Pierangelo Lazzari

Impaired circadian modulation of sympathovagal activity in diabetes. A possible explanation for altered temporal onset of cardiovascular disease.

BackgroundDiabetic subjects have a high incidence of cardiovascular accidents, with an altered circadian distribution. Abnormalities in the circadian rhythm of autonomic tone may be responsible for this altered temporal onset of cardiovascular disease. Methods and ResultsTo assess circadian changes of sympathovagal balance in diabetes, we performed 24-hour power spectral analysis of RR interval fluctuations in 54 diabetic subjects (age, 44±2 years) with either normal autonomic function or mild to severe autonomic neuropathy and in 54 age-matched control subjects. The power in the low-frequency (LF, 0.03–0.15 Hz) and high-frequency (HF, 0.18–0.40 Hz) bands was considered an index of relative sympathetic and vagal activity, respectively. Diabetic subjects with autonomic abnormalities showed a reduction in LF compared with control subjects (5.95±0.12 In-msece versus 6.73±0.11, p<0.001) and an even greater reduction in LF, particularly during the night and the first hours after awakening (5.11±0.18 In-msece versus 6.52±0.14, p<0.001). Day-night rhythm in sympathovagal balance was reduced or absent in diabetic subjects compared with control subjects. ConclusionsDiabetic subjects with or without signs of autonomic neuropathy have a decreased vagal activity (and hence a relatively higher sympathetic activity) during night hours and at the same time of the day, during which a higher frequency of cardiovascular accidents has been reported. These observations may provide insight into the increased cardiac risk of diabetic patients, particularly if autonomic neuropathy is present.

ACE inhibition but not angiotensin II antagonism reduces plasma fibrinogen and insulin resistance in overweight hypertensive patients.

The aim of this study was to compare the effects of the angiotensin-converting enzyme (ACE) inhibitor perindopril and the angiotensin II antagonist losartan on insulin sensitivity and plasma fibrinogen in overweight hypertensive patients. Twenty-eight overweight mild to moderate [diastolic blood pressure (DBP) >90 and <110 mm Hg] hypertensives aged 43-64 years, after a 4-week placebo period, were randomized to perindopril, 4 mg o.d., or losartan, 50 mg o.d., for 6 weeks. Then, after a new placebo period, patients were crossed to the alternative regimen for further 6 weeks. At the end of the placebo and of the treatment periods, blood pressure was measured, plasma fibrinogen was evaluated, and insulin sensitivity was assessed by the euglycemic, hyperinsulinemic clamp technique. Glucose infusion rate (GIR) during the last 30 min of clamp and total glucose requirement (TGR) were evaluated. Both perindopril and losartan reduced SBP (by a mean of 20.2 mm Hg, p < 0.001 vs. placebo; and 15.8 mm Hg, p = 0.002 vs. placebo, respectively) and DBP (by a mean of 15.2 mm Hg, p = 0.001 vs. placebo, and 11.8 mm Hg, p = 0.01 vs. placebo respectively), with no difference between the two treatments. GIR was significantly increased by perindopril (+2.91 mg/min/kg, p = 0.042 vs. placebo), but not by losartan (+0.28 mg/min/kg, NS). TGR was not modified by losartan but was increased by perindopril (+9.3 g, p = 0.042 vs. placebo). Plasma fibrinogen levels were reduced by perindopril (-53.4 mg/dl, p = 0.022 vs. placebo) but not by losartan (-16.8 mg/dl, NS). The perindopril-induced decrease in fibrinogen was correlated with the increase in GIR (r = 0.39; p < 0.01). These findings suggest that fibrinogen decrease produced by the ACE inhibitor is related to its action on insulin sensitivity, which seems to be dependent not on angiotensin II blockade but rather on other mechanisms.

Effect of valsartan addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients

The aim of this study was to assess the effect of valsartan addition to amlodipine on ankle foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP), two objective measures of ankle oedema. After a 4-week placebo period, 80 grade 1–2 hypertensive patients (diastolic blood pressure (DBP)>90 mm Hg and <110 systolic blood pressure (SBP)>140 mm Hg) were randomized to amlodipine 10 mg or valsartan 160 mg or amlodipine 10 mg plus valsartan 160 mg for 6 weeks according to an open-label, blinded end point, crossover design. At the end of the placebo period and of each treatment period, blood pressure, AFV and PSTP were evaluated. AFV was measured using the principle of water displacement. PSTP was assessed connecting the subcutaneous pretibial interstitial environment with a water manometer. Both amlodipine and valsartan monotherapy significantly reduced SBP (−16.9 and –14.5 mm Hg, respectively, P<0.01 vs baseline), and DBP (−12.9 and −10.2 mm Hg, respectively, P<0.01 vs baseline) but the reduction was greater with the combination (−22.9 mm Hg for SBP, P<0.01 vs monotherapy; −16.8 mm Hg for DBP, P<0.01 vs monotherapy). Amlodipine monotherapy significantly increased both AFV (+23%, P<0.01 vs baseline) and PSTP (+75.5%, P<0.001 vs baseline) whereas valsartan monotherapy did not influence them. As compared to amlodipine alone, the combination produced a less marked increase in AFV (+6.8%, P<0.01 vs amlodipine) and PSTP (+23.2%, P<0.001 vs amlodipine). Ankle oedema was clinically evident in 24 patients with amlodipine and in six patients with the combination. These results suggest that angiotensin receptor blockers partially counteract the microcirculatory changes responsible for calcium channel blockers induced oedema formation.

Long-term effects of ramipril and nitrendipine on albuminuria in hypertensive patients with type II diabetes and impaired renal function.

The aim of this study was to compare the effects of ramipril and nitrendipine chronic treatment on urinary albumin excretion (UAE) in hypertensive patients with type II non-insulin-dependent diabetes mellitus (NIDDM) and impaired renal function. A 2-year, prospective, randomised study was conducted on 51 men with a diastolic blood pressure (DBP) ⩾95 and ⩽105 mm Hg, stable NIDDM, serum creatinine between 1.6 and 3.0 mg/dl and persistent UAE >300 and <2000 mg/24 h. after a 3-month preliminary observation period, during which patients began a low-protein, low-sodium diet, and a subsequent 4-week run-in period on placebo, patients were randomly treated with ramipril 5 mg or nitrendipine 20 mg for 2 years. both drugs similarly reduced bp without affecting glucose homeostasis. in the ramipril group uae significantly decreased after only 3 months of treatment, whereas in the nitrendipine group a significant although lesser reduction in uae was observed only after 1 year. during the second year the uae% change was not statistically different between the two treatments. serum creatinine and creatinine clearance showed no significant change with both drugs. the progression of renal insufficiency as assessed by the rate of reduction of creatinine clearance over the 2 years of the study was similar in the ramipril and the nitrendipine groups. in conclusion both ramipril and nitrendipine were associated with a decrease in uae although such a reduction was earlier and more marked with ramipril. the decline of renal function did not differ significantly between the two treatments.

Losartan and perindopril effects on plasma plasminogen activator inhibitor-1 and fibrinogen in hypertensive type 2 diabetic patients

BACKGROUND This study compared the effects of losartan and perindopril on plasma plasminogen activator inhibitor-1 (PAI-1) and fibrinogen in hypertensive type 2 diabetic patients. METHODS We studied 85 nonsmoking outpatients, aged 46 to 64 years, with mild to moderate essential hypertension (diastolic blood pressure [BP] > 90 and < 110 mm Hg) and well controlled type 2 diabetes mellitus. After a 4-week washout placebo period, patients were randomized to received perindopril 4 mg once daily (n = 42) or losartan 50 mg once daily (n = 43) for 12 weeks according to a double-blind, parallel-group design. At the end of the placebo and active treatment periods, BP was measured and plasma PAI-1 and fibrinogen were evaluated. RESULTS Both perindopril and losartan reduced systolic and diastolic BP values (-16/15 mm Hg and -15/14, respectively; P < .001 v placebo), with no difference between the two treatments. Plasma PAI-1 was reduced by perindopril (-10 ng/dL, P = .028 v placebo) but not by losartan (+4 ng/dL, NS), the difference between the two treatments being statistically significant (P < .01). Plasma fibrinogen showed no significant change with both drugs, although a decreasing trend was noted with perindopril. CONCLUSIONS These findings indicate that perindopril but not losartan decreases PAI-1 in hypertensive type 2 diabetic patients, which suggests that the PAI-1 lowering effect is unrelated with AT, receptor blockade and could rather be due to the fact that the endothelial receptors that mediate PAI-1 expression in response to angiotensin II are not type 1 receptor subtypes. Different effects of the two drugs on the bradykinin system might also be implicated.

Effect of telmisartan/hydrochlorothiazide vs lisinopril/hydrochlorothiazide combination on ambulatory blood pressure and cognitive function in elderly hypertensive patients

The aim of this study was to compare the effects of telmisartan/hydrochlorothiazide (HCTZ) vs lisinopril/HCTZ combination on ambulatory blood pressure and cognitive function in elderly hypertensive patients. A total of 160 patients, 76 men and 84 women, aged 61–75 years, with sitting diastolic blood pressure (DBP) >90 mmHg and <110 mmHg and systolic blood pressure (SBP) >140 mmHg were randomized to receive temisartan 80 mg/HCTZ 12.5 mg o.d. or lisinopril 20 mg/HCTZ 12.5 mg o.d. for 24 weeks, according to a prospective, open-label, blinded end point, parallel-group design. At the end of a 2-week wash-out period and after 12 and 24 weeks of active treatment, 24-h noninvasive ambulatory BP monitoring (ABPM) was performed and cognitive function was evaluated through six different tests (verbal fluency, Boston naming test, word-list memory, word-list recall, word-list recognition and Trails B). Both treatments significantly reduced ambulatory BP. However, the telmisartan/HCTZ combination produced a greater reduction in 24-h, day-time and night time ABPM values. Lisinopril/HCTZ did not induce significant changes in any of the cognitive function test scores at any time of the study, whereas at both 12 and 24 weeks telmisartan/HCTZ significantly improved the word-list memory score (+17.1 and +15.7%, respectively, P<0.05 vs baseline), the word-list recall score (+13.5 and +16.9%, P<0.05) and the Trails B score (−33 and −30.5%, P<0.05). These results suggest that in elderly hypertensive patients treatment with telmisartan/HCTZ produces a slightly greater reduction in ambulatory BP than lisinopril/HCTZ combination and, unlike this latter, improves some of the components of cognitive function, particularly episodic memory and visuospatial abilities.

Comparative effects of nebivolol and atenolol on blood pressure and insulin sensitivity in hypertensive subjects with type II diabetes

The aim of this double-blind, parallel group study was to compare the effects of nebivolol and atenolol on blood pressure (BP) and insulin sensitivity in hypertensive patients with type II, non-insulin dependent diabetes mellitus (NIDDM). After a 4-week run-in period on placebo, 30 patients (14 males and 16 females) aged 43 to 69 years, with stable NIDDM and mild to moderate hypertension (DBP ⩾95 and <116 mm hg) were randomised to receive either nebivolol 5 mg or atenolol 50 mg, both administered once daily for 6 months. at the end of the placebo and the active treatment periods, supine and standing bp was measured, 24-h urinary c-peptide, hba1c, plasma glucose and lipid levels were evaluated and an euglycaemic hyperinsulinaemic clamp was performed to evaluate insulin sensitivity: glucose infusion rate during the last 60 min of clamp and total glucose requirements were evaluated. Nebivolol 5 mg once daily was of an equivalent efficacy as atenolol 50 mg once daily at reducing supine and standing systolic and diastolic BP values. Neither β-blocker adversely affected carbohydrate metabolism in terms of insulin sensitivity, whole body glucose utilization, HbA1c and 24-h urinary C-peptide excretion. No significant changes in cholesterol (total, high density and low density lipoprotein) and triglycerides plasma levels were observed with both β-blockers. These findings indicate that, in hypertensive patients with NIDDM, ie, in subjects who have established insulin resistance, treatment with nebivolol and atenolol neither further deteriorated insulin sensitivity nor adversely affected the lipid profile.

Comparison of the effects of valsartan and felodipine on plasma leptin and insulin sensitivity in hypertensive obese patients

Aim of this study was to compare the effect of valsartan and felodipine on blood pressure (BP), plasma leptin (L), insulin sensitivity and plasma norepinephrine (NE) in obese hypertensive patients. Ninty-six obese patients (body mass index [BMI] ≥30 kg/m2) with mild to moderate essential hypertension (diastolic blood pressure [DBP] >90 and <110 mmHg, as evaluated with an appropriately sized cuff) aged 31–60 years, were randomized to a valsartan (80 mg/day for 16 weeks; n=48) or felodipine (5 mg/day for 16 weeks; n=48) treatment group after a 2-week wash-out period. After the first 4 weeks of treatment there was a titration with dose-doubling in non responder patients (DBP > 90 mmHg). At the end of the placebo period and of active treatment period, BP and BMI were evaluated and a venous sample was drawn at the same hour in the morning to evaluate plasma L and NE. Insulin resistance index (HOMA-IR) was calculated. No dietary advice was prescribed. Both valsartan and felodipine significantly decreased BP values (-19.3/15 mmHg and -18.9/13.6 mmHg, respectively p<0.001 vs. placebo), with no difference between treatments. However, felodipine increased plasma NE (+124 pg/ml, +38.2%, p<0.05 vs. placebo and <0.01 vs. valsartan) and had no effect on L, body weight and HOMA-IR index, while valsartan did not modify NE and produced a significant reduction in L (-3.7 ng/ml, -10.1%, p<0.05 vs. placebo), BMI (-1.7 kg/m2, -4.7%, p<0.01 vs. placebo) and HOMA-IR index (-1.6, -20%, p<0.05 vs. placebo). These results suggest that in hypertensive obese subjects, treatment with valsartan might offer an advantage over treatment with felodipine, since valsartan may help to improve obesity-related disorders in addition to lowering BP.

Comparative Evaluation of Effect of Valsartan/Amlodipine and Atenolol/Amlodipine Combinations on Atrial Fibrillation Recurrence in Hypertensive Patients With Type 2 Diabetes Mellitus

The aim of this study was to compare the effect of valsartan/amlodipine and atenolol/amlodipine combination in preventing the recurrence of atrial fibrillation (AF) in hypertensive diabetic patients with a history of recent paroxysmal atrial fibrillation. Two hundred ninty-six hypertensive patients with well-controlled type 2 diabetes in sinus rhythm but with at least 2 ECG-documented episodes of AF in the previous 6 months were randomized to 160 mg of valsartan plus amlodipine (titrated from 2.5 to 10 mg) or to 100 mg of atenolol plus amlodipine (2.5 to 10 mg) in addition to their previous antiarrhythmic treatment (if any) and were followed up for 1 year. Blood pressure (BP) and a 24-hour ECG were evaluated monthly. The patients were asked to report any episode of symptomatic AF and to perform an ECG as early as possible. SBP/DBP values were significantly reduced after 12 months with valsartan/amlodipine (from 150.4/93.5 to 126.37/7.4 mm Hg, P < 0.001) and atenolol/amlodipine (from 151.1/94.2 to 127.1/77.9 mm Hg, P < 0.001), with no difference between the 2 regimens. At least 1 ECG-documented episode of AF was reported in 20.3% of the patients treated with valsartan/amlodipine and in 34.1% of those treated with atenolol/amlodipine, with a significant difference between treatments (P < 0.01). The positive effect of valsartan/amlodipine combination on AF recurrence was more evident in patients treated with amiodarone or propafenone than in patients treated with other antiarrhythmic drugs or without antiarrhythmic treatment. Despite similar BP reduction, valsartan/amlodipine combination was more effective in patients treated with amiodarone or propafenone than atenolol/amlodipine in preventing new episodes of AF in hypertensive diabetic patients.

Comparative effects of telmisartan and eprosartan on insulin sensitivity in the treatment of overweight hypertensive patients

The aim of this study was to compare the effect of telmisartan and eprosartan on insulin sensitivity in overweight hypertensive patients. Fifty overweight (BMI > or = 25 and <30 kg/m (2)) outpatients, aged 41-65 years, with mild to moderate hypertension [systolic blood pressure (SBP) >140 and diastolic blood pressure (DBP) > or = 90 and < or = 110 mmHg], after a 4-week placebo period, were randomized to receive telmisartan 80 mg or eprosartan 600 mg for 8 weeks. Following another 4-week placebo period, patients were crossed to the alternative regimen for further 8 weeks. At the end of each placebo and active treatment period, blood pressure (BP), insulin sensitivity (by euglycemic hyperinsulinemic clamp), fasting plasma glucose (FPG), insulin (FPI), total cholesterol (TC), LDL-C, HDL-C, and triglycerides (Tg) were evaluated. Insulin sensitivity was expressed as the amount of glucose infused during the last 30 min (glucose infusion rate, GIR) in micromol/min/kg. Both telmisartan and eprosartan significantly reduced SBP/DBP values (by a mean of 19.4/13.3 mmHg and 17.9/12.1 mmHg respectively, all p<0.001 vs. placebo), with no significant difference between the two treatments. GIR was significantly increased by telmisartan (2.25+/-0.61 micromol/min/kg, p<0.05 vs. placebo) but not by eprosartan (0.25+/-0.14 micromol/min/kg, p=ns), the difference between the two drugs being statistically significant (p<0.02). No change in FPG, FPI, HDL-C, and Tg was observed with either treatment. Telmisartan significantly reduced TC (-9.9 mg/dl, -5%, p<0.04 vs. placebo) and LDL-C (-8.8 mg/dl, -7%, p<0.03 vs. placebo), whereas eprosartan did not influence them. These findings indicate a superiority regarding an improvement of insulin sensitivity and plasma lipid profile in overweight hypertensives by telmisartan as compared to eprosartan, possibly related to the selective stimulating PPAR-gamma property of telmisartan.