Pulse pressure and mortality in hypertensive type 2 diabetic patients. A cohort study

HYPOTHESIS: Hypertension is a well-known cardiovascular risk factor in type 2 diabetic patients. It has been suggested that pulse pressure (PP) could be an independent cardiovascular risk factor in the general population, particularly in the elderly. An association between office PP and cardiovascular mortality has been previously reported in diabetic patients, while the relationship between ambulatory measurements of PP and all-cause mortality has not been assessed so far. AIM: To assess the relationship between ambulatory PP and all-cause mortality in diabetic patients with hypertension. METHODS: A cohort study was performed on a consecutive series of 435 diabetic outpatients. All patients underwent office blood pressure measurement (OBP) and 24-h ambulatory blood pressure monitoring (ABPM). Mortality was assessed through queries at the Registry Offices of the city of residence for each patient. Mean follow-up was 3.8 +/- 1.2 years. RESULTS: Fifty-eight patients (13.3%) died during the follow-up. Mortality was significantly (p < 0.05) higher in patients in the highest quartile and lower in patients in the lowest quartile, when compared to the intermediate quartiles, both for office and ABPM-PP. In a multivariate analysis, after adjustment for numerous variables (including current hypoglycaemic, antihypertensive statin and aspirin treatment), mortality was increased by 3.1 and 5.3% for each incremental mmHg of office PP (p < 0.05) and ABPM-PP (p < 0.001) respectively. CONCLUSIONS: High PP, assessed through office measurement or ABPM, was associated with increased mortality in hypertensive type 2 diabetic patients. In our sample, PP assessed with ABPM is a better predictor of mortality than office PP.     

Effect of chronic ACE inhibition on glucose tolerance and insulin sensitivity in hypertensive type 2 diabetic patients.

The question, of whether long-term treatment of essential hypertension with angiotensin-converting enzyme (ACE) inhibitors is capable of modifying glucose tolerance or insulin sensitivity in Type 2 (non-insulin dependent) diabetes, is still unsolved. We studied 14 moderately overweight Type 2 diabetic patients with essential hypertension in stable metabolic control after a run-in period and again after 3 months of antihypertensive treatment with the ACE inhibitor, captopril. Glucose tolerance was tested with a 75-g oral glucose load and insulin sensitivity was measured by the insulin suppression test, while dietary and drug treatment of the diabetes remained constant. In the whole group, mean blood pressure (MBP) fell progressively over 3 months from a baseline value of 123 +/- 3 mmHg to a final value of 115 +/- 2 mmHg (p < 0.005); in six patients, the change in MBP was < 5 mmHg (non-responders), thus giving a clinical response rate of approximately 60%. After treatment, fasting plasma glucose, insulin, free fatty acid (FFA), potassium, and glycated haemoglobin concentrations were unchanged from baseline. During the oral glucose tolerance test, the incremental glucose area-under-curve was 0.75 +/- 0.05 mol 120 min l-1 before and 0.76 +/- 0.06 mol 120 min l-1 after treatment (p = ns). Endogenous insulin response and suppression of plasma FFA levels were superimposable on the two occasions. During the insulin suppression test, steady-state plasma glucose levels were 14.4 +/- 1.3 vs 14.2 +/- 1.1 mmol l-1 before and after chronic ACE inhibition, respectively, at comparable hyperinsulinaemic plateaux (291 +/- 21 vs 287 +/- 14 pmol l-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of moxonidine vs. metoprolol on blood pressure and metabolic control in hypertensive subjects with type 2 diabetes.

Subjects with type 2 diabetes experience an increased cardiovascular morbidity and mortality, related to a high prevalence of hypertension, dyslipidemia, and obesity. Antihypertensive treatment with beta-adrenergic receptor blockers may have deleterious metabolic consequences, including worsening of lipid profiles and insulin sensitivity. The centrally-acting sympatholytic agent moxonidine may improve these variables. In this randomised, double-blind multicenter study, the effects of two widely used antihypertensive agents--moxonidine (MOX) and the beta (1)-selective adrenergic receptor blocker metoprolol (MET)--on blood pressure and metabolic control were directly compared in hypertensive subjects with type 2 diabetes. Patients received either MOX (0.2 - 0.6 mg/d) or MET (50 - 150 mg/d) for 12 weeks, intending comparable blood pressure control. In total 200 patients were randomized. Here we report results from the per protocol population consisting of 127 patients (MOX 66, MET 61) but similar results were found in the ITT population. Reductions in systolic (SBP) and diastolic (DBP) blood pressures after 12 weeks were similar in both groups: In the MOX group, mean SBP (+/- SD) decreased from 154 +/- 12 to 142 +/- 17 mmHg and mean DBP from 91 +/- 9 to 83 +/- 9 mmHg. In the MET group, mean SBP decreased from 152 +/- 13 to 140 +/- 15 mmHg, and mean DBP from 90 +/- 8 to 84 +/- 10 mmHg. Mean HbA (1C) values did not differ between groups after 12 weeks (MOX 8.1 +/- 1.4 Hb%, MET 8.1 +/- 1.5 Hb%, intention-to-treat population). However, fasting plasma glucose decreased in the MOX group (median change - 5 mg/dl), but increased in the MET group (+ 16 mg/dl; p < 0.05). Median changes in the insulin resistance index (HOMA (IR)) were + 0.56 micro IU x mol/L (2) in the MET group, and - 0.27 micro IU x mol/L (2) in the MOX group. Correspondingly, fasting triglycerides increased with a median change of + 29.5 mg/dL in the MET group, but decreased in the MOX group (- 27.5 mg/dl; p < 0.05). These results indicate that MOX, unlike MET, may elicit beneficial adaptations in glucose and lipid metabolism in hypertensive subjects with type 2 diabetes, although mean HbA (1c) values did not differ. In long-term treatment in this high-risk population, MOX thus may decrease global vascular disease risk to a greater extent than MET.     

Renoprotective effect of diltiazem in hypertensive type 2 diabetic patients with persistent microalbuminuria despite ACE inhibitor treatment

The aim of the study was to evaluate the effects of the non-dihydropyridine calcium antagonist (NDCA) diltiazem on the development of urinary albumin excretion (UAE) in type 2 hypertensive diabetic patients with persistent microalbuminuria despite ACE inhibitor treatment. Thirty-six type 2 diabetic hypertensive patients with microalbuminuria persisting after at least 1 year of treatment with ACE inhibitors were randomized to receive captopril (n=22) or combined therapy with captopril and 120 mg diltiazem (n=14) for 2 years. Captopril dose was individualized according to blood pressure. Changes in UAE, blood pressure, and metabolic control were monitored to analyze the influence of the addition of diltiazem on progression of diabetic nephropathy. In patients treated with captopril and diltiazem, absolute UAE did not change during the study (baseline: 101 mg/24 h, range 39-298; 2 years after randomization: 74 mg/24 h, range 12-665). In contrast, UAE increased in patients treated with captopril monotherapy (baseline: 118 mg/24 h, range 32-282; 2 years after randomization: 164 mg/24 h, range 15-1161, p<0.05). In addition, fewer patients in the captopril/diltiazem group progressed to macroalbuminuria (eight patients in captopril group and one in captopril/diltiazem group, p<0.05). The beneficial effects of the addition of diltiazem were independent of blood pressure and metabolic control. We suggest that the combination of ACE inhibitors and NDCA should be considered in type 2 microalbuminuric patients at high risk for progression to established diabetic nephropathy.     

Low-dose candesartan cilexetil prevents early kidney damage in type 2 diabetic patients with mildly elevated blood pressure.

To determine the effect of a low-dose angiotensin receptor blocker, candesartan, on early kidney damage associated with diabetes. Fifty-two patients with type 2 diabetes with normo- and microalbuminuria participated in this study. Nineteen patients with high-normal and mildly high blood pressure received low-dose candesartan cilexetil at 4 mg daily (candesartan group), and 33 patients did not receive candesartan (control group). Blood pressure, urinary excretion of albumin, transferrin, and type IV collagen (expressed as urinary creatinine index) and plasma parameters were determined at baseline and at 2, 6, 12 and 18 months after the start of candesartan therapy. Baseline urinary albumin, transferrin, and type IV collagen excretions was similar in the control and candesartan groups. The higher baseline systolic blood pressure was decreased by candesartan treatment to a level similar to that in the control group, such that blood pressure was comparable between the control and candesartan groups during the run-in period. In the control group, urinary albumin excretion was significantly increased at 18 months when compared with baseline, while urinary albumin excretion did not increase in the candesartan group throughout the study. Urinary transferrin excretion was significantly increased at 6, 12, and 18 months when compared with baseline in the control group, while it did not increase in the candesartan group during the study. In both groups, urinary type IV collagen excretion did not change significantly during the study. Hemoglobin A1c, serum urea nitrogen, creatinine, albumin, and lipids were comparable between the two groups throughout the study. In conclusion, low-dose candesartan can prevent early kidney damage in type 2 diabetic patients with mildly higher blood pressure independently of its hypotensive action.     

Cardioprotective effects of vasopeptidase inhibition vs. angiotensin type 1-receptor blockade in spontaneously hypertensive rats on a high salt diet.

The aim of our study was to compare the cardioprotective effects of vasopeptidase inhibition with those of angiotensin type 1 (AT1)-receptor blockade, a diuretic and the combination of AT1-receptor blockade and a diuretic in an experimental rat model of essential hypertension on a high salt diet. Spontaneously hypertensive rats (SHR) (n =73) were divided into 6 groups to receive the following diet and drug regimens for 8 weeks: 1) low salt controls (NaCl 0.5%); 2) high salt controls (NaCl 6%); 3) omapatrilat (40 mg/kg/d) on a high salt diet; 4) losartan (30 mg/kg/d) on a high salt diet; 5) hydrochlorothiazide (HCTZ; 10 mg/kg/d) on a high salt diet; and 6) losartan+HCTZ (30+10 mg/kg/d) on a high salt diet. Blood pressure was measured by tail-cuff plethysmography. The histological score of myocardial damage, myocardial collagen volume fraction (CVF), connective tissue growth factor (CTGF) expression and cardiomyocyte apoptosis were determined. As an antihypertensive, omapatrilat showed greater efficacy than monotherapy with losartan or HCTZ, and was equally effective as the combination of losartan+HCTZ. Assessed by myocardial damage score, omapatrilat and losartan protected cardiac morphology better than HCTZ or the drug combination. Omapatrilat decreased CVF to a greater extent than the other therapies, whereas losartan was most effective in decreasing CTGF expression. All drug treatments, except HCTZ, decreased cardiomyocyte apoptosis. Our findings provide evidence that both vasopeptidase inhibition and AT1-receptor blockade exert cardioprotective properties beyond their blood pressure-lowering effects. Cardioprotection was associated with prevention of cardiomyocyte apoptosis and inhibition of extracellular matrix formation.     

Aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or lisinopril as initial choice in hypertensive type II diabetic individuals: effects on albumin excretion, endothelial function and inflammation in a double-blind, randomized clinical trial

We investigated the effects of aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or lisinopril on urinary albumin excretion, endothelial function and inflammatory activity in hypertensive type II diabetic individuals. A total of 70 hypertensive type II diabetic individuals were treated with three antihypertensive strategies in a randomized, double-blind, double-dummy design. Blood pressure was titrated to levels below 130/85 mmHg or a decrease in systolic pressure of 10% with a diastolic pressure below 85 mmHg. After titration, patients were treated for 12 months. Mean blood pressures changed from 157/93, 151/94 and 149/93 at baseline to 135/80, 135/82 and 131/80 mmHg after titration in the hydrochlorothiazide (n=24), candesartan (n=24) and lisinopril (n=22) groups. About 70% reached target blood pressures. However, only 45% had blood pressures <130/85 mmHg. Urinary albumin excretion and levels of soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 decreased (GEE regression coefficients, -2.40 mg/24 h (P<0.001), -85 ng/ml (P=0.01) and -50 ng/ml (P=0.02)), but brachial artery endothelium-dependent and -independent vasodilation and levels of von Willebrand factor and C-reactive protein did not change (GEE regression coefficients, 0.21 mm (P=0.07), 0.04 mm (P=0.43), 0.04 IU/ml (P=0.33) and -1.15 mg/l (P=0.64)). No differences in outcome variables between treatment groups were observed. These data show that achievement of target blood pressures below 130/85 mmHg in hypertensive type II diabetes is difficult. Aggressive antihypertensive therapy can improve urinary albumin excretion, endothelial function and inflammatory activity in hypertensive type II diabetic individuals, regardless of the type of antihypertensive therapy used.     

Reduction in arterial stiffness with angiotensin II antagonism and converting enzyme inhibition. A comparative study among malay hypertensive subjects with a known genetic profile

BACKGROUND: Data comparing the effect of losartan and perindopril on aortic stiffness among hypertensive subjects without A(1166)C polymorphism was not available. METHODS: The short-term and long-term effects of losartan (50 mg) and perindopril (4 mg) on aortic stiffness measured as carotid femoral pulse wave velocity (PWV) were compared in 39 middle-aged Malay subjects with mild-to-moderate hypertension in a 4-month, double-blind, randomized, controlled, parallel-design study. RESULTS: Four-month treatment with both drugs showed a significant reduction in blood pressure (BP) (P < .005) and PWV (P < .05) as compared to the baseline. On the other hand 1-month treatment showed a significant reduction in BP only in perindopril group (P < .05) but not in the losartan group. There was no significant reduction in pulse pressure and PWV after 1 month treatment by both drugs. No significant difference was seen in reduction in BP after 1 month and 4 months treatment between the two drugs. Similarly no significant difference was seen in reduction in PWV between the two drugs after 1 month (P = .613) and 4 months (P = .521) of treatment. Reduction in PWV by losartan (r = 0.470) and perindopril (r = 0.457) correlated significantly only with reduction in DBP (P < .05) and remained significant even after controlling for reduction in DBP (P < .05). Reduction in PWV by both losartan and perindopril was independent of reduction in BP by these drugs. CONCLUSIONS: These results showed that long-term treatment with losartan shows similar pressure independent reduction in PWV as perindopril among Malay hypertensive subjects with a homogenous "AA" genotype for angiotensin II type 1 receptor and may serve as a suitable alternative to perindopril.     

Evaluation of blood pressure control by ambulatory blood pressure monitoring and study of factors associated with poor blood pressure control in 300 treated hypertensive type 2 diabetic patients

Hypertension is frequently associated with type 2 diabetes and is often difficult to control.

Aim

Evaluate the frequency of controlled hypertension in our type 2 diabetic patients with known and treated hypertension and determine the factors associated with poor blood pressure control.

Subjects and methods

Prospective study concerning 300 type 2 diabetic patients with a known and treated hypertension, sex-ratio: 0.64, mean age: 61.2 ± 9.1 years (37–86). All subjects underwent physical examination, biological investigations and a 24 hours ambulatory blood pressure monitoring (ABPM).

Results

Hypertension was well controlled in 70 patients (23.3%). The concordance rate between clinical measure of blood pressure and ABPM was 70.3%. Subjects with uncontrolled hypertension were older (61.8 ± 8.9 vs 59.1 ± 9.3 years, P < 0.05), more frequently of male sex (sex-ratio: 0.77 vs 0.34, P < 0.01), smokers (36.4 vs 21.7%, P < 0.05) and with abdominal adiposity (P < 0.05). Duration of diabetes, body mass index and the frequency of peripheral neuropathy, retinopathy and coronary insufficiency were not different between the two groups. Diabetic nephropathy was more frequent (29.8 vs 16.1%, P < 0.05) in the group with uncontrolled hypertension. Loss of circadian blood pressure rhythm was noted in 239 patients (79.6%) and it was more frequently observed in patients with uncontrolled hypertension (84 vs 66%, P < 0.001).

Conclusion

Our type 2 diabetic patients had a poorly controlled hypertension. Close monitoring of blood pressure with adjustment of antihypertensive treatment are necessary to improve cardiovascular prognosis of our patients.     

Sight-threatening retinopathy is associated with lower mortality in type 2 diabetic subjects: a 10-year observation study

AIMS: To study associations between diabetic retinopathy and development of stroke, myocardial infarction and death in type 2 diabetic patients. METHODS: During a 10-year observation period, 363 type 2 diabetic patients (diagnosis > or =30 years of age) attending an outpatient clinic were studied regarding the prevalence and incidence of retinopathy and associated risk factors, i.e., (HbA(1c), blood pressure, albuminuria, plasma creatinine, age, sex and diabetes duration) in relation to the development of myocardial infarction, stroke and death. The degree of retinopathy was classified as no retinopathy, background or sight-threatening retinopathy, i.e., clinically significant macular edema, severe non-proliferative or proliferative retinopathy. RESULTS: During the study period, 62 patients had had myocardial infarction, 54 stroke and 99 patients died. Patients with sight-threatening retinopathy at baseline (n=41) had a 2.2-fold increased (p<0.01) risk for death compared to patients with no or background retinopathy, even when controlled for medical risk factors. When adjusted for medical risk factors, patients with no retinopathy at baseline (n=226) who remained without retinopathy or developed background retinopathy (n=187) during the study period, had a 3.6-fold increased risk for death (95% CI, 1.1, 11.8), (p=0.03), compared to patients who developed sight-threatening retinopathy (n=39), while the incidence of myocardial infarction did not differ. More patients who developed sight-threatening retinopathy were treated with ACE inhibitors than patients who did not (41% versus 24%; p=0.03). CONCLUSION: Despite more medical risk factors, patients who developed sight-threatening retinopathy had lower mortality compared to patients with no or background retinopathy at follow-up. More patients who developed sight-threatening retinopathy were treated with ACE inhibitors but this seemed not to have influenced the lower mortality rate in this group, whereas the use of ACE inhibitors in patients who did not develop sight-threatening retinopathy was connected with lower mortality rate.     

Angiotensin receptor antagonist vs. angiotensin-converting enzyme inhibitor in Asian subjects with type 2 diabetes and albuminuria - a randomized crossover study

BACKGROUND: Subjects with type 2 diabetes mellitus (T2DM) and albuminuria are at risk for progressive diabetic nephropathy. The relative blood pressure lowering and antialbuminuric efficacy of angiotensin receptor antagonist (ARB) vs. angiotensin-converting enzyme (ACE) inhibitor has not been well studied. METHODS: Forty-one ARB- and ACE inhibitor-naive T2DM subjects with albuminuria (>30 mg/g creatinine) were given either 50 mg of losartan (ARB) or 20 mg of quinapril (ACE inhibitor) (50% maximum dose) for 4 weeks, with a 4-week wash-out period in-between interventions in a crossover fashion. The order of intervention was randomized. The primary endpoint was the reduction of blood pressure and albuminuria. Secondary endpoint was changes in plasma transforming growth factor beta (TGF-beta). RESULTS: Among the 41 subjects, 66% were male. The mean age (s.d.) was 52 (10) years, and duration of diabetes was 8 (14) years. Blood pressure reduction (though not statistically significant) was similar on both interventions [systolic: losartan 3 (15) vs. quinapril 2 (13) mmHg, p = 0.52; diastolic: losartan 1 (9) vs. quinapril 2 (8) mmHg, p = 0.55]. However, amelioration of albuminuria [mean (s.e.)] was significantly greater with losartan [losartan vs. quinapril: -93 (82) vs. -49 (65) mg/g, p = 0.02]. There was no change in plasma TGF-beta levels [mean (s.d.)] on either treatment, losartan [before 12.1 (8.9) vs. after 11.9 (9.6) ng/ml, p = 0.68] and quinapril [11.1 (7.9) vs. 11.1 (7.8) ng/ml, p = 0.87). CONCLUSION: In Asian subjects with T2DM and albuminuria, 4 weeks of losartan therapy at 50 mg daily appeared to have greater antialbuminuric effect than 20 mg of quinapril.     

Microalbuminuria reduction with telmisartan in normotensive and hypertensive Japanese patients with type 2 diabetes: a post-hoc analysis of The Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) study

The Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) study previously showed that treatment with telmisartan, an angiotensin II receptor blocker, effectively reduced the transition from incipient to overt nephropathy in Japanese type 2 diabetic patients. However, that large study included both normotensive and hypertensive patients. In the present post hoc analysis, we aimed to assess whether or not telmisartan elicits beneficial effects on the progression of microalbuminuria in normotensive patients. We randomized 163 microalbuminuric (urinary albumin-to-creatinine ratio: UACR of 100 to 300 mg/g creatinine) normotensive type 2 diabetic patients to treatment with telmisartan (40 or 80 mg once daily) or placebo over 52 weeks. The patients treated with either dose of telmisartan showed lower transition rates from microalbuminuria to overt nephropathy compared to the placebo group. In addition, more patients on telmisartan reverted to normoalbuminuria (UACR<30 mg/g creatinine): 15.5% of the 40 mg group, 19.6% of the 80 mg group, and 1.9% of the placebo group. In normotensive patients treated with telmisartan, changes in UACR were not significantly correlated with changes in blood pressure. Side effects did not differ among the groups. The present study demonstrates that telmisartan prevents the progression of microalbuminuria (in some cases induces remission of albuminuria) in normotensive Japanese patients with type 2 diabetes. Telmisartan is shown to be safe and well tolerated in these patients.     

The effect of achieving a systolic blood pressure of 140 mmHg. A prospective study of ambulatory measurements in type 2 diabetic patients with nephropathy

ObjectivesWhat is the prognostic significance of achieving a systolic blood pressure of < 140 mmHg?SettingDiabetic renal policlinic, university hospital of Lund, Sweden.Subjects118 type 2 diabetic patients with micro-macroalbuminuria were followed for four years (range 1–8 years).Method and main outcome measuresThe prognostic significance of office, day- and nighttime measurements of blood pressure (BP) for development of cardiovascular complications was studied.ResultsForty-two percent (n = 49) developed one or more of the following cardiovascular endpoints: 23% (n = 27) death, 9% (n = 10) stroke, 9% (n = 11) myocardial infarction, 9% (n = 11) heart failure, 31% (n = 36) uremia and 17% (n = 20) need for dialysis. Reaching the goal for day- and nighttime systolic BP (SBP) at baseline of < 140 mmHg was associated with lower risk for developing uremia. Reaching the goal for nighttime SBP was associated with a decreased risk for developing myocardial infarction and need for dialysis treatment. None of these associations was found for office SBP.Patients not achieving the goal for nighttime systolic blood pressure of < 140 mmHg had a 12.9 times higher risk of developing myocardial infarction and 3.9 times increased risk of uremia and 2.7 times increased risk for death than patients achieving the goal.ConclusionNighttime blood pressure had better prognostic significance for developing cardiovascular and renal complications than office and daytime blood pressure.     

Effects of telmisartan compared with eprosartan on blood pressure control, glucose metabolism and lipid profile in hypertensive, type 2 diabetic patients: a randomized, double-blind, placebo-controlled 12-month study.

We evaluated the antihypertensive activity, glucose homeostasis and plasma lipid profile in patients with mild hypertension and type 2 diabetes mellitus treated by diet and exercise, and not in receipt of oral hyperglycemics, following 12-month treatment with either telmisartan or eprosartan. In this double-blind, placebo-controlled trial, 119 patients with mild essential hypertension (diastolic blood pressure [DBP] 91-104 mmHg) and type 2 diabetes were divided into three groups and randomized to receive once-daily telmisartan 40 mg, eprosartan 600 mg, or placebo for 12 months. At enrollment, patients were advised on diet (1,400-1,600 kcal/day) and exercise (physical aerobics on a bicycle for at least 30 min on 4 days each week). Compared with baseline, a significant reduction (p<0.01) in seated trough systolic blood pressure (SBP) was detected after 12-month treatment with either telmisartan or eprosartan. Seated trough DBP was also reduced by telmisartan (p<0.01) and eprosartan (p<0.05); the antihypertensive effect of telmisartan was significantly superior (p<0.05). No change in body mass index or glucose metabolism was observed with either active treatment, or with placebo. Telmisartan, but not eprosartan, significantly improved plasma total cholesterol (p<0.01), low-density lipoprotein cholesterol (p<0.01) and triglycerides (p<0.05) compared with eprosartan. In conclusion, 12-month telmisartan treatment produced a significantly greater reduction in DBP than eprosartan and significantly improved plasma lipids. The improvement could be due to varying pharmacokinetic/pharmacodynamic properties of telmisartan compared with eprosartan, even if it is not clear about the relationship between angiotensin-II receptor blockade and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition.     

Transforming growth factor beta1 and additional renoprotective effect of combination ACE inhibitor and angiotensin II receptor blocker in hypertensive subjects with minor renal abnormalities: a 24-week randomized controlled trial

OBJECTIVE: To verify the benefit of renin-angiotensin system blockade in hypertension, the effects of 24 weeks' losartan and ramipril treatment, both alone and in combination, on urinary albumin excretion (UAE) and circulating transforming growth factor beta1 (TGF beta1) have been evaluated in hypertensive subjects with minor renal abnormalities. DESIGN AND METHODS: Fifty-one patients with stage 1 and 2 essential hypertension and with UAE > or = 20 mg/24 h but with maintained renal function have been included. After a 4-week run-in with placebo administration, a randomized double-blind, three-arm double-dummy trial was used. All the hypertensives (HT) were allocated randomly to three treatment arms (17 patients for each group) and they were single-matched for age, gender, body mass index (BMI), systolic and diastolic blood pressure. Active treatment consisted of losartan (50 mg/day), ramipril (5 mg/day) and combined (losartan 50 mg/day plus ramipril 5 mg/day) for 24 weeks. Hydrochlorothiazide 12.5 mg/day was added in HT patients with uncontrolled blood pressure (> or = 140/90 mmHg) during the active treatment period. In all patients UAE, by immunonephelometric assay; circulating TGF beta1 by a solid-phase specific sandwich enzyme-linked immunosorbent assay (ELISA); and blood urea nitrogen (BUN), creatinine and creatinine clearance and potassium, by routine laboratory methods, were determined after placebo treatment and 24 weeks follow-up. RESULTS: The three treatment groups were comparable for gender, age, BMI, blood pressure, UAE and renal function measurements. During the active treatment period it was necessary to add hydrochlorothiazide in five patients--two each of the losartan and ramipril groups and one of the combined group. At the end of treatment, significant (P < 0.05) reductions in systolic, diastolic and mean blood pressure, UAE and TGF beta1 levels were observed in all the groups. No change in renal function measurements were observed. The absolute and percentage reduction in UAE and TGF beta1 were significantly higher in the combined group than in the losartan or ramipril groups. No significant changes in absolute and percentage reduction of systolic, diastolic and mean blood pressure were found. All treatment regimens were well tolerated with few and transient side-effects. CONCLUSION: These data indicate an additional renoprotective effect of dual blockade of the renin-angiotensin system (RAS) in hypertensive patients with minor renal abnormalities. In addition, the contemporaneus and marked decrease in TGF beta1 and UAE levels in hypertensives treated with combined therapy might indicate the presence of a subset of subjects who may benefit from complete RAS blockade.     

Effect of antihypertensive combinations on arterial pressure,albuminuria, and glycemic control in patients with type II diabetic nephropathy: a randomized study

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.     

Pentoxifylline,albumin excretion rate and proteinuria in type I and type II diabetic patients with microproteinuria. Results of a short-term randomized study

Summary An association between renal microvascular complications and hemorheological alterations has been suggested in diabetes mellitus. Therefore, a hemorheologic approach in the treatment of diabetic microproteinuria has been proposed. Eighty-two type I and type II diabetic patients with microproteinuria were randomized and assigned to two different protocols: protocol A, patients treated with pentoxifylline (Trental 400Ŗ); protocol B, patients without hemorheologic treatment, in whom hypoglycemic therapy was just more strictly enforced. A significant improvement of the hemorheologic pattern and a significant marked reduction of albumin excretion rate and proteinuria was found in diabetic patients treated with pentoxifylline, independently of the degree of metabolic control. These results were readily achieved and were confirmed throughout the study. Moreover, these results were comparable to those obtained in diabetic patients of protocol B. Pentoxifylline might therefore be considered as the first useful therapeutic agent in the treatment of diabetic microproteinuria.     

Effects of multiple factorial intervention on ambulatory BP profile and renal function in hypertensive type 2 diabetic patients with overt nephropathy - a pilot study

Accumulating evidence has shown that diabetic patients are increasing in number, and renal and cardiovascular complications are the most common cause of death in diabetic patients. Thus, it would be of considerable value to identify the mechanisms involved in the progression of renal impairment and cardiovascular injury associated with diabetes. Recent evidence also indicated that multifactorial intervention is able to reduce the risk of cardiovascular disease and death among patients with diabetes and microalbuninuria. In this pilot study, we examined the effects of intensified multifactorial intervention, with tight glucose regulation and the use of valsartan and fluvastatin on ambulatory blood pressure (BP) profile, estimated glomerular filtration rate (eGFR), and urinary albumin to creatinine ratio (UACR), in 20 hypertensive patients (16 male and 4 female) with type 2 diabetes mellitus and overt nephropathy. After 12 months of intensified treatment, office BP, fasting plasma glucose (FPG), and low-density lipoprotein cholesterol (LDLC) were significantly decreased compared to baseline (systolic blood pressure (SBP), 130 ± 2 vs. 150 ± 1 mmHg; diastolic blood pressure (DBP), 76 ± 1 vs. 86 ± 1 mmHg; FPG, 117 ± 5 vs. 153 ± 7 mg/dl; LDLC, 116 ± 8 vs. 162 ± 5 mg/dl, P < 0.0001). Also, compared to the baseline values, the daytime and nighttime ambulatory BP and short-term BP variability were significantly decreased after 12 months. Furthermore, while eGFR was not altered (44.3 ± 5.1 vs. 44.3 ± 6.5 ml/min/1.73 m(2), not significant (NS)), UACR showed a significant reduction after 12 months of intensified treatment (1228 ± 355 vs. 2340 ± 381 mg/g-cr, P < 0.05). These results suggest that the intensified multifactorial intervention is able to improve ambulatory BP profile, preserve renal function, and reduce urinary albumin excretion in type 2 diabetic hypertensive patients with overt nephropathy.     

Safety and tolerability of vildagliptin vs. thiazolidinedione as add-on to metformin in type 2 diabetic patients with and without mild renal impairment: A retrospective analysis of the GALIANT study

ObjectiveThis retrospective analysis assessed safety and tolerability of vildagliptin (Vilda) as an add-on to metformin in type 2 diabetes mellitus (T2DM) patients with normal renal function (GFR > 80 mL/min/1.73 m²) and mild renal impairment (GFR: >50 to ≤80 mL/min/1.73 m²).MethodsAdverse events (AE) from this 12-week, randomized, open-label study comparing Vilda 100 mg and thiazolidinediones (TZD) as an add-on therapy in patients with T2DM inadequately controlled (HbA_1c: 7–10%) on a stable dose of metformin (≥1000 mg/day) were analyzed.ResultsOf 2627 randomized patients, 1278 in the Vilda and 635 in the TZD groups had normal renal function; 463 in the Vilda and 230 in the TZD groups had mild renal impairment. Higher incidence of headache and rash was noted in both Vilda groups, whereas those with mild renal impairment receiving TZD experienced a higher incidence of peripheral edema and URI. Fewer patients in the Vilda group discontinued the study due to AEs compared to TZD group. Serious AEs were greater in TZD groups (normal: 2.4%; mild renal impairment: 3.0%) compared to Vilda groups (normal: 1.6%; mild renal impairment: 2.4%).ConclusionThe safety profile of Vilda or TZD as an add-on to metformin was similar in patients with mild renal impairment and normal renal function.     

Effect of two antihypertensive combinations on metabolic control in type-2 diabetic hypertensive patients with albuminuria: a randomised, double-blind study.

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.