uric Acid

Antihypertensive treatment is frequently needed in type 2 diabetes. In this study we measured the rates of total, oxidative, and nonoxidative glucose disposal, glycogen synthesis, glycolysis, endogenous glucose production, and lipid oxidation using a 4-h euglycemic (approximately 5 mmol/L) hyperinsulinemic (approximately 300 pmol/L) clamp in combination with a dual glucose tracer infusion ([3-(3)H]- and [U-14C] D-glucose) and indirect calorimetry in 40 nonobese subjects with type 2 diabetes. Subjects were studied twice: after a 4-week run-in period and after a 16-week period of double blind, randomized treatment with 4-6 mg/day lacidipine, a calcium channel blocker (n = 19), or 10-20 mg/day lisinopril, an angiotensin-converting enzyme inhibitor (n = 21). Antihypertensive treatment resulted in a significant increase in total glucose disposal during insulin clamp as well as in basal and insulin-stimulated nonoxidative glucose disposal rates. On the contrary, oxidative glucose disposal was significantly decreased by antihypertensive treatment, mainly in the basal state. The changes in glucose disposal rates were not significantly different in subjects treated with lacidipine and in those treated with lisinopril. The suppression of endogenous glucose production during insulin clamp was significantly greater after lacidipine than after lisinopril. These results suggest that treatment of subjects with type 2 diabetes with either lacidipine or lisinopril has no adverse effect on glucose metabolism. Conversely, both drugs seem to improve insulin sensitivity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Body Composition; Body Height; Body Weight; Calcium Channel Blockers; Calorimetry, Indirect; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Lisinopril; Male; Middle Aged

To evaluate the effects of cilnidipine (CNP), L- and N-type calcium channel blocker and nilvadipine (NVP) on 24-h urinary epinephrine (U-EP), norepinephrine (U-NE), dopamine (U-DA) and C-peptide (U-CPR) in patients associated with hypertension and non-insulin-dependent diabetes mellitus (HT-NIDDM), a randomized crossover study was performed with 35 HT-NIDDM patients. The patients were given CNP (10 mg/day) and NVP (8 mg/day), separately, for 4 weeks each. After CNP treatment, U-NE, U-DA and U-CPR levels were significantly reduced compared with pre-treatment levels: 160.4 +/- 12.7 to 111.7 +/- 8.9 microg/day (mean +/- S.E., P < 0.005); 934.8 +/- 163.4 to 590.3 +/- 33.4 microg/day (P < 0.05); 86.7 +/- 9.9 to 57.6 +/- 7.4 microg/day (P < 0.05), respectively. Although no significant differences were observed in U-EP, U-NE, U-DA and U-CPR levels by NVP treatment, U-NE, U-DA and U-CPR levels after CNP treatment were significantly lower than those after NVP treatment: 111.7 +/- 8.9 versus 155.0 +/- 13.7 microg/day (P < 0.02); 590.3 + 33.4 versus 822.2 +/- 104.3 microg/day (P < 0.05); 57.6 +/- 7.4 versus 80.6 +/- 8.1 microg/day (P < 0.05), respectively. In conclusion, it was demonstrated that CNP treatment significantly reduced U-NE, U-DA and U-CPR excretion compared with NVP treatment in HT-NIDDM patients.

Topics: Aged; C-Peptide; Calcium Channel Blockers; Catecholamines; Chromatography, High Pressure Liquid; Cross-Over Studies; Diabetes Mellitus, Type 2; Dihydropyridines; Dopamine; Epinephrine; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine; Norepinephrine

Arterial hypertension is a chronic condition regarded as one of the main risk factors for development of coronary atherosclerosis. As dyslipidemia and reduced glucose tolerance are also risk factors for coronary disease, it is considered important to use antihypertensive drugs having no negative effects on lipid and glucose metabolism when diabetic patients are treated for hypertension. Lacidipine, a new dihydropyridine-like calcium antagonist, has been shown in in vivo and in vitro preclinical studies to possess potent, long-lasting antihypertensive activity. The present study compared the efficacy and safety of once-daily treatment with lacidipine versus nifedipine SR given twice-daily in non-insulin-dependent diabetic patients. Results have shown a similar efficacy of the two treatments: 6 months later, both drugs had reduced blood pressure values [lacidipine from 184.8/105.2 mm Hg to 144.4/87.1 mm Hg; nifedipine slow-release (SR) from 182.3/106.8 mm Hg to 143.6/89.4 mmHg]. However, lacidipine exhibited a lower incidence of adverse events (particularly ankle edema and tachycardia) than nifedipine SR. Finally, both treatments showed no negative effect on metabolic parameters (total cholesterol, high-density lipoprotein cholesterol, triglycerides, and blood glucose).

Topics: Antihypertensive Agents; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Cholesterol; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nifedipine; Triglycerides

Diabetes mellitus is often associated with hypertension and is an additional cardiovascular risk factor. It is therefore important that antihypertensive drugs should have no negative metabolic effects. We present here the results of two distinct studies investigating the clinical efficacy and the metabolic effects of lacidipine in hypertensive patients without concomitant diabetes. Patients in the first study (group A) were hypertensive with non-insulin-dependent diabetes mellitus (NIDDM) and stable blood glucose levels in the 3 months before entering the study. Patients in the second study (group B) were hypertensive without diabetes mellitus. Before the commencement of the study, antihypertensive treatment was discontinued in all patients for a 4-week washout period, followed by 4 weeks of run-in with placebo. Patients were then treated with lacidipine (4 mg o.d.) for 6 months. After 1-2 months, the dose was doubled in patients with uncontrolled blood pressure. Every 2 months, lipid and carbohydrate metabolism were investigated by blood chemistry analyses. The results demonstrate that lacidipine 4-8 mg o.d. is efficacious and well tolerated in hypertensive patients, even in the presence of diabetes mellitus.

Topics: Adult; Aged; Antihypertensive Agents; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Humans; Hypertension; Lipids; Male; Middle Aged

Effects of manidipine, a new calcium antagonist, and delapril, an angiotensin converting enzyme inhibitor, on glucose and lipid metabolism were investigated in mild to moderate hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM). The patients were treated with either manidipine 10 mg/day (n = 12, mean age 63 +/- 2 years) or delapril 30 mg/day (n = 8, 62 +/- 3 years) for 12 weeks. Glucose and insulin (IRI) responses to 75 g oral glucose load, glycosylated hemoglobin A1c (Hb A1c), serum levels of total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, triglyceride and apolipoproteins, and 24 h urinary excretion of C-peptide were measured before and at the end of treatment. Both manidipine and delapril showed adequate hypotensive effects. Neither manidipine nor delapril affected blood glucose and IRI responses to glucose load. Manidipine showed no effect on lipids whereas delapril increased HDL cholesterol (47 +/- 5 mg/dL to 61 +/- 7, p < 0.05), although total cholesterol and triglyceride were not altered. The ratio of TC-HDL cholesterol/HDL cholesterol was decreased by delapril (3.44 +/- 0.30 to 2.61 +/- 0.45, p < 0.05). There were no significant changes in apolipoproteins. Both manidipine and delapril have adequate antihypertensive actions without unfavorable effects on glucose and lipid metabolism in hypertensive patients with NIDDM. Delapril seems to have a beneficial effect on lipid metabolism.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Indans; Lipids; Male; Middle Aged; Nitrobenzenes; Piperazines

The aim of the present study was to compare the effects of olmesartan combined with azelnidipine versus olmesartan combined with trichlormethiazide, on home blood pressure (BP) and pressure variability in type II diabetes mellitus patients using home BP telemonitoring system. We performed an open-label cross-over pilot study of 28 patients with type II diabetes mellitus. Patients received combination treatment with either olmesartan 20 mg plus azelnidipine 16 mg or olmesartan 20 mg plus trichlormethiazide 1 mg for more than 6 weeks each in a cross-over method. The coefficient of morning systolic BP variability in the olmesartan plus azelnidipine group was significantly lower than that in the olmesartan plus trichlormethiazide group (6.4 ± 1.9 vs. 7.5 ± 2.6, P = .004). There were no significant differences in mean morning systolic BP between the two groups. Using home BP telemonitoring for hypertensive patients with type II diabetes, this study revealed for the first time that the olmesartan with azelnidipine combination is superior to the olmesartan with trichlormethiazide combination in reducing home BP variability.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Cross-Over Studies; Diabetes Mellitus, Type 2; Dihydropyridines; Diuretics; Drug Therapy, Combination; Female; Humans; Hypertension; Imidazoles; Male; Middle Aged; Pilot Projects; Tetrazoles; Trichlormethiazide

Topics: Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Combinations; Female; Gliclazide; Humans; Hypertension; Indapamide; Male; Perindopril

Cilnidipine (Cil), which is an L-/N-type calcium channel blocker (CCB), has been known to provide renal protection by decreasing the activity of the sympathetic nervous system (SNS) and the renin-angiotensin system. In this study, we compared the effects of the combination of Cil and amlodipine (Aml), which is an L-type CCB, with an angiotensin (Ang) II receptor blocker on diabetic cardiorenal damage in spontaneously type 2 diabetic rats. Seventeen-week-old Otsuka Long-Evans Tokushima Fatty rats were randomly assigned to receive Cil, Aml, valsartan (Val), Cil + Val, Aml + Val, or a vehicle (eight rats per group) for 22 weeks. Antihypertensive potencies were nearly equal among the CCB monotherapy groups and the combination therapy groups. The lowering of blood pressure by either treatment did not significantly affect the glycemic variables. However, exacerbations of renal and heart failure were significantly suppressed in rats administered Cil or Val, and additional suppression was observed in those administered Cil + Val. Although Val increased the renin-Ang system, Aml + Val treatment resulted in additional increases in these parameters, while Cil + Val did not show such effects. Furthermore, Cil increased the ratio of Ang-(1-7) to Ang-I, despite the fact that Val and Aml + Val decreased the Ang-(1-7) levels. These actions of Cil + Val might be due to their synergistic inhibitory effect on the activity of the SNS, and on aldosterone secretion through N-type calcium channel antagonism and Ang II receptor type 1 antagonism. Thus, Cil may inhibit the progression of cardiorenal disease in type 2 diabetes patients by acting as an N-type CCB and inhibiting the aldosterone secretion and SNS activation when these drugs were administered in combination with an Ang II receptor blocker.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Cardio-Renal Syndrome; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dihydropyridines; Male; Rats; Rats, Inbred OLETF

Hypertension stimulates the sympathetic nervous system and this phenomenon is exacerbated by diabetes mellitus. We investigated the effects of cilnidipine, an N/L-type calcium channel blocker, on aspects of this system in patients with type 2 diabetes mellitus.. In 33 hypertensive patients with type 2 diabetes mellitus treated with a calcium channel blocker other than cilnidipine, we evaluated the influence of switching to cilnidipine on blood pressure, heart rate, catecholamine, plasma renin and aldosterone concentration, brain natriuretic peptide, urine liver-type fatty acid binding protein, and urinary albumin excretion ratio in the same patients by a cross-over design. Other biochemical parameters were also evaluated.. Switching to cilnidipine did not change blood pressure but caused reduction in catecholamine concentrations in blood and urine and plasma aldosterone concentration, accompanied by significant reduction in brain natriuretic peptide, urine liver-type fatty acid binding protein, and albumin excretion ratio. These parameters other than brain natriuretic peptide were significantly increased after cilnidipine was changed to the original calcium channel blocker.. In 33 hypertensive patients with type 2 diabetes mellitus, compared to other calcium channel blockers, cilnidipine suppressed sympathetic nerve activity and aldosterone, and significantly improved markers of cardiorenal disorders. Therefore, cilnidipine may be an important calcium channel blocker for use in combination with renin-angiotensin-aldosterone system inhibitors when dealing with hypertension complicated with diabetes mellitus.

Topics: Aged; Aged, 80 and over; Aldosterone; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Heart Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Natriuretic Peptide, Brain; Prognosis; Renin-Angiotensin System; Sympathetic Nervous System

We evaluated the antialbuminuric advantage of cilnidipine, an N/L-type calcium channel blocker (CCB), compared with L-type CCBs in diabetic patients with normoalbuminuria and microalbuminuria. The study was a multicenter, non-randomized crossover trial. Participants were 90 type 2 diabetic patients exhibiting either normo- or microalbuminuria, and undergoing CCB treatment for ≥6 months prior to study entry. The CCB at the time of entry was continued for the first 6 months (Period 1). Treatment was subsequently switched from cilnidipine to an L-type CCB, or vice versa, for the second 6-month observation period (Period 2). During Period 1, the L-type CCB group showed a significant increase of urinary albumin excretion (UAE) over time, while the cilnidipine group showed no significant elevation. During Period 2, switching of the treatment from the L-type CCB to cilnidipine resulted in significant reduction of the UAE, whereas switching from cilnidipine to the L-type CCB resulted in no significant change in the UAE. This study demonstrated that the antialbuminuric effect of Cilnidipine, but not the L-type CCBs, was sustained even in patients treated for a long time. In addition, the antialbuminuric effect can be anticipated after switching from an L-type CCB to cilnidipine, but not vice versa.

Topics: Aged; Albuminuria; Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Drug Administration Schedule; Female; Humans; Hypertension; Japan; Male; Treatment Outcome

It has been proved that cilnidipine has N-type calcium channels inhibitory activity as well as L-type calcium channels and inhibits excessive release of norepinephrine from the sympathetic nerve ending. This study was undertaken to compare the efficacy of amlodipine (an inhibitor of L-type calcium channels) and cilnidipine (an inhibitor of both L-type and N-type calcium channels) in patients with hypertension and type II diabetes mellitus. Seventy-seven hypertensive patients were divided into two groups according to presence/absence of type II diabetes mellitus. In these two groups of patients, the effects of amlodipine and cilnidipine on glucose and lipid metabolism and renal function were compared. As for glucose and lipid metabolism, homeostasis model assessment insulin resistance (HOMA-R) level in the non-diabetic group and triglyceride in the diabetes group were significantly lower with cilnidipine than with amlodipine. As regards renal function in the diabetic group, estimated glomerular filtration rate (eGFR) was significantly higher and urinary albumin/creatinine ratio was significantly lower with cilnidipine than with amlodipine. Cilnidipine which inhibits N-type calcium channels is more useful for patients with hypertension and diabetes mellitus from its effects on glucose and lipid metabolism and renal function.

Topics: Adult; Aged; Amlodipine; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Glucose; Humans; Hypertension; Kidney; Lipid Metabolism; Male; Middle Aged

Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Azetidinecarboxylic Acid; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Humans; Hypertension; Imidazoles; Male; Tetrazoles

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Humans; Hypertension; Indans; Male; Nitrobenzenes; Piperazines

We investigated whether benidipine, a long-acting calcium channel blocker (CCB), can normalize cardiac expression profiles of the endothelin (ET)-1 system in insulin-resistant diabetes. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of human Type 2 diabetes, were treated for 12 wk with vehicle or benidipine (3 mg.kg(-1).day(-1)). OLETF rats exhibited a significant increase in ET-1 in plasma and left ventricular (LV) tissues compared with nondiabetic controls. Expression of prepro-ET-1, ET-converting enzyme, and ET(A) and ET(B) receptors in LV tissues was also significantly higher in OLETF rats. The two MAPKs, JNK and p38MAPK, both of which are activated by ET-1, were more abundantly expressed in OLETF rat LV tissues. All these alterations were reversed to nondiabetic levels when OLETF rats were treated with the subdepressor dose of benidipine. Furthermore, benidipine therapy resulted in hindering cardiomyocyte hypertrophy and cardiac perivascular fibrosis in OLETF rats. The beneficial actions of benidipine at the subdepressor dose on cardiac remodeling in insulin-resistant diabetes may involve normalization of the upregulated ET-1 system.

Topics: Animals; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Dose-Response Relationship, Drug; Endothelin-1; Male; Rats; Up-Regulation; Ventricular Dysfunction, Left; Ventricular Remodeling

A decrease in renal synthesis of nitric oxide (NO) in the progression of diabetic nephropathy has been documented. As (6R)-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor of NO synthase, we investigated whether BH4 deficiency is involved in the pathogenesis of nephropathy. Ten-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were used as a type II diabetic model, and Long-Evans Tokushima Otsuka (LETO) rats as the healthy controls. OLETF rats were orally treated with BH4 (10 mg/kg daily) or with water from 10 to 61 weeks of age. In another experiment, OLETF rats were treated orally with a calcium channel blocker, benidipine (5 mg/kg daily), or with 0.3% carboxymethyl cellulose (nontreated) from 10 to 52 weeks of age. Proteinuria was observed periodically, and at the end of the study, BH4 level and GTP cyclohydrolase I (GTPCH) activity in the kidney were measured. Proteinuria was observed at 13 weeks of age in the OLETF rats, and deteriorated until 61 weeks of age. Supplemental BH4 reduced the proteinuria. At 52 weeks of age, GTPCH activity and the BH4 level were decreased in the plasma and kidneys of OLETF rats, whereas they were significantly higher in the benidipine group than in the nontreated group. Proteinuria was milder in the benidipine group than in the nontreated group, without a concomitant decrease in blood pressure. Histologically observed glomerulosclerosis was mild in the BH4 and benidipine groups. In type II diabetic rats, renal BH4 is considered to play a crucial role in the pathogenesis of diabetic nephropathy. Benidipine was found to preserve BH4 levels, suggesting therapeutic renoprotective effects.

Topics: Animals; Biopterins; Blood Glucose; Blood Pressure; Body Weight; Calcium Channel Blockers; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Kidney; Male; Nitric Oxide; Proteinuria; Rats; Rats, Inbred OLETF; Rats, Long-Evans

The potential combined effect and mechanism of calcium channel blockers (CCB) and angiotensin II type 1 receptor blockers (ARB) to improve insulin resistance were investigated in type 2 diabetic KK-Ay mice, focusing on their antioxidative action. Treatment of KK-Ay mice with a CCB, azelnidipine (3 mg/kg/day), or with an ARB, olmesartan (3 mg/kg/day), for 2 weeks lowered the plasma concentrations of glucose and insulin in the fed state, attenuated the increase in plasma glucose in the oral glucose tolerance test (OGTT), and increased 2-[(3)H]deoxy-d-glucose (2-[(3)H]DG) uptake into skeletal muscle with the increase in translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Both blockers also decreased the in situ superoxide production in skeletal muscle. The decrease in plasma concentrations of glucose and insulin in the fed state and superoxide production in skeletal muscle, as well as GLUT4 translocation to the plasma membrane, after azelnidipine administration was not significantly affected by coadministration of an antioxidant, 2,2,6,6-tetramethyl-1-piperidinyloxy (tempol). However, those changes caused by olmesartan were further improved by tempol. Moreover, olmesartan enhanced the insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 induced in skeletal muscle, whereas azelnidipine did not change it. Coadministration of azelnidipine and olmesartan further decreased the plasma concentrations of glucose and insulin, improved OGTT, and increased 2-[(3)H]DG uptake in skeletal muscle. These results suggest that azelnidipine improved glucose intolerance mainly through inhibition of oxidative stress and enhanced the inhibitory effects of olmesartan on glucose intolerance, as well as the clinical possibility that the combination of CCB and ARB could be more effective than monotherapy in the treatment of insulin resistance.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antimetabolites; Antioxidants; Azetidinecarboxylic Acid; Blood Glucose; Calcium Channel Blockers; Cyclic N-Oxides; Deoxyglucose; Diabetes Mellitus, Type 2; Dihydropyridines; Glucose Intolerance; Glucose Tolerance Test; Glucose Transporter Type 4; Imidazoles; Insulin; Insulin Receptor Substrate Proteins; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Phosphoproteins; Spin Labels; Superoxides; Tetrazoles

We investigated the effects of long-term benidipine treatment on levels of monocyte and endothelial cell activation markers in hypertensive patients with (n = 28) and without (n = 10) type 2 diabetes mellitus. Benidipine, 4 mg/day, was administered for 6 months; there were no other changes in any of the patients pharmacologic regimens during benidipine treatment. Clinical and biochemical data obtained before and after benidipine administration were compared; all markers were measured by ELISA. The levels of platelet activation markers (CD62P, CD63, and PAC-1), microparticles (monocyte-derived microparticles: MDMPs, and endothelial cell-derived microparticles: EDMPs), chemokines (monocyte chemotactic peptide 1: MCP-1, regulated on activation normally T-cell expressed and secreted: RANTES) and soluble adhesion markers (soluble E-selectin and soluble ICAM-1) differed in the control and hypertension groups. In addition, levels of platelet, monocyte, and endothelial cell activation markers, microparticles, chemokines, and soluble adhesion molecules were higher in hypertensive patients than in those without type 2 diabetes. Furthermore, benidipine administration decreased the concentrations of all these markers. The effect of this drug was significant in diabetes patients with high levels of antioxidized low-density lipoprotein (LDL) antibody. These results suggest that benidipine is effective for the treatment of oxLDL-dependent vascular disorders in hypertensive patients with type 2 diabetes.

Topics: Aged; Autoantibodies; Biomarkers; Diabetes Mellitus, Type 2; Dihydropyridines; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Hypertension; Lipoproteins, LDL; Male; Middle Aged; Monocytes; Oxidation-Reduction; Retrospective Studies; Time Factors; Vasodilator Agents

Cardiovascular complications are the central feature of type 2 diabetes mellitus, and insulin resistance is an early clinical manifestation of type 2 diabetes mellitus. Calcium channel blockers are widely used to treat cardiovascular diseases in diabetic patients; however, it remains unknown how endothelin-1 (ET-1) is altered and associated with cardiac lesions at the insulin-resistant early stage of type 2 diabetes mellitus, and, if so, whether calcium channel blockers can reverse such alterations. We examined plasma and cardiac expression of ET-1 in male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a spontaneous model of human type 2 diabetes mellitus. At 8 weeks of age, OLETF rats were treated for 12 weeks with a long acting calcium channel blocker, benidipine (3 mg/kg per day p.o.) (BEN, n = 15), or with vehicle (OLETF, n = 15), and age-matched genetic control, male Long-Evans Tokushima Otsuka (LETO) rats were also used (n = 15). Blood pressure was significantly higher in OLETF than LETO rats, and benidipine treatment of OLETF rats for 12 weeks did not reduce their blood pressure significantly. Plasma and cardiac levels of ET-1 were significantly higher in OLETF compared with LETO rats (both P < 0.01), and were reversed after benidipine treatment. Our results suggest that ET-1 plays a pivotal role in the pathogenesis of cardiac complications at the insulin-resistant stage of diabetes mellitus, and that benidipine treatment may have a beneficial effect on these complications.

Topics: Age Factors; Animals; Blood Pressure; Calcium Channel Blockers; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Dihydropyridines; Disease Models, Animal; Down-Regulation; Endothelin-1; Insulin Resistance; Male; Myocardium; Rats; Rats, Inbred OLETF; Rats, Long-Evans

The influence of treatment with the dihydropyridine-type Ca2+ antagonist lercanidipine on heart and coronary microanatomic changes was investigated in spontaneously hypertensive rats, Cohen-diabetic rats, and Cohen-Rosenthal diabetic hypertensive rats. At 12 weeks of age, animals were left untreated (control groups) or were treated for 8 weeks with an oral dose of 3 mg/kg per day of lercanidipine. Wistar-Kyoto rats were used as a normotensive reference group. In spontaneously hypertensive rats and diabetic hypertensive rats, systolic blood pressure was higher in comparison with Wistar-Kyoto rats. Augmented pressure values were decreased by lercanidipine treatment. Systolic blood pressure was slightly higher in Cohen-diabetic rats than in Wistar-Kyoto rats, and this increase was countered by treatment with lercanidipine. In spontaneously hypertensive rats, diabetic rats, and diabetic hypertensive rats, the thickness of left ventricle and cardiocyte area were increased. Focal connective tissue areas and diffuse accumulation of connective tissue were observed in the left ventricle of spontaneously hypertensive and Cohen-diabetic rats, respectively. Pharmacological treatment countered left ventricle thickening and restored cardiocyte area values in subendocardium. An increased thickness of tunica media accompanied by luminal narrowing was found in coronary artery branches of control spontaneously hypertensive and diabetic hypertensive rats. Treatment with lercanidipine countered vascular changes primarily in small-sized coronary arteries. These results indicate that hypertensive, diabetic, and diabetic hypertensive rats undergo cardiac hypertrophy and vascular changes affecting small-sized coronary arteries. Treatment with lercanidipine countered hypertension-related cardiac and coronary changes, suggesting that this dihydropyridine-type Ca2+ antagonist may improve heart and coronary structure in diabetes associated with hypertension.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Calcium Channel Blockers; Coronary Vessels; Diabetes Mellitus, Type 2; Dihydropyridines; Heart; Hypertension; Male; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY

Calcium channel blockers, widely used for the treatment of hypertension and angina, could prevent cardiovascular complications in patients with diabetes. They can improve cardiac remodelling in animal models of a variety of cardiovascular diseases. Here, we examined the therapeutic effect of benidipine, a long-acting calcium channel blocker, on cardiac remodelling in Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a Type II (non-insulin-dependent) diabetes mellitus model.. The methods for morphometric analysis included double staining for coronary capillaries, dye-binding staining for collagen content and Masson's trichrome staining for perivascular fibrosis. Immunohistochemical and in situ hybridization techniques were used for detecting protein and mRNA expressions for vascular endothelial growth factors (VEGF), basic fibroblast growth factors (bFGF) and TGF-beta(1), endothelial nitric oxide synthase (eNOS), and anti- and pro-apoptotic markers.. OLETF rats showed an increased coronary capillary density, a reduced venular capillary proportion, an increased cardiac collagen content and prominent cardiac perivascular fibrosis. In OLETF rat hearts, significant increases in vascular expressions for VEGF, bFGF and TGF- beta(1) were found. Furthermore, the apoptosis signalling pathways, involving eNOS and apoptotic markers, were markedly altered, and coronary endothelial cell apoptosis was lower. These alterations with the exception of eNOS expression were significantly blocked by benidipine treatment.. The suppressive effect of benidipine on overproduction of angiogenic growth factors could prevent cardiac angiogenesis and fibrosis, resulting in an improvement of cardiac remodelling in diabetes. As VEGF and bFGF potently block endothelial cell apoptosis execution, physiological apoptosis revived by benidipine treatment could also contribute to coronary vessel regression.

Topics: Animals; Calcium Channel Blockers; Capillaries; Collagen; Coronary Vessels; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dihydropyridines; Disease Models, Animal; Endothelial Growth Factors; Fibroblast Growth Factor 2; Gene Expression Regulation; Lymphokines; Male; Neovascularization, Pathologic; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Rats; Rats, Inbred Strains; RNA, Messenger; Species Specificity; Transcription, Genetic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Follow-Up Studies; Humans; Hypertension; Hypertrophy, Left Ventricular; Treatment Outcome

Among the antihypertensive drugs, fast-acting Ca2+ antagonists have been reported to worsen insulin sensitivity. This effect may be attributable to reflex increases in sympathetic activity. On the other hand, however, it has been reported that long-acting, dihydropiridine Ca2+ antagonists improve insulin-resistance. The purpose of this study was to investigate whether cilnidipine, another long-acting dihydropidine Ca2+ antagonist, improves insulin sensitivity in Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of spontaneous NIDDM. 25 weeks OLETF rats were divided into the following groups; normal-diet group, cilnidipine-supplemented group (cilnidipine 3 mg/kg/day) and angiotensin II receptor antagonist CS-866-supplemented group (CS-866 1 mg/kg/day). As a non-diabetic control, we used Long-Evans-Tokushima-Otsuka rats (non-diabetic rats). Glucose infusion rate (GIR), an index of insulin resistance, as measured by the hyperinsulinemic euglycemic clamp technique was significantly decreased in OLETF rats. Cilnidipine-treatment partially but significantly improved insulin sensitivity in addition to systolic blood pressure in OLETF rats at 30 weeks of age, although it did not decrease accumulation of abdominal fat or serum levels of glucose or insulin. CS-866, an angiotensin II receptor antagonist, which lowers blood pressure through a different mechanism, did not improve insulin resistant states in OLETF rats. These results suggest that cilnidipine has a beneficial effect on insulin-resistance together with the antihypertensive effect.

Topics: Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Body Weight; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dihydropyridines; Glucose Tolerance Test; Imidazoles; Insulin; Insulin Resistance; Lipid Metabolism; Male; Olmesartan Medoxomil; Rats; Rats, Inbred OLETF; Tetrazoles; Time Factors

The open trial was designed to evaluate the effects of long-term antihypertensive treatment with the calcium-channel blocker, manidipine and the angiotensin converting enzyme (ACE) inhibitor, delapril on insulin sensitivity in Japanese non-insulin dependent diabetes mellitus (NIDDM) patients with essential hypertension. We measured the insulin sensitivity index (SI) and the glucose-effectiveness (SG) by the use of Bergman's minimal model method in 18 hypertensive NIDDM patients before and after administration of manidipine (group A) or delapril (group B) for 3 months. Manidipine treatment for 3 months significantly improved SI in group A from 3.35 +/- 0.61 (x 10(-4) min-1 microU-1 ml-1) to 4.70 +/- 1.34 (P < 0.05). Delapril treatment for 3 months also significantly improved SI in group B from 3.56 +/- 1.04 to 5.00 +/- 0.87 (P < 0.05). Manidipine significantly improved SG in group A from 1.60 +/- 0.64 (x 10(-2) min) to 2.19 +/- 0.38 (P < 0.05). Delapril treatment also significantly improved SG in the group B from 1.41 +/- 0.56 to 1.91 +/- 0.35 (P < 0.05). Manidipine and delapril did not affect urinary C-peptide excretion for 24 h in the hypertensive NIDDM patients. Treatment with manidipine or delapril significantly reduced systolic and diastolic blood pressures in the hypertensive NIDDM patients. There were no differences between plasma glucose, serum total triglycerides, and cholesterol or lipoprotein cholesterol fractions, heart rate and body weight after 3 months on manidipine or delapril. This study confirmed the improving effects on SI and SG by long-term treatment with manidipine or delapril in the hypertensive NIDDM patients.

Topics: Antihypertensive Agents; Blood Glucose; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Glycated Hemoglobin; Humans; Hypertension; Indans; Insulin Resistance; Male; Middle Aged; Nitrobenzenes; Piperazines