trandolapril and Diabetes-Mellitus--Type-2

Antihypertensive treatment mitigates the progression of chronic kidney disease. Here, we comparatively assessed the effects of antihypertensive agents in normotensive and hypertensive diabetic patients with microalbuminuric kidney disease.. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were systematically searched for randomized controlled trials (RCTs) comparing oral antihypertensive agents in adult diabetic patients with microalbuminuria. The primary efficacy outcome was reduction in albuminuria, and the primary safety outcomes were dry cough, presyncope, and edema. Random-effects pairwise and Bayesian network meta-analyses were performed to produce outcome estimates for all RCTs, only hypertensive RCTs, or only normotensive RCTs. Surface under the cumulative ranking (SUCRA) probability rankings were calculated for all outcomes. Sensitivity analyses on type 2 diabetes status, age, or follow-up duration were also performed.. A total of 38 RCTs were included in the meta-analyses. The angiotensin-converting enzyme inhibitor-calcium channel blocker (ACEI-CCB) combination therapy of captopril+diltiazem was most efficacious in reducing albuminuria irrespective of blood pressure status. However, the ACEI-angiotensin receptor blocker (ACEI-ARB) combination therapy of trandolapril+candesartan was the most efficacious in reducing albuminuria for normotensive patients, while the ACEI-CCB combination therapy of fosinopril+amlodipine was the most efficacious in reducing albuminuria for hypertensive patients. The foregoing combination therapies displayed inferior safety profiles relative to ACEI monotherapy with respect to dry cough, presyncope, and edema. With respect to type 2 diabetic patients with microalbuminuria, the Chinese herbal medicine Tangshen formula followed by the ACEI ramipril were the most efficacious in reducing albuminuria.. Trandolapril+candesartan appears to be the most efficacious intervention for reducing albuminuria for normotensive patients, while fosinopril+amlodipine appears to be the most efficacious intervention for reducing albuminuria for hypertensive patients. For practitioners opting for monotherapy, our SUCRA analysis supports the use of trandolapril and fosinopril in normotensive and hypertensive adult diabetic patients with microalbuminuria, respectively.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Bayes Theorem; Benzimidazoles; Biphenyl Compounds; Diabetes Mellitus, Type 2; Follow-Up Studies; Fosinopril; Humans; Hypertension; Indoles; Kidney Diseases; Middle Aged; Patient Safety; Probability; Randomized Controlled Trials as Topic; Tetrazoles; Treatment Outcome; Young Adult

Cardiovascular diseases are directly affected by arterial hypertension. When associated with diabetes mellitus, the potential deleterious effects are well amplified. Both conditions play a central role in the pathogenesis of coronary artery disease, heart failure, stroke, and renal insufficiency. Prevalence of hypertension is much higher among diabetic than non-diabetic patients, and the hypertensive patient is more likely to develop type 2 diabetes. Current international guidelines recommend aggressive reductions in blood pressure (BP) in hypertensive patients with additional risk factors, including cardiovascular risk factors, and emphasize the relevance of intensive reduction in patients with diabetes mellitus; a goal of 130/80 mm Hg is required. To achieve BP target a combination of antihypertensives will be needed, and the use of long-acting drugs that are able to provide 24-hour efficacy with a once-daily dosing confers the noteworthy advantages of compliance improvement and BP variation lessening. Lower dosages of the individual treatments of the combination therapy can be administered for the same antihypertensive efficiency as that attained with high dosages of monotherapy. Angiotensin-converting enzyme inhibitors and calcium-channel blockers as a combination have theoretically compelling advantages for vessel homeostasis. Trandolapril/verapamil sustained release combination has showed beneficial effects on cardiac and renal systems as well as its antihypertensive efficacy, with no metabolic disturbances. This combination can be considered as an effective therapy for the diabetic hypertensive population.

Topics: Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypertension; Indoles; Treatment Outcome; Verapamil

Trandolapril/verapamil sustained release (SR) [Tarka] is an oral, fixed-dose combination of the ACE inhibitor trandolapril and the SR formulation of the phenylalkylamine calcium channel antagonist verapamil. It is indicated for the treatment of hypertension in patients who require more than one agent to achieve blood pressure (BP) targets. In the large, randomised, multicentre INVEST (INternational VErapamil SR/trandolapril STudy), a verapamil SR-based treatment strategy that included trandolapril in most patients was as effective as an atenolol-based treatment strategy in reducing the risk of the primary outcome (first occurrence of death [all-cause], nonfatal myocardial infarction [MI] or nonfatal stroke) in patients with hypertension and coronary artery disease (CAD) and was as well tolerated. Trandolapril/verapamil SR is generally more effective at controlling hypertension than either component as monotherapy, and is as effective as a number of other fixed-dose combination therapies. The combination is as well tolerated as trandolapril monotherapy and is at least as well tolerated as verapamil SR monotherapy. In hypertensive patients with type 2 diabetes mellitus in the BENEDICT (BErgamo NEphrologic DIabetes Complications Trial), trandolapril/verapamil SR prolonged the time to the onset of persistent microalbuminuria compared with placebo, as did trandolapril monotherapy. Thus, trandolapril/verapamil SR is an effective option for the treatment of essential hypertension in patients requiring more than one agent to achieve BP targets, including those with compelling indications, such as CAD or type 2 diabetes.

Topics: Adult; Aged; Antihypertensive Agents; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Combinations; Drug Interactions; Humans; Hypertension; Indoles; Liver Failure; Randomized Controlled Trials as Topic; Renal Insufficiency; Verapamil

Perindopril is a long-acting, once-daily lipophilic angiotensin-converting enzyme inhibitor with high tissue angiotensin-converting enzyme affinity, lowering angiotensin II and potentiating bradykinin. Efficacy, safety, and tolerability of perindopril are well established in the treatment of hypertension and heart failure. Moreover, large morbidity-mortality trials, such as the EUROPA, PROGRESS, and PREAMI have shown that treatment with perindopril reduces morbidity and mortality and prevents cardiovascular disease in a large range of patients with vascular diseases, whether or not they are hypertensive. Thus, the outcomes of these and other trials support the concept of cardiovascular protective properties of angiotensin-converting enzyme inhibition with perindopril in addition to the obvious blood-pressure-lowering effect. Considering its properties and the clinical evidence on efficacy and tolerability that has been gathered, perindopril should be considered a first-line therapeutic agent in hypertension, heart failure and acute myocardial infarction and a tool of secondary prevention of coronary artery disease.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Heart Failure; Humans; Hypertension; Indoles; Male; Middle Aged; Multicenter Studies as Topic; Myocardial Infarction; Perindopril; Prospective Studies; Ramipril; Randomized Controlled Trials as Topic; Risk; Risk Factors; Stroke; Time Factors

SEVERAL MECHANISMS: The progression in renal failure first implies hemodynamic mechanisms and among which angiotensin II has a central role, but also an increase in proteinuria and the induction of many inflammatory and mitogenic mediators that enhance fibrosis (TGF-beta), an effect stimulating the thrombotic mechanism. Among these factors of progression in renal failure, hypertension and proteinuria are the two major factors. Proteinuria is "nephrotoxic" and leads to glomerular and tubulo-interstitial lesions. THE ROLE OF ANGIOTENSIN-CONVERTING ENZYME INHIBITORS: Angiotensin-converting enzyme inhibitors (ACE) affect the different mechanisms that lead to glomerulosclerosis: antihypertensive effect, with the normalisation of blood pressure having demonstrated its determining role in the production of nephrosis in various epidemiological studies; hemodynamic effect with a decrease in glomerular capillary pressure, in the filtration fraction, and inhibition of the bradykinin deterioration; antiproteinuric effect superior to that of other anti-hypertensive drugs (excepting angiotensin II-receptor antagonists). Two indications ACE inhibitors have demonstrated their efficacy in slowing the progression of renal failure in two large pathological fields: diabetic nephropathy in which this effect is demonstrated in type I diabetes, although the results are not as obvious in type II diabetes in which the nephropathy is multi-factor. The recent French and American recommendations are that ACE inhibitors should be used in first intention in diabetic nephropathies and aimed at tight blood pressure control; non-diabetic nephropathies Two pivotal studies have demonstrated the efficacy of ACE inhibitors in nephropathies whatever their type. These data have led to propose ACE inhibitors in first intention in patients exhibiting chronic nephropathies, whether hypertensive or not THE COMBINATION WITH OTHER HYPERTENSIVE DRUGS: Calcium channel blockers have a beneficial trophic effect in renoprotection and can be combined with ACE inhibitors, particularly in the case of diabetic nephropathies. ACE inhibitors and angiotensin II-receptor antagonists have comparable effect on hemodynamics and glomerulosclerosis factors. Clinically, the decrease in proteinuria is identical. Endothelin antagonists have also been studied in renoprotection and appear to have a beneficial effect when combined with ACE inhibitors. GLOBALLY: ACE inhibitors remain the only treatment with demonstrated lon

Topics: Amlodipine; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Biphenyl Compounds; Calcium Channel Blockers; Clinical Trials as Topic; Cohort Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Endothelins; Hemodynamics; Humans; Hypertension; Indoles; Irbesartan; Kidney; Kidney Failure, Chronic; Proteinuria; Randomized Controlled Trials as Topic; Receptors, Angiotensin; Renin-Angiotensin System; Tetrazoles; Verapamil

Micro- or macroalbuminuria is associated with increased cardiovascular risk factors among patients with type 2 diabetes, but whether albuminuria within the normal range predicts long-term cardiovascular risk is unknown. We evaluated the relationships between albuminuria and cardiovascular events in 1208 hypertensive, normoalbuminuric patients with type 2 diabetes from the BErgamo NEphrologic Diabetes Complication Trial (BENEDICT), all of whom received angiotensin-converting enzyme inhibitor (ACEI) therapy at the end of the trial and were followed for a median of 9.2 years. The main outcome was time to the first of fatal or nonfatal myocardial infarction; stroke; coronary, carotid, or peripheral artery revascularization; or hospitalization for heart failure. Overall, 189 (15.6%) of the patients experienced a main outcome event (2.14 events/100 patient-years); 24 events were fatal. Albuminuria independently predicted events (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.02-1.08). Second-degree polynomial multivariable analysis showed a continuous nonlinear relationship between albuminuria and events without thresholds. Considering the entire study population, even albuminuria at 1-2 μg/min was significantly associated with increased risk compared with albuminuria <1 μg/min (HR, 1.04; 95% CI, 1.02-1.07). This relationship was similar in the subgroup originally randomly assigned to non-ACEI therapy. Among those originally receiving ACEI therapy, however, the event rate was uniformly low and was not significantly associated with albuminuria. Taken together, among normoalbuminuric patients with type 2 diabetes, any degree of measurable albuminuria bears significant cardiovascular risk. The association with risk is continuous but is lost with early ACEI therapy.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Cardiotonic Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Humans; Indoles; Longitudinal Studies; Male; Middle Aged; Risk Factors; Verapamil

To address whether nondihydropyridine calcium-channel blocker added-on angiotensin-converting-enzyme inhibitor therapy ameliorates albuminuria and cardiovascular outcomes in type 2 diabetes patients.. The Bergamo Nephrologic Diabetes Complications Trial-B was a multicentre, prospective, double-blind, parallel-group trial comparing renal and cardiovascular outcomes in 281 hypertensive type 2 diabetes patients with microalbuminuria randomized to at least 2-year VeraTran (verapamil/trandolapril 180 mg/2 mg daily) or trandolapril (2 mg daily, identical image) treatment. Main outcome was persistent macroalbuminuria (albuminuria >200 µg/min in two consecutive visits). Treatment targets were SBP/DBP less than 120/80 mmHg and HbA1C less than 7%.. Over a median follow-up of 4.5 years, 18 patients (13%) on VeraTran vs. 15 (10.5%) on trandolapril [unadjusted hazard ratio (95% confidence interval [CI]) 1.07 (0.54-2.12), P = 0.852] progressed to macroalbuminuria, respectively; 62 (44.9%) vs. 71 (49.7%) [0.80 (0.57-1.12), P = 0.198] regressed to normoalbuminuria (urinary albumin excretion <20 µg/min), and 20 (14.5%) vs. 21 (14.7%) [hazard ratio 0.93 (0.50-1.72), P = 0.816] had major cardiovascular events. BP and metabolic control were similar between groups. Patients with cardiovascular events were significantly less [13 (9.8%) vs. 28 (18.9%), hazard ratio: 0.37 (0.19-0.71), P = 0.003] among those regressing to normoalbuminuria than those without regression. Difference was independent of treatment allocation and was significant also after adjusting for baseline characteristics [0.40 (0.20-0.79), P = 0.009], follow-up SBP [0.40 (0.20-0.80), P = 0.010] or DBP [0.36 (0.18-0.73), P = 0.004] BP or HbA1C [0.43 (0.21-0.88), P = 0.021].. In hypertensive type 2 diabetes patients with microalbuminuria, verapamil added-on trandolapril did not improve renal or cardiovascular outcomes. Independent of verapamil, trandolapril normalized albuminuria in half of patients and this translated into significant cardioprotection.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypertension; Indoles; Male; Middle Aged; Prospective Studies; Treatment Outcome; Verapamil

Adiponectin is secreted from adipose tissue and exhibits a protective effect against cardiovascular disease; plasma adiponectin concentrations are decreased in type 2 diabetic and in hypertensive patients.. The aim of this study was to compare the effect of trandolapril (T) and its fixed-dose combination with verapamil (FDTV) on adiponectin levels in hypertensive type 2 diabetic patients.. A total of 40 type 2 diabetic patients with never-treated hypertension were randomly assigned to two groups. One group received FDTV 180 mg + T 2 mg, once a day; the other group received T 2 mg once a day, administered for 3 months in both groups. Adiponectin was measured by enzyme-linked immunosorbent assay (ELISA) at the beginning and end of the study. Patients were evaluated monthly for blood pressure, fasting serum glucose and adverse events. Statistical analysis was performed with analysis of variance (ANOVA).. All patients experienced a significant reduction of blood pressure. Both therapeutics regimens increased the levels of adiponectin, However, FDTV produces a higher increase in the levels of the hormone (8.15 ± 4.6 to 10.96 ± 5.6 µg/ml) when compared with the T treatment (7.64 ± 3.8 to 8.92 ± 4.4 µg/ml), p < 0.05. None of the patients suffered adverse events.. Our results show that the addition of FDTV to T produced a greater increase on adiponectin levels than trandolapril alone.

Topics: Adiponectin; Aged; Analysis of Variance; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Drug Combinations; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension; Indoles; Male; Middle Aged; Treatment Outcome; Verapamil

Endothelial dysfunction in hypertensive type-2 diabetic patients is associated with increased levels of circulating soluble adhesion molecules (SAM). SAM participate in the development of diabetic macroangiopathy and microangiopathy. The aim of this study was to compare the effect of trandolapril (T) and its fixed-dose combination with verapamil (FDTV) on SAM levels in hypertensive type-2 diabetic patients.. Forty type-2 diabetic patients with never-treated hypertension were randomly assigned to two groups. One group (FDTV) received 2/180 mg once a day; the other group received T 2 mg once a day. Study drugs were administered for three months in both groups. VCAM-1, ICAM, and E-selectin were measured by ELISA at the beginning and end of the study. Patients were evaluated monthly for blood pressure, fasting serum glucose, and adverse events. Statistical analysis was performed with ANOVA.. Both therapeutics regimens reduced significantly the levels of the SAM tested. When both groups were compared, we did not find a significant difference in ICAM and E-selectin reduction. However, VCAM-1 presented a significantly greater reduction (p = 0.022) in the trandolapril-verapamil group. No patient suffered adverse events.. Our results show that FDTV produces a greater reduction of VCAM-1 circulating levels than trandolapril alone. This may explain some of the beneficial effects of this fixed dosed combination that are non-related to its antihypertensive effects.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Cell Adhesion Molecules; Diabetes Complications; Diabetes Mellitus, Type 2; Drug Combinations; E-Selectin; Female; Humans; Hypertension; Indoles; Intercellular Adhesion Molecule-1; Male; Middle Aged; Vascular Cell Adhesion Molecule-1; Verapamil

Diabetic nephropathy management should include the use of an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker with additional antihypertensive medications to reduce proteinuria and cardiovascular events. Some studies suggest that adding a nondihydropyridine rather than a dihydropyridine calcium channel blocker (CCB) may more effectively lower proteinuria. We hypothesized that a trandolapril/verapamil SR (T/V) fixed-dose combination (FDC) was superior to a benazepril/amlodipine (B/A) FDC for reducing albuminuria in 304 hypertensive diabetic nephropathy patients when treated for 36 weeks. No statistically significant differences were observed between groups in the primary end point; adjusted percentage change in urinary albumin/creatinine ratio (UACR), which increased (mean T/V, 29.29%; mean B/A, 8.49%; difference, 20.80%; P=.34); or in change in absolute UACR, which decreased (mean [g/g] T/V, -0.11; mean [g/g] B/A, -0.08; difference -0.03; P=.78). There were significant reductions in log UACR (mean change in T/V, -0.28; P<.01; mean change in B/A, -0.31; P<.001) and diastolic blood pressure in both groups and in systolic blood pressure in the B/A group. T/V was not superior to B/A for reducing UACR. Both ACEI/CCB FDCs may reduce albuminuria; in the case of T/V, this appears to be independent of systolic blood pressure reduction in patients who had previously been treated and had baseline blood pressure levels of 142/77 mm Hg.

Topics: Aged; Albuminuria; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Synergism; Drug Therapy, Combination; Female; Humans; Indoles; Male; Middle Aged; Prospective Studies; Proteinuria; Treatment Outcome; Verapamil

The aim of the study was to assess the effect of an antihypertensive treatment adjustment on 24-hour blood pressure variation in type 2 diabetes patients.. The study group included 59 hypertensive type 2 diabetes patients subjected to a single one-step antihypertensive agent dose adjustment (increase or decrease). Ambulatory blood pressure monitoring was performed at baseline and 4-6 weeks after the treatment modification. Controls were 41 matched patients, in whom antihypertensive treatment remained unchanged.. At baseline, 45 (76%) study group patients and 29 (71%) controls were 'non-dippers'; a similar number of patients in both groups converted to 'dipping' or vice versa: 11 (19%) from the study group and 7 (17%) controls. 'Converters' from the study group were significantly younger (47.5 +/- 3.9 vs. 56.4 +/- 12.2 years; p < 0.05) and had lower 24-hour systolic blood pressure than 'non-converters': 113.7 +/- 7.2 vs. 127.7 +/- 20.3 mm Hg (p < 0.01).. A single one-step antihypertensive medication adjustment does not affect 'dipping' status in type 2 diabetes patients. However, the assessment of blood pressure variation should be made with greater caution in younger type 2 diabetes subjects with low systolic blood pressure.

Topics: Adult; Aged; Amlodipine; Antihypertensive Agents; Bisoprolol; Blood Pressure; Circadian Rhythm; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Hypertension, Renal; Indapamide; Indoles; Male; Middle Aged; Nitrendipine; Perindopril; Spironolactone

For assessment of the independent renoprotective effect of BP control and angiotensin-converting enzyme inhibitor (ACEi) therapy, the relationships of baseline BP, BP reduction, and follow-up BP with the incidence of persistent microalbuminuria were evaluated in 1204 hypertensive patients who had type 2 diabetes and normoalbuminuria and were included in the BErgamo Nephrologic Diabetic Complications Trial (BENEDICT) study and were randomly assigned to 3.6 yr of treatment with the ACEi trandolapril (2 mg/d), the nondihydropyridine calcium channel blocker (ndCCB) verapamil SR (240 mg/d), their fixed combination Veratran (trandolapril 2 mg/d plus verapamil SR 180 mg/d), or placebo, plus other antihypertensive medications targeted at systolic/diastolic BP <130/80 mmHg. Follow-up (from month 3 to study end) systolic, diastolic, mean, and pulse BP and their reductions versus baseline--but not baseline BP--independently predicted (P < 0.001) the risk for microalbuminuria. In patients with follow-up BP above medians, ACEi significantly reduced the risk for microalbuminuria to levels that were observed among patients with BP below medians, regardless of ACEi treatment. The same trend was observed among patients with BP reductions below medians. ndCCB therapy did not independently affect microalbuminuria. Patients who were on Veratran had lower BP and less frequently received diuretics, beta blockers, or dihydropyridine dCCB. In hypertensive, normoalbuminuric patients with type 2 diabetes, BP reduction and ACEi therapy both independently may prevent microalbuminuria. ACEi therapy is particularly effective when BP is poorly controlled, whereas ndCCB therapy is ineffective at any level of achieved BP. As compared with trandolapril, Veratran may help with achievement of target BP with less need for concomitant antihypertensive medications.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Drug Combinations; Female; Follow-Up Studies; Humans; Hypertension; Indoles; Male; Middle Aged; Proportional Hazards Models; Verapamil

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

Arterial hypertension greatly increases the risk of cardiovascular disease, renal insufficiency, and retinopathy in patients with type 2 diabetes. Epidemiological studies all document a reduced risk for the aforementioned consequences at a blood pressure (BP) lower than 130/80 mmHg. For this reason, lower target BPs are recommended by recent guidelines committees. A lower threshold BP for treatment, also proposed in guidelines, could facilitate the attainment of the recommended target BP. However, little data exist on the efficacy and safety of starting pharmacological therapy in type 2 diabetic patients exhibiting high-normal BP (HNBP) or the first stage of isolated systolic hypertension previously considered as borderline isolated systolic hypertension (BISH).. To determine the antihypertensive efficacy and safety of the fixed-dose combination of the non-dihydropiridine calcium channel blocker (CCB) and ACE inhibitor verapamil SR/trandolapril 180/2 mg (V + T), versus trandolapril 2 mg (T), versus placebo (P) in previously untreated type 2 diabetic patients diagnosed as having HNBP or BISH.. Multicentric, double-blind, placebo-controlled study with a 16-week follow-up in three groups totalling 438 participants. The primary end-point was to attain the recommended guideline goal of a systolic BP (SBP) value lower than 130 mmHg in all patients and a diastolic BP (DBP) value lower than 85 mmHg in HNBP. Participants were randomized (2:2:1) to verapamil V + T, T, or P. Doses were doubled at week 8 if BP was not controlled.. Both active groups were more effective than placebo to decrease SBP and DBP. The mean difference in SBP from placebo was 7.1 mmHg (3.3-10.9, 95% confidence interval (CI); P < 0.001) for T and 7.8 mmHg (3.9-11.6, 95% CI; P < 0.001) for V + T, with no statistical difference between both active groups. Combined treatment (V + T) decreased DBP by 4.6 mmHg (2.3-6.9, 95% CI; P < 0.001) more than placebo and 2.1 mmHg (0.3-4.0, 95% CI; P = 0.021) more than T. At the end of the study, 36.5% in the T group, 37.8% in the V + T group, and 14.9% (P = 0.009, P versus V + T and T) had attained the primary end-point. No significant difference was found between T and V + T with regard to the percentage of good control for SBP, but the control rate on the DBP (DBP < 85 mmHg) was significantly higher in the V + T group (88.8%), when compared with T (79.1%) or P (63.5%) (P = 0.002). Withdrawal rates due to adverse effects did not differ among trandolapril alone (9.4%), the combination (11.7%) and placebo (8.1%).. Antihypertensive treatment is more effective than placebo for controlling SBP and DBP in previously untreated participants with type 2 diabetes exhibiting low threshold BP values. Combination therapy with verapamil SR/trandolapril was more effective than trandolapril alone for controlling DBP.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diastole; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Heart Rate; Humans; Hypertension; Indoles; Male; Middle Aged; Prospective Studies; Systole; Time Factors; Treatment Outcome; Verapamil

To compare the effect of fixed-dose trandolapril-verapamil (FDTV) with that of trandolapril on proteinuria in normotensive, type 2 diabetic patients.. A total of 60 normotensive, type 2 diabetic patients with 24-h proteinuria >300 mg were randomly assigned to two groups for open-label treatment. One group received 2 mg trandolapril/180 mg verapamil FDTV once daily; the other group received 2 mg trandolapril once daily. Study drugs were administered for 6 months in both groups. Creatinine clearance and 24-h urinary protein excretion were measured at the beginning and the end of the study. Patients were evaluated monthly for blood pressure, fasting blood glucose level, heart rate, and adverse events. Statistical analysis was performed using ANOVA.. Both groups experienced a statistically significant (P < 0.005) mean decrease in mean proteinuria from baseline: FDTV ([mean +/- SD] 1200 +/- 200 to 540 +/- 79 mg; P < 0.001) and trandolapril (1,105 +/- 212 to 750.9 +/- 134 mg; P < 0.005). A significantly greater reduction from baseline in proteinuria was observed in the FDTV group compared with the trandolapril group. Patients who received trandolapril experienced a statistically significant (P < 0.05) decrease in mean creatinine clearance (91.1 +/- 3.4 to 75.3 +/- 3 ml/min; P < 0.05) compared with patients who received FDTV (88.3 +/- 3.6 to 82.9 +/- 3.5 ml/min; P > 0.05). Final fasting blood glucose was significantly lower in the FDTV group (139 +/- 19) compared with the trandolapril group (154 +/- 22; P < 0.001). No significant differences were observed between the two groups in mean baseline or final measurements of blood pressure, mean heart rate, or frequency of adverse events.. Our results suggest that FDTV is more effective than trandolapril in reducing proteinuria in normotensive, type 2 diabetic patients. This effect on proteinuria is not related with blood pressure reduction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Body Weight; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Heart Rate; Humans; Indoles; Infant, Newborn; Male; Middle Aged; Proteinuria; Reference Values; Verapamil

The multicenter double-blind, randomized Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) was designed to assess whether angiotensin-converting-enzyme inhibitors and non-dihydropyridine calcium-channel blockers, alone or in combination, prevent microalbuminuria in subjects with hypertension, type 2 diabetes mellitus, and normal urinary albumin excretion.. We studied 1204 subjects, who were randomly assigned to receive at least three years of treatment with trandolapril (at a dose of 2 mg per day) plus verapamil (sustained-release formulation, 180 mg per day), trandolapril alone (2 mg per day), verapamil alone (sustained-release formulation, 240 mg per day), or placebo. The target blood pressure was 120/80 mm Hg. The primary end point was the development of persistent microalbuminuria (overnight albumin excretion, > or =20 microg per minute at two consecutive visits).. The primary outcome was reached in 5.7 percent of the subjects receiving trandolapril plus verapamil, 6.0 percent of the subjects receiving trandolapril, 11.9 percent of the subjects receiving verapamil, and 10.0 percent of control subjects receiving placebo. The estimated acceleration factor (which quantifies the effect of one treatment relative to another in accelerating or slowing disease progression) adjusted for predefined baseline characteristics was 0.39 for the comparison between verapamil plus trandolapril and placebo (P=0.01), 0.47 for the comparison between trandolapril and placebo (P=0.01), and 0.83 for the comparison between verapamil and placebo (P=0.54). Trandolapril plus verapamil and trandolapril alone delayed the onset of microalbuminuria by factors of 2.6 and 2.1, respectively. Serious adverse events were similar in all treatment groups.. In subjects with type 2 diabetes and hypertension but with normoalbuminuria, the use of trandolapril plus verapamil and trandolapril alone decreased the incidence of microalbuminuria to a similar extent. The effect of verapamil alone was similar to that of placebo.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension; Indoles; Male; Middle Aged; Proportional Hazards Models; Treatment Outcome; Verapamil

There is evidence that diuretics and beta blockers impair glucose tolerance, whereas calcium channel blockers and angiotensin converting enzyme blockers lack this metabolic effect. We compared the effect of a combination therapy with a nondihydropyridine calcium channel blocker plus an angiotensin converting enzyme inhibitor and a beta blocker plus a diuretic on hemoglobin A(1c) (Hb A(1c)) in patients with type 2 diabetes and mild-to- moderate hypertension.. A total of 463 hypertensive outpatients with non-insulin treated type 2 diabetes on stable antidiabetic therapy for at least 3 months and with HbA(1c) between 6.5% and 10% were recruited. In a randomized, double blind trial patients were treated for 20 weeks with fixed combinations of verapamil sustained release (SR) plus trandolapril and of atenolol plus chlorthalidone following a 2-week placebo run-in period. The main outcome measures were HbA(1c), fasting plasma glucose, and fructosamine levels as well as systolic and diastolic blood pressure.. HbA(1c) remained stable at 7.9% after administration of verapamil SR plus trandolapril and increased from 7.8% to 8.6% with atenolol plus chlorthalidone; the differences between treatment groups were significant at 4, 12, and 20 weeks of treatment and at last visit (P <.0001). Mean blood pressure fell from 169/96 to 150/85 and from 168/95 to 145/83 mm Hg after administration of verapamil SR plus trandolapril and atenolol plus chlorthalidone, respectively. Both combinations were well tolerated.. HbA(1c) and other parameters of short- and long-term glycemic control were in a more favorable range after antihypertensive treatment with verapamil SR plus trandolapril as compared with atenolol plus chlorthalidone.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atenolol; Biomarkers; Blood Glucose; Blood Pressure; Chlorthalidone; Diabetes Mellitus, Type 2; Diastole; Diuretics; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Glycated Hemoglobin; Heart Rate; Humans; Hypertension; Indoles; Male; Middle Aged; Patient Compliance; Systole; Treatment Outcome; Vasodilator Agents; Verapamil

Microalbuminuria is an early marker of diabetic nephropathy and its prevention is considered key for the primary prevention of diabetic nephropathy. Angiotensin-converting enzyme (ACE) inhibitors and nondihydropyridine calcium channel blockers (CCBs) have specific renoprotective properties in diabetes, and preliminary evidence is available that they are more effective in combination than either of the two agents alone in limiting albuminuria either in micro- or macroalbuminuric type 2 diabetic patients. The BErgamo NEphrologic DIabetes Complications Trial (BENEDICT) is a prospective, randomized, double-blind parallel-group study primarily aimed at evaluating the possibility of preventing the progression to microalbuminuria (urinary albumin excretion [UAE] rate 20-200 microg/min, i.e., incipient nephropathy) in 1209 hypertensive, type 2 diabetic patients with a normal UAE rate (<20 microg/min). During phase A of the study, patients are randomized to a 3-year treatment with one of the following: (1) a nondihydropyridine CCB (verapamil SR 240 mg/day); (2) an ACE inhibitor (trandolapril 2 mg/day); (3) the combination of the above study drugs (verapamil SR 180 mg/day plus trandolapril 2 mg/day); or (4) placebo. Phase B of the study evaluates the progression to macroalbuminuria (UAE> or =200 microg/min) in patients who progress to microalbuminuria in phase A or are found with microalbuminuria during the screening phase; these patients are randomized to a 2-year treatment with either trandolapril (2 mg/day) alone or verapamil SR (180 mg/day) plus trandolapril (2 mg/day). BENEDICT final results are expected to be available by the end of 2003 for phase A and 2 years later for phase B. The BENEDICT study, in addition to exploring whether primary prevention of diabetic nephropathy is an achievable goal, will also offer an opportunity to study prospectively risk factors of nephropathy and other chronic complications of type 2 diabetes. Here we provide an overview of the protocol and summarize the main baseline demographic, biochemical, and clinical characteristics of randomized participants.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Drug Therapy, Combination; Endpoint Determination; Female; Glomerular Filtration Rate; Humans; Indoles; Male; Middle Aged; Research Design; Verapamil

The aim of this study was to assess the influence of 3 hypotensive drugs on the metabolic disorders: dyslipidemia, insulin resistance, hyperuricemia. There were 39 patients aged 20-55, with mild-to-moderate essential hypertension. The patients with other serious diseases or treated earlier with cholesterol or uric acid lowering drugs were excluded. Patients were divided into 3 groups, each was treated during 8 weeks with one drug: gr 1--trandolapril (T), gr 2--felodipine ER (F), gr 3--rilmenidine (R). Glucose and insulin in oral glucose tolerance test, I/G proportion, serum lipids and uric acid were tested before and after therapy. The therapy did not influence lipid parameters: LDL, HDL, triglyceride. In the T group there could be observed a significant reduction of total cholesterol value. Examined drugs did not induce changes in serum carbohydrate. The significant reduction of serum uric acid could be observed only after F therapy. Analysed drugs are very useful in therapy of hypertension with metabolic disorders.

Topics: Adult; Antihypertensive Agents; Diabetes Mellitus, Type 2; Felodipine; Female; Humans; Hyperlipidemias; Hypertension; Hyperuricemia; Indoles; Male; Metabolic Syndrome; Middle Aged; Oxazoles; Rilmenidine

Type II diabetic patients with albuminuria are at high risk for cardiovascular complications; the intense antihypertensive treatment required often involves using drug combinations. The aim of the present study was to compare the effect of two different, renin-angiotensin blocking combinations, on blood pressure (BP), albuminuria and glycemic control. Its design was prospective, randomised, controlled, of parallel branches, and performed in one Endocrinology Department, in Spain. 77 type-II diabetic patients, with stable albuminuria (30-1,000 mg/day) were included. After a pre-inclusion time of 2 weeks, patients were randomised to verapamil SR/trandolapril 180/2 (VT) or losartan/hydrochlorothiazide (LH) 20/12.5 mg/day. Duration of treatment was 1 year. The evaluated parameters were changes in blood pressure, urinary albumin excretion for 24 hours, glycated hemoglobin and plasmatic urea. Overall BP significantly decreased from 161.6 +/- 18.7/83.6 +/- 10.2 mmHg to 137.2 +/- 15.7/70.9 +/- 8.3 mmHg (p < 0.0005). Values, by treatment, were: For VT, 164.3 +/- 18.5/87.2 +/- 10.7 mmHg at baseline and 135.0 +/- 15.1/71.3 +/- 8.4 mmHg at conclusion. For LH, 158.8 +/- 17.4/80.1 +/- 8.4 mmHg at baseline and 139.3 +/- 16.1/70.5 +/- 8.2 mmHg at conclusion. Albuminuria significantly decreased from 308.2 +/- 544.7 mg/day to 198.0 +/- 285.3 mg/day. Both parameters showed no significant difference between treatments. Glycated hemoglobin decreased from 7.59 +/- 1.3% to 7.14 +/- 1.2% in the VT group, and from 7.96 +/- 1.29% to 7.84 +/- 1.62% in the LH group (ANOVA, p = 0.022). Changes adjusted from baseline values showed a trend to the difference between both treatments (p = 0.092). Plasmatic urea increased from 39.8 +/- 12.7 to 40.5 +/- 11.1 mg/dL in the TV group and from 43.4 +/- 12.0 mg/dL to 52.4 +/- 19.4 mg/dL in the LH group (ANOVA, p = 0.028). In conclusion, both treatments reduce blood pressure and albuminuria in a similar way in type II diabetic patients. The verapamil/trandolapril combination contributes to a better carbohydrate metabolism than losartan/hydroclorothiazide.

Topics: Aged; Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Blood Pressure; Carbohydrate Metabolism; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diuretics; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hydrochlorothiazide; Hypertension; Indoles; Lipids; Losartan; Male; Middle Aged; Prospective Studies; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Sodium Chloride Symporter Inhibitors; Treatment Outcome; Vasodilator Agents; Verapamil

The objective of this study was to compare, at equal blood pressure (BP) reduction, the effect of two different combinations on metabolic control and albuminuria in type 2 diabetic hypertensive patients with albuminuria. This was a prospective, randomised, double-blind, parallel, controlled trial carried out in 11 Spanish hospitals. A total of 103 type 2 diabetic patients with stable albuminuria and BP not controlled on monotherapy were randomised of which 93 finished the study. After a 4-week single-blind placebo period, patients were randomised to verapamil SR/trandolapril 180/2 mg (VT) or to enalapril/hydroclorothiazide 20/12.5 mg (EH). Treatment duration was 6 months. The main outcome measures were changes in BP, 24-h albuminuria, blood glucose and glycated haemoglobin. Overall BP was significantly reduced from 157.3 +/- 12.0/98.3 +/- 6.4 mm Hg to 140.5 +/- 14.5/86.1 +/- 8.2 mm Hg (P < 0.001) and albuminuria significantly decreased from 508.6 +/- 693.8 mg/24 h to 253.4 +/- 517.2 mg/24 h (P < 0.001), both without significant differences between treatments. Glycated haemoglobin was not modified on VT: baseline, 5.91 +/- 1.43%; end of treatment, 5.94 +/- 1.62%, but increased on EH: baseline, 5.96 +/- 1.25%; final, 6.41 +/- 1.51%, (ANOVA interaction P = 0.040). At the end of the study, a blood glucose <126 mg/dL was attained in 72.7% of the VT group-improving in 29.5% and worsening in 6.8% of patients (P = 0.021)-and in 50% of the EH group, 13.6% of patients improved and 11.4% worsened (P = 1.000). There were no changes in body weight, serum creatinine, uric acid, potassium, cholesterol, tryglicerides and serum albumin. In hypertensive type 2 diabetic patients not controlled on monotherapy, both treatments similarly reduced albuminuria. The combination verapamil/ trandolapril seems to allow a better metabolic control than enalapril/hydroclorothiazide.

Topics: Aged; Albuminuria; Analysis of Variance; Antihypertensive Agents; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Indoles; Male; Middle Aged; Multivariate Analysis; Probability; Prospective Studies; Spain; Treatment Outcome; Verapamil

The aims of this study were to examine the effects of trandolapril, a long acting angiotensin converting enzyme (ACE) inhibitor with high tissue uptake, on insulin sensitivity and lipid concentrations in hypertensive patients with Type 2 diabetes mellitus.. Insulin sensitivity was assessed after an acute dose (day 3) and 19 days continuous treatment (days 3-21) using the isoglycaemic, hyperinsulinaemic glucose clamp with D[3-3H] labelled glucose, a variable D[3-3H] priming dose and a 'hot' glucose infusion. Rates of glucose appearance (Ra) and glucose disappearance (Rd) were isotopically determined during the basal and insulin stimulated periods of the clamp. Twenty-four (5 female) hypertensive (blood pressure >75th centile for age and sex) patients with Type 2 diabetes mellitus were studied. Patients were randomized, in a double-blind manner, to either trandolapril 4 mg daily (T) or placebo (P).. Baseline (day 1) systolic (mean +/- SD; P 164+/-14 and T 168+/-13 mm Hg) and diastolic (P 93+/-6, and T 98+/-10 mm Hg) blood pressures were comparable. On days 3 and 21, significant reductions were observed in both groups (P<0.001). In the trandolapril-treated group, serum trandolapril concentrations were >200 pg/ml on days 3 and 21, in all patients apart from one subject at a single visit, while trandolapril was undetectable in the placebo group. Body mass index (BMI) was greater in T compared with P (32.2+/-5.4 v. 28.3+/-4.6, P = 0.07). After correcting for BMI, basal hepatic glucose output (HGO) P 2.6 (95% CI 2.23-3.13) and T 1.91 (1.33-2.51) mg x kg(-1) x min(-1) and clamped HGO P 0.32 (-0.44-1.09) and T 0.87 (0.40-1.34) mg x kg(-1) x min(-1) were similar in both groups. The insulin sensitivity index was comparable in both groups on all days. Total cholesterol concentrations were similar in both groups throughout the study. Triglyceride concentrations were significantly lower in group P 1.38 (1.07-1.68); T 2.14 (1.70-2.58) mmol/l, P<0.01), no significant treatment effect being observed.. An acute dose and 19 days' continuous treatment with trandolapril resulted in no change in insulin sensitivity or plasma lipid profiles in patients with Type 2 diabetes mellitus and hypertension. These data support the metabolic neutrality of trandolapril in patients with Type 2 diabetes mellitus and hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Blood Pressure; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucose Clamp Technique; Humans; Hypertension; Indoles; Insulin; Lipids; Male; Middle Aged; Placebos

It has been demonstrated that antihypertensive treatment of hypertensive diabetic patients is quite effective in preventing macrovascular and microvascular complications and improving prognosis. Nevertheless, the target blood pressure level of antihypertensive treatment in hypertensive diabetic patients with microalbuminuria (i.e., with early diabetic nephropathy) remains to be established. In this study, we evaluated the effect of intensive blood pressure control (diastolic blood pressure <80 mmHg) on urinary albumin excretion in hypertensive, type II diabetic patients with microalbuminuria. We examined the effects of a combination therapy using an angiotensin-converting enzyme (ACE) inhibitor plus a long-acting calcium channel blocker (amlodipine), and compared them with the effect of an ACE inhibitor alone. Thirty hypertensive, type II diabetic patients with microalbuminuria were treated with either an ACE inhibitor alone (group I, n=17) or an ACE inhibitor plus amlodipine (group II, n=13) for 32 weeks. With treatment, blood pressures in both groups were significantly reduced, and diastolic blood pressure was lowered to a much greater extent in group II (76 +/- 2 mmHg) than in group I (83 +/- 2 mmHg, p < 0.05). Although the urinary albumin excretion rate was decreased in both groups, the decrease attained statistical significance only in group II (from 141 +/- 25 mg/day to 69 +/- 18 mg/day, p < 0.05); the extent of reduction in microalbuminuria during antihypertensive treatment was significantly greater in group II (50 +/- 10%) than in group I (14 +/- 13%, p < 0.05). In conclusion, this study showed that in hypertensive microalbuminuric type II diabetic patients, the combination of an ACE inhibitor plus amlodipine resulted in a more pronounced decreased in blood pressure (diastolic blood pressure <80 mmHg) and a greater reduction in urinary albumin excretion than did use of an ACE inhibitor alone. This combination strategy should thus be a more effective tool for obtaining optimal blood pressure control in patients with diabetic nephropathy.

Topics: Aged; Albuminuria; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension, Renal; Imidazoles; Imidazolidines; Indoles; Male; Middle Aged

Angiotensin-converting enzyme (ACE) inhibitors are increasingly used as first-line therapy for hypertension in type 2 diabetes mellitus and are widely believed to improve insulin sensitivity (M). However, the evidence for the latter effect does not stand close scrutiny. We have assessed the effect of the ACE inhibitor trandolapril on M in 16 patients (mean +/- SD age, 58 +/- 10.6 yr) with mild-to-moderate essential hypertension (initial blood pressure, 173 +/- 14.5/93 +/- 8.0 mm Hg), obesity (body mass index, 30 +/- 5.4 kg/m2), and impaired glucose intolerance (n = 4) or type 2 diabetes (n = 12) in a double-blind, placebo-controlled crossover design. All patients underwent three 3-h euglycemic hyperinsulinemic clamp studies (soluble insulin, 1.5 mU/kg x min) after a 2-week placebo run-in and at the end of two 4-week periods of treatment with 2 mg trandolapril or placebo (2-week washout). M (mean +/- SD) did not change with trandolapril: placebo (run-in), 5.2 +/- 1.98 mg/kg x min; placebo, 5.3 +/- 1.70 mg/kg x min; trandolapril, 5.1 +/- 1.65 mg/kg x min; P = 0.58; 95% confidence intervals, -0.74, 0.43 (trandolapril vs. placebo); 95% power to exclude an 8% increase in M. In conclusion, trandolapril had no clinically relevant effect on M in patients with hypertension and type 2 diabetes. Previous reports of improved M during ACE inhibitor treatment may be attributable to suboptimal study design and/or use of surrogate measures of M.

Topics: Adult; Aged; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Female; Glucose; Glucose Clamp Technique; Heart Rate; Humans; Hyperinsulinism; Hypertension; Indoles; Insulin; Male; Middle Aged; Peptidyl-Dipeptidase A; Placebos; Renin

To compare the anti-hypertensive effect of combination therapy versus a single drug regimen schedule (dose-titration or switching to a different drug class) in type 2 diabetic hypertensive patients with inadequate blood pressure (BP) control on monotherapy.. Prospective, randomized, open-fashion, parallel study of two therapeutic strategies during an 8-week period.. Primary care centers in Spain.. A total of 898 men and women with type 2 diabetes mellitus and hypertension, receiving antihypertensive treatment with one single drug and whose BP was > 140 and/or 90 mmHg.. Patients were randomized to a fixed combination therapy (verapamil 180 mg plus trandolapril 2 mg; Knoll AG, Ludwigshafen, Germany) or continued on a single drug regimen, either increasing the dose of the current drug or switching to a different drug class.. Absolute BP reduction in the two groups of treatment, and the percentage of normalized patients (< 140/90 mmHg) in each group.. The diastolic BP (DBP) decrease (5.6 mmHg) was significantly greater in patients treated with combination therapy, compared to patients on monotherapy (2.9 mmHg). The decrease in systolic BP (SBP) was not significantly different (11.1 versus 10.0 mmHg). In addition, a significantly higher number of patients treated with combination therapy (82% versus 74%) reached diastolic BP normalization (< 90 mmHg).. In type 2 hypertensive patients with uncontrolled BP despite anti-hypertensive monotherapy, the change to combination therapy was more effective in attaining DBP control than any monotherapy schedule (either increasing the dose or switching to another different drug class).

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Attitude to Health; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diastole; Drug Therapy, Combination; Female; Humans; Hypertension; Indoles; Male; Middle Aged; Prospective Studies; Verapamil

Abnormalities of renal autoregulation with glomerular hyperfiltration and raised intraglomerular pressure have been suggested as important factors in the initiation and development of diabetic nephropathy. Angiotensin converting enzyme (ACE) inhibition appears to have a specific reno-protective role in diabetic nephropathy, possibly by reducing intraglomerular pressure. The acute effects of ACE inhibition on renal haemodynamics in normotensive, non-insulin-dependent diabetes mellitus (NIDDM) have not been previously reported. We measured simultaneous glomerular filtration rate (GFR) and renal plasma flow (RPF) in 29 (4 female) subjects, mean age 52 years (range 27-70), using 51Cr EDTA and 125I Hippuran. Clearances were corrected to 1.73 m(-2). All patients were normotensive (blood pressure < 75th centile for age and sex), newly diagnosed (< 30 days), taking no antihypertensive or hypoglycaemic medication. Subjects were randomly allocated (double blind) to receive the ACE inhibitor trandolapril 4mg day(-1) (H) (hypotensive dose), trandolapril 0.5 mg day(-1)(L) (non-hypotensive dose) or placebo (P) for 10 days after which renal haemodynamics were remeasured. For all subjects baseline GFR, RPF and filtration fraction (FF) were 97+/-21 ml min(-1) mean+/-SD, 439+/-120 ml min(-1) and 22.3+/-2.9 % respectively. Glomerular hyperfiltration (GFR> 120 ml min[-1]) was only demonstrated in 3 subjects (10.3 %). In group H mean arterial pressure (103+/-8 vs 93+/-9 mmHg, p < 0.001) and FF (23.8+/-2.3 vs 20.0+/-4.0%, p = 0.03) fell while RPF increased (376+/-111 vs 426+/-60 ml min(-1), p = 0.02), there was no significant change in GFR. No significant change in mean arterial pressure, GFR, RPF or FF occurred in groups P and L. These studies suggest that in newly diagnosed normotensive NIDDM subjects normal renal autoregulation occurs and glomerular hyperfiltration is uncommon.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glomerular Filtration Rate; Homeostasis; Humans; Indoles; Kidney; Male; Middle Aged; Renal Plasma Flow

Microalbuminuria is an early marker of diabetic nephropathy, and its prevention can be considered to be the primary prevention of diabetic nephropathy. Angiotensin converting enzyme inhibitors and non-dihydropyridinic calcium antagonists have specific renoprotective properties in diabetes, and preliminary evidence is available that their combination can delay the onset and limit the progression of nephropathy in experimental diabetes more effectively than either of the two agents alone.. The Bergamo Nephrologic Diabetes Complication Trial is a prospective, randomized, double-blind, parallel-group study aimed at evaluating the possibility of preventing the onset of nephropathy in 2400 hypertensive non-insulin-dependent diabetes mellitus patients who have a normal albumin excretion rate. During phase A of the study, patients will be randomized to one of the following treatments for 3 years: a non-dihydropyridinic calcium antagonist (slow-release verapamil 240 mg/day), an angiotensin converting enzyme inhibitor (trandolapril 2 mg/day), the combination of these drugs (verapamil 180 mg/day plus trandolapril 2 mg/day) and placebo. Other antihypertensive agents will be allowed in order to achieve and maintain systolic and diastolic blood pressures consistently below 140 and 90 mmHg, respectively, in all patients. The primary efficacy variable of phase A will be progression to microalbuminuria. In phase B progression to macro-albuminuria will be evaluated in patients who became microalbuminuric in phase A. These patients will be randomized to 2 years of treatment with trandolapril (2 mg/day) alone or combined with verapamil (180 mg/day).

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Drug Combinations; Humans; Indoles; Kidney Failure, Chronic; Prospective Studies; Verapamil

The degree of proteinuria in patients with diabetes correlates strongly with both an increase in progression of nephropathy as well as cardiovascular events. Moreover, post hoc analyses of recent clinical trials support the concept that reductions of blood pressure and proteinuria correlate with a slowed progression of nephropathy. Both angiotensin converting enzyme (ACE) inhibitors and the nondihydropyridine calcium antagonists, (non-DHPCAs) reduce both arterial pressure and proteinuria in those with diabetic nephropathy.. The present randomized, open label, parallel group designed study tests the hypothesis that, at similar levels of blood pressure, the combination of an ACE inhibitor, trandolapril (T) with the non-DHPCA, verapamil (V) produces a greater reduction in proteinuria over either agent alone at one year. Thirty-seven participants, mean age 59.6 +/- 5.8 years, with nephropathy (baseline creatinine 1.4 +/- 0.3 mg/dl and proteinuria of 1342 +/- 284 mg/dl) secondary to type 2 diabetes completed the study. Doses of drug were titrated in each group over eight weeks to achieve a goal blood pressure of < 140/90 mm Hg. All participants were counseled to ingest a sodium diet of < 120 mEq/day.. Proteinuria reduction from baseline was significantly greater in the T+V group compared to either T alone (-33 +/- 8%, T vs. -62 +/- 10%, T+V; P < 0.001) or V alone (-27 +/- 8%, V vs. -62 +/- 10%, T+V; P < 0.001). No significant differences in either glomerular filtration rate, arterial pressure, fasting blood glucose or urinary sodium excretion were noted at one year. The mean daily dose of the individual components of T+V (2.9 +/- 0.8 mg, T/219 +/- 21.1 mg V) was significantly lower than the dose of either T alone 5.5 +/- 1.1 mg/day (P < 0.01) or V alone 314.8 +/- 46.3 mg, given in two divided doses (P < 0.01).. These data support the concept that the combination of an ACE inhibitor with a non-DHPCA reduce proteinuria to a greater extent than either agent alone. This added antiproteinuric effect occurs at lower doses of each drug and is independent of further reductions in arterial pressure. These findings could have ramifications for slowing renal disease progression in patients with nephropathy from type 2 diabetes.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Synergism; Drug Therapy, Combination; Female; Humans; Indoles; Male; Middle Aged; Proteinuria; Verapamil

To investigate the metabolic, antihypertensive and albuminuria-modifying effects of a heart rate-modulating calcium antagonist-angiotensin converting enzyme inhibitor combination compared with those of a beta-blocker-low-dose diuretic combination in non-insulin-dependent diabetic hypertensives.. A prospective randomized double-blind study.. Twenty-four diabetics with diastolic blood pressure 90-115 mmHg without azotemia (plasma creatinine level < 150 mumol/l) were evaluated after 4 weeks receiving placebo and 12 weeks receiving treatment either with combined slow-release verapamil (retard formulation) and trandolapril (mean maintenance doses, 180 and 1.6 mg daily) or with atenolol and chlortalidone (71 and 18 mg daily). Insulin sensitivity (by the minimal model method of Bergman), additional metabolic variables, clinic blood pressure, ambulatory blood pressure profile and renal indices were assessed at the end of the placebo and active treatment phases.. Compared with placebo, the two therapies produced similar decreases in mean supine clinic blood pressure [10 +/- 3 versus 11 +/- 3% (means +/- SEM)], upright clinic blood pressure (10 +/- 4 versus 11 +/- 4%) and ambulatory daytime blood pressure (9 +/- 2 versus 12 +/- 3%). However, although the verapamil-trandolapril combination was found to be metabolically neutral, the atenolol-chlortalidone combination aggravated insulin resistance [insulin sensitivity index, from (0.8 +/- 0.2) to (0.3 +/- 0.1) x 10(-4)/min per U per ml], increased the serum triglycerides level and decreased the high-density lipoprotein cholesterol and plasma potassium levels. Although both therapies tended to reduce 24 h albuminuria, this was significant for the verapamil-trandolapril treatment only.. Because the effect of any antihypertensive drug, including diuretics and beta-blockers, on cardiovascular morbidity and on mortality in non-insulin-dependent diabetic patients is not known, rational treatment selection can presently be based only on surrogate end-points. Therefore, the triad of metabolic neutrality with antihypertensive and antiproteinuric efficacy supports combined verapamil-trandolapril as a potentially valuable therapy for hypertension accompanying diabetes mellitus.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Antihypertensive Agents; Carbohydrate Metabolism; Chlorthalidone; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension; Indoles; Male; Middle Aged; Prospective Studies; Verapamil

The aim of this study was to evaluate the action of trandolapril on blood glucose control and microalbuminuria in mild to moderate hypertensive in patients with non-insulin-dependent diabetes. Sixty-seven patients, aged between 33 and 79, were enrolled. After a two week placebo run-in period, treatment with trandolapril as monotherapy was given for 3 months. The dose of trandolapril was adjusted between 1 and 4 mg/day according to antihypertensive response. Patients were assessed clinically and by laboratory investigations each month. Two patients were excluded from efficacy analysis because of major protocol deviations. Mean DBP fell, under the influence of treatment, from 101 +/- 5 mmHg to 82 +/- 7 mmHg (p < 0.0001) and mean SBP from 171 +/- 9 mmHg tp 147 +/- 11 mmHG (p < 0.0001). At three months, 54 patients (84%) had a DBP < or = 90 mmHg. Microalbuminuria decreased significantly (p = 0.03) during treatment. Microalbuminuria returned to normal in 11 of the 13 patients in whom the baseline value was above 21 micrograms/min and increased to above normal in 2 of the 26 patients who had a normal baseline value. Blood glycosylated hemoglobin, fructosamine, glucose and creatinine, and creatinine clearance remained stable. Plasma potassium rose slightly in 7 patients. Six adverse events were reported (4 coughs, 1 peripheral edema, 1 plantar mal perforans). One patient died from pulmonary embolism. In conclusion, trandolapril is an effective antihypertensive agent in hypertensive diabetics. Trandolapril causes a significant decrease in microalbuminuria and does not interfere with blood glucose control in these patients.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Hypertension; Indoles; Male; Middle Aged

The International Verapamil SR-Trandolapril Study (INVEST), a randomized trial of 22,576 predominantly elderly patients with an average 2.7-year follow-up, compared a calcium antagonist-led strategy (verapamil SR plus trandolapril) with a beta-blocker-led strategy (atenolol plus hydrochlorothiazide) for hypertension treatment and prevention of cardiovascular outcomes in coronary artery disease patients. Patients received individualized dose and drug titration following a flexible, multi-drug, guideline-based treatment algorithm, with the objective of achieving optimal blood pressure (BP) control individualized for comorbidities (e.g., diabetes). The primary outcome (PO) was first occurrence of death (all-cause), nonfatal myocardial infarction or nonfatal stroke. The strategies resulted in significant and very similar BP reduction, with approximately 70% of patients in both strategies achieving BP control (<140/90 mmHg). Increasing number of office visits with BP in control was associated with reduced risk of the PO. Overall, there was no difference in the PO comparing the strategies; however, new-onset diabetes occurred more frequently in those assigned the atenolol strategy. This report summarizes findings from INVEST and puts them in perspective with our current state of knowledge derived from other large hypertension treatment trials. INVEST findings support that BP reduction is important for prevention of adverse cardiovascular morbidity and mortality, and selection of antihypertensive agents should be based on patient comorbidities and other risk factors (e.g., risk for diabetes) and not necessarily that any one drug be given to all.

Topics: Adrenergic beta-Antagonists; Aged; Antihypertensive Agents; Atenolol; Calcium Channel Blockers; Coronary Artery Disease; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diuretics; Drug Combinations; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Indoles; Male; Randomized Controlled Trials as Topic; Verapamil

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Clinical Trials as Topic; Data Interpretation, Statistical; Diabetes Mellitus, Type 2; Drug Combinations; Humans; Hypertension; Indoles; Verapamil

Topics: Albumins; Albuminuria; Antihypertensive Agents; Diabetes Mellitus, Type 2; Humans; Hypertension; Indoles; Renin-Angiotensin System

Topics: Adrenergic beta-Antagonists; Adult; Aspirin; Blood Glucose; Calcium Channel Blockers; Clinical Trials as Topic; Coronary Disease; Diabetes Complications; Diabetes Mellitus, Type 2; Diuretics; Female; Glycated Hemoglobin; Heart Failure; Humans; Hypertension; Hypolipidemic Agents; Indoles; Male; Platelet Aggregation Inhibitors; Prognosis; Risk Factors; Sex Factors; Verapamil

The pathomechanisms that cause renal damage in diabetes have not been completely clarified. Treatment with angiotensin-converting enzyme inhibitors (ACE-i) is highly effective but fails to completely prevent end-stage renal disease. The effects of ET(A)-receptor blockers (ET(A)-RB) on renal damage are controversial and have rarely been investigated in type 2 diabetes. We compared the influence of the selective ET(A)-RB LU135252 and the ACE-i Trandolapril on renal structure in the SHR/N-cp rat model of type 2 diabetes. Three-month-old male SHR/N-cp rats were left untreated or received daily either Trandolapril or LU135252. The experiment was terminated after 6 months. The glomerulosclerosis index; tubulointerstitial damage index; and glomerular geometry, glomerular cell number, and capillary density were investigated. Proliferating cell nuclear antigen and desmin expression of podocytes, renal mRNA expression of endothelin (ET-1) and transforming growth factor-beta, blood pressure, and urine albumin excretion were measured. The glomerulosclerosis index was significantly higher in untreated diabetic animals than in the groups that were treated with ACE-i and ET(A)-RB. There were analogous changes in tubulointerstitial damage index. Treatment with either substance comparably lowered urinary albumin excretion in diabetic SHR/N-cp. Podocyte and endothelial cell numbers per glomerulus decreased in untreated diabetic animals; this was prevented by the ACE-i but not by the ET(A)-RB. Glomerular capillary length density was lower in SHR/N-cp, and this was normalized by ACE-i only. Increased expression of desmin and proliferating cell nuclear antigen expression of podocytes in the SHR/N-cp was abrogated by ACE-i but not by ET(A)-RB. Treatment with ACE-i or ET(A)-receptor antagonist resulted in less structural and functional alterations, but the ET(A)-RB was inferior to the ACE-i. This is particularly the case for podocyte changes pointing to angiotensin II-dependent pathomechanisms.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Immunohistochemistry; Indoles; Kidney; Male; Phenylpropionates; Proliferating Cell Nuclear Antigen; Pyrimidines; Rats; RNA, Messenger; Transforming Growth Factor beta

Topics: Antihypertensive Agents; Diabetes Mellitus, Type 2; Drug Combinations; Humans; Hypertension; Indoles; Verapamil

Topics: Antihypertensive Agents; Coronary Disease; Diabetes Mellitus, Type 2; Drug Combinations; Humans; Hypertension, Renal; Indoles; Verapamil

Detection of podocytes in the urinary sediments of children with glomerulonephritis has been shown to indicate severe injury to the podocytes. The aim of the present study was to determine whether podocytes are present in the urine sediments of adult patients with diabetes with and without nephropathy and whether trandolapril is effective for podocyte injury.. Fifty diabetic patients (10 with normoalbuminuria, 15 with microalbuminuria, 15 with macroalbuminuria and 10 with chronic renal failure) and 10 healthy controls were studied. Urinary podocytes were examined by immunofluorescence using monoclonal antibodies against podocalyxin, which is present on the surface of podocytes. In addition, we studied plasma metalloproteinase (MMP)-9 concentrations in all patients.. Urinary podocytes were absent in healthy controls, diabetic patients with normoalbuminuria and diabetic patients with chronic renal failure. Podocytes were detected in the urine of eight diabetic patients with microalbuminuria (53%) and of 12 patients with macroalbuminuria (80%). The number of podocytes in the urine of patients with macroalbuminuria was significantly greater than in patients with microalbuminuria (P:<0.01). However, there was no relationship between urinary albumin excretion and urinary podocytes. In addition, plasma MMP-9 concentrations were significantly correlated with the number of urinary podocytes (P:<0.01). Twelve diabetic patients with macroalbuminuria and eight patients with microalbuminuria who had urinary podocytes were treated with the angiotensin-converting enzyme inhibitor trandolapril. Urinary albumin excretion, the number of podocytes and plasma MMP-9 concentrations were reduced by the trandolapril treatment.. Podocytes in the urine may be a useful marker of disease activity in diabetic nephropathy. Trandolapril may be effective for podocyte injury.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Monoclonal; Basement Membrane; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Fluorescent Antibody Technique; Humans; Indoles; Kidney Failure, Chronic; Male; Matrix Metalloproteinase 9; Middle Aged; Osmolar Concentration; Reference Values; Sialoglycoproteins; Urine

The inhibitors of the angiotensin-converting-enzyme (ACEI) are considered as the best pharmacological class for the treatment of patients with diabetic nephropathy. Independently of lowering the arterial blood pressure they reduce the proteinuria and slow the evolution of the renal failure. Calcium-channels blockers not belonging to the dehydropyridine-type (verapamil-diltiazem) possess some of these features, too, contrarily to the rest of calcium-antagonists (nifedipine-like). Two clinical studies dealing with type-II diabetic-patients whose nephropathy was complicated by a nephrotic syndrome and a rapid progressive renal failure showed that the combination of verapamil with an ACEI, further dietetic measures (protein restriction, saltless diet), permitted a significant decrement of the proteinuria as well as a stabilisation of the kidney function. This effect could not be shown under treatment with only ACEI. Thus the proteinuria-inhibiting and kidney-protecting effects of the combination of theses two substances-groups should be known when the physician is confronted at this clinical situation that determines the prognostic of the kidney function in such a dramatic way and short laps of time.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Enalapril; Humans; Indoles; Kidney Function Tests; Male; Middle Aged; Nephrotic Syndrome; Verapamil

The aim of the present study was to examine the relationships between ambulatory blood pressure (ABPM) and urinary albumin excretion (UAE) in diabetic (non-insulin dependent [NIDDM] and insulin-dependent [IDDM]) hypertensives at baseline and after treatment by an angiotensin converting enzyme (ACE) inhibitor. After a 3-week placebo period, patients were treated for 16 weeks with trandolapril, 2 to 4 mg/day. The UAE and blood pressure (mercury sphygmomanometer and 24-h ABPM) were measured at baseline and repeated on trandolapril. Predictive factors of abnormal UAE (24-h UAE > or = 30 mg) were determined using univariate and multivariate analysis (logistic regression). Predictors of UAE decrease were also searched. One hundred seventy-one patients entered the analysis. Baseline office BP was 164+/-14 / 97+/-6 mm Hg and 24-h BP was 142+/-17 / 83+/-10 mm Hg. Seventy-four patients (43%) had UAE > or = 30 mg. Independent risk factors for abnormal UAE were nighttime diastolic BP (odds ratio [OR] = 4.1, confidence interval [CI] = 2.0 to 8.6, P = .0001), diabetes duration (OR = 2.4, CI = 1.1 to 5.0, P = .025), and presence of retinopathy (OR = 3.2, CI = 1.0 to 10.0, P = .047). Conversely, office BP level was not significantly related to UAE. On treatment, office BP levels decreased to 143+/-13 / 82+/-8 mm Hg (P < .0001) and 24-h BP levels to 134+/-17 / 78+/-9 mm Hg (P < .0001). In the abnormal UAE group, UAE significantly decreased from 76 to 50 mg/day (P = .006). After treatment, independent predictive factors of abnormal UAE were: on-drug fasting plasma glucose (OR = 3.5, CI = 1.7 to 7.4, P = .0009) and on-drug nighttime diastolic BP (OR = 3.5, CI = 1.7 to 7.4, P = .001). The only predictor of UAE decrease was a 24-h systolic BP decrease (OR = 2.3, CI = 1.3 to 4.3, P = .007). We conclude that in diabetic hypertensives with abnormal UAE, trandolapril exhibited a sustained 24-h antihypertensive effect and provided a consistent reduction of microalbuminuria. This study confirmed the superiority of ABPM over clinical BP to predict target organ damage.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypertension; Indoles

Topics: Antihypertensive Agents; Calcium Channel Blockers; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diet, Diabetic; Female; Humans; Hypertension; Indoles; Middle Aged; Obesity; Verapamil