Elena Fogari

What is known and objective There is considerable interest in pharmacogenetic and molecular biomarkers. Our aim was to evaluate the effects of enalapril/lercanidipine combination on some emerging biomarkers for cardiovascular risk stratification of hypertensive patients, such as lipoprotein(a) [Lp(a)], soluble advanced glycation end products (sRAGE), soluble CD40 ligand (sCD40L) and serum myeloperoxidase (MPO). Research design and methods Three hundred and forty‐five patients were enrolled in this randomized, double‐blind, clinical trial: 120 hypertensive patients were randomized to enalapril 20 mg, 110 to lercanidipine 10 mg and 115 to enalapril/lercanidipine 20/10 mg fixed combination. We measures the following markers at baseline and after 6, 12, 18 and 24 months: blood pressure, fasting plasma glucose (FPG), lipid profile, Lp(a), sRAGE, sCD40L and MPO. Results There was a decrease in blood pressure in all groups compared with baseline, even if, as expected, enalapril/lercanidipine combination was more effective in reducing blood pressure compared with the monotherapies. No variations in lipid profile or FPG were recorded in any of the groups. Lercanidipine, but not enalapril, improved Lp(a) levels compared with baseline. The combination enalapril/lercanidipine improved it more than the single therapies. All treatments increased sRAGE levels, and decreased sCD40L and MPO, with a better effect seen with the enalapril/lercanidipine combination compared with single monotherapies. What is new and conclusion The combination enalapril/lercanidipine seems to be better than the single monotherapies in reducing not only blood pressure, but also the levels of some emerging biomarkers, potentially useful for cardiovascular risk stratification of hypertensive patients.

To compare pioglitazone or glibenclamide alone and in combination with rosuvastatin on hepatic steatosis in type 2 diabetic patients. After 3 months of metformin, patients were randomized to add pioglitazone 15 mg twice a day or glibenclamide 5 mg twice a day for 6 months, and then rosuvastatin 5 mg was added for other 6 months. Patients underwent an ultrasound examination for evaluation of steatosis degree, subcutaneous adipose tissue, and visceral adipose tissue diameter, an euglycemic hyperinsulinemic clamp, and blood sample collection for evaluation of glycemic control, fasting plasma insulin, lipid profile, adipocytokines at randomization, and after 6 and 12 months. Both pioglitazone and glibenclamide improved glycemic control. Pioglitazone reduced fasting plasma insulin, whereas glibenclamide increased it. Pioglitazone increased the glucose infusion rate compared with glibenclamide. Pioglitazone, but not glibenclamide, improved the lipid profile, and, when rosuvastatin was added, there was a greater improvement with pioglitazone and rosuvastatin. Adiponectin was increased by pioglitazone (+0.5 μg/ml), with a further increase (+0.4 μg/ml) when rosuvastatin was added. A significant decrease in leptin (-3.1 ng/ml) and interleukin-6 (-0.4 pg/ml) was found only with pioglitazone; a similar trend (-2.5 ng/ml and -0.3 pg/ml, respectively) was maintained after the addition of rosuvastatin.Rosuvastatin+pioglitazone decreased tumor necrosis factor-α (-0.3 ng/ml) and were superior to glibenclamide+rosuvastatin in reducing high-sensitivity C-reactive protein (-0.4 mg/l).Pioglitazone decreased ultrasound parameters, and the addition of rosuvastatin further decreased them both compared with randomization and glibenclamide. Pioglitazone was more effective than glibenclamide in improving inflammation and hepatic steatosis indices.

We evaluated the levels of some inflammatory adipocytokines in 363 obese and 365 non-obese subjects. We measured: body mass index (BMI), waist circumference (WC), fasting plasma glucose, fasting plasma insulin (FPI), homeostasis model assessment (HOMA) index, blood pressure, lipid profile, retinol binding protein-4 (RBP-4), vaspin, omentin-1, leptin, interleukin-6 (IL-6), visfatin, resistin, adiponectin (ADN), adipsin, tumor necrosis factor-α (TNF-α), and high sensitivity C-reactive protein (Hs-CRP). We observed higher BMI, WC, FPI, HOMA index, TC, LDL-C, RBP-4, leptin, IL-6, adipsin, Hs-CRP, vaspin, resistin and TNF-α levels, and lower visfatin, and ADN levels in obese compared to non-obese subjects. Higher WC correlated with lower ADN and visfatin levels, and higher vaspin levels. Higher HOMA index correlated with higher resistin, adipsin, RBP-4, and leptin concentrations, while higher leptin levels correlated with higher TNF-α, Hs-CRP, and IL-6 concentration, and lower ADN values. We confirmed obese subjects’ predisposition to develop dysmetabolic disease and hormonal dysfunctions.

Objectives: This study evaluated if triple oral therapy can be useful in improving glycemic control compared with metformin monotherapy and with a metformin and pioglitazone combination. Furthermore, we also compared a triple metformin+pioglitazone+glibenclamide combination with a metformin+pioglitazone+sitagliptin one. Subjects and Methods: After a 2-year run-in therapy-augmenting phase with metformin and pioglitazone, 453 overweight, type 2 diabetes patients were randomized to 1 year of sitagliptin versus 1 year of glibenclamide to evaluate, as the primary outcome, the variation of β-cell function both in a fasting state and after an euglycemic hyperinsulinemic and hyperglycemic clamp. As secondary outcomes we evaluated glycemic control and insulin resistance. Results: Both the triple therapy combinations were more effective in reducing glycated hemoglobin compared with metformin monotherapy and with dual therapy metformin+pioglitazone. Fasting plasma insulin level and the homeostasis model assessment insulin resistance index were significantly increased by triple therapy with glibenclamide and decreased by the one with sitagliptin. Although sitagliptin did not change the homeostasis model assessment β-function index, this value was significantly increased by glibenclamide. The fasting plasma proinsulin level was decreased by sitagliptin. Triple therapy with sitagliptin greatly improved β-cell function measures compared with the glibenclamide one and also compared with metformin monotherapy and with the metformin+pioglitazone combination. Conclusions: Dual combination therapy is more effective than monotherapy in improving glycemic control. When double therapy is not enough to reach an adequate glycemic control, sitagliptin should be preferred to glibenclamide as the third agent because of its positive effect on β-cells.

What is known and Objective: To evaluate the effects of an olmesartan/amlodipine single pill combination compared with olmesartan or amlodipine monotherapies on blood pressure control, lipid profile, insulin sensitivity and some adipocytokines levels. Methods: Two hundred and seventy‐six patients were enroled in the study and were randomly assigned to take olmesartan 20 mg, amlodipine 10 mg, or a single pill containing an olmesartan/amlodipine combination 20 mg/5 mg for 12 months. We evaluated at the baseline, and after 6 and 12 months: body weight, body mass index, systolic and diastolic blood pressure (SBP and DBP), fasting plasma glucose (FPG), fasting plasma insulin (FPI), lipid profile, adiponectin (ADN), resistin (r), interleukin‐1β (IL‐1β) and interleukin‐5 (IL‐5). At the baseline, and after 6 and 12 months, patients underwent an euglycemic, hyperinsulinemic clamp to assess insulin sensitivity (M value). Results and Discussion: There was a similar decrease in SBP and DBP after 6 and 12 months in all groups, even if olmesartan/amlodipine combination gave a major decrease in SBP and DPB compared with amlodipine and olmesartan monotherapies. Olmesartan/amlodipine combination decreased FPG after 12 months compared with amlodipine monotherapy. Olmesartan/amlodipine combination decreased FPI and HOMA index and increased M value both compared with baseline and compared with olmesartan and amlodipine monotherapies. Both olmesartan and olmesartan/amlodipine increased ADN and reduced r, without significant differences between the two groups. Regarding interleukins, no differences emerged in group to group comparison. What is new and Conclusion: Olmesartan/amlodipine combination resulted more effective than olmesartan and amlodipine monotherapies in reducing blood pressure, and in increasing insulin sensitivity parameters, but not resulted more effective in improving adipocytokines and interleukins levels analysed, compared with amlodipine or olmesartan monotherapy in hypertensive patients in this double‐blind, randomized clinical trial.

(2012). Vildagliptin action on some adipocytokine levels in type 2 diabetic patients: a 12-month, placebo-controlled study. Expert Opinion on Pharmacotherapy: Vol. 13, No. 18, pp. 2581-2591.