Steven G. Terra

Potential implications of matrix metalloproteinase-9 in assessment and treatment of coronary artery disease

Background: Matrix metalloproteinase (MMP)-9, a member of the MMP superfamily is consistently implicated in the pathophysiology of atherosclerosis and plaque rupture, the most common mechanism responsible for acute coronary syndrome (ACS). Aim: To summarize the role of MMP-9 in atherosclerosis and its potential implications in assessment and treatment of coronary artery disease (CAD). Methods: We reviewed the PubMed database for relevant data regarding the role of MMP-9 in the pathophysiology of atherosclerosis. In the light of these data, we postulate potential implications of MMP-9 in the management and treatment of CAD. Results and conclusions: Existing data strongly support the role of MMP-9 in plaque destabilization and rupture. Based on the current knowledge, MMP-9 can potentially serve as a diagnostic biomarker in ACS and a prognostic biomarker in ACS and chronic CAD patients. MMP-9 is reduced by therapies that are associated with favourable outcome in atherosclerosis and thus may serve as a surrogate biomarker of treatment efficacy. However, large morbidity and mortality trials are still required to confirm that MMP-9 reduction is associated with improved outcome independent of the traditional risk factors (i.e. low-density lipoprotein cholesterol). Given its role in plaque rupture, inhibition of MMP-9 may promote plaque stabilization and consequently reduce cardiovascular events. Yet, the efficacy and safety of MMPs inhibitors should be first studied in preclinical models of atherosclerosis.

Angiotensin Receptor Blockers

Angiotensin receptor blockers (also known as ARBs) are a class of medications that are widely used by patients with high blood pressure, kidney disease, and heart failure. This article provides information for patients who receive this type of medication. The Table lists the brand and chemical names for the angiotensin receptor blockers that are available in the United States. View this table: List of Angiotensin Receptor Blockers Available in the United States Angiotensin receptor blockers work by inhibiting the effects of a hormone called angiotensin 2, which produces a number of effects in the body: Constriction of blood vessels, increased salt and water retention, activation of the sympathetic nervous system, stimulation of blood vessel and heart fibrosis (stiffening), and promotion of heart cell growth. Together, these effects can increase blood pressure and in some situations be harmful to the heart and kidneys. For angiotensin 2 to produce its effects in the body, it must bind to a receptor in much the same way that a …

Phase III, efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone

To conduct a phase III study to evaluate the efficacy and safety of ertugliflozin monotherapy in people with type 2 diabetes.

Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo-controlled randomized study

To assess ertugliflozin in patients with type 2 diabetes who are inadequately controlled by metformin and sitagliptin.

Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial

To evaluate the efficacy and safety of ertugliflozin and sitagliptin co‐administration vs the individual agents in patients with type 2 diabetes who are inadequately controlled with metformin.

Efficacy and safety of a potent and selective peroxisome proliferator activated receptor alpha agonist in subjects with dyslipidemia and type 2 diabetes mellitus.

The weak peroxisome proliferator activated receptor-alpha (PPAR-alpha) agonists gemfibrozil and fenofibrate achieve only small increases in high-density lipoprotein (HDL) cholesterol. CP-778,875 is a more potent PPAR-alpha agonist developed to produce greater HDL cholesterol increases. This randomized, multicenter, double-blinded, placebo-controlled study evaluated the efficacy and safety of CP-778,875 in subjects with mixed dyslipidemia and type 2 diabetes. Eight-six subjects with low HDL cholesterol (< or =45 mg/dl for men and < or =55 mg/dl for women) and increased triglycerides (150 to 500 mg/dl) who had coexisting type 2 diabetes were randomized. Subjects received CP-778,875 doses of 0.5, 2, or 6 mg/day or placebo for 6 weeks. Any other lipid-altering therapy was stopped at screening. The primary end point was percent change in HDL cholesterol from baseline. The 2-mg/day dose of CP-778,875 significantly increased HDL cholesterol by 14%. The 2-mg dose also increased concentrations of apolipoprotein (apo) A-I, HDL(2) cholesterol, and HDL(3) cholesterol by 13%, 12%, and 19%, respectively. An unusual dose-response pattern was observed in that at 6 mg/day CP-778,875 only increased HDL cholesterol by 3% and decreased HDL(2) cholesterol by 24%. Fasting triglyceride levels were significantly decreased to a similar extent (26%) by all 3 doses of CP-778,875. CP-778,875 significantly increased homocysteine levels. There was no significant relation between change in homocysteine and change in apoA-I or HDL cholesterol. No subjects developed myopathy. In conclusion, CP-778,875 2 mg/day significantly increased HDL cholesterol, significantly lowered fasting triglycerides, and increased apoA-I and HDL subfractions. The clinical relevance of the increase in homocysteine levels is unknown.

Non-traditional biomarkers of atherosclerosis in stable and unstable coronary artery disease, do they differ?

Background: Biomarkers of atherosclerosis are emerging as a potential tool for assessment of coronary artery disease (CAD) patients. As acute coronary syndrome (ACS), and stable CAD are distinguished in their pathophysiology it is conceivable that they are also characterized by different biomarkers of atherosclerosis. Methods: We systematically reviewed the literature for clinical studies of several non‐traditional biomarkers of atherosclerosis reflecting various pathophysiological processes, namely macrophage‐activity, oxidative‐stress, tissue remodeling, and thrombosis in ACS and stable CAD to determine whether circulating biomarkers are differently expressed/predict outcome in these two clinical conditions. Results: Macrophage‐activity (monocyte chemoattractant protein‐1, neopterin), tissue‐remodeling (matrix metalloproteinase‐9) and thrombosis (tissue‐factor) related biomarkers were consistently elevated in ACS compared to stable CAD, in accordance with the pathophysiological role of these mediators in plaque rupture, characterizing ACS. Thus, these biomarkers may be applicable for diagnosis of ACS. Additionally, neopterin was consistently shown to predict outcome in both stable and ACS patients and myeloperoxidase was strongly shown to predict outcome in ACS, implying for their potential role in risk stratification of these patients. Conclusions: As ACS and stable CAD are characterized by different pathophysiological processes, it appears that the biomarkers that are associated with them are differently expressed in these two clinical conditions.

Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET)

We evaluated the efficacy and safety of ertugliflozin, an SGLT2 inhibitor, in type 2 diabetes mellitus (T2DM) inadequately controlled (HbA1c, 7.0%‐10.5%) with metformin monotherapy (≥1500 mg/d for ≥8 weeks).

The Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Ertugliflozin in Subjects With Type 2 Diabetes Mellitus.

Ertugliflozin is a highly selective and potent inhibitor of the sodium‐glucose cotransporter 2 in development for the treatment of type 2 diabetes mellitus. The glycemic efficacy of sodium‐glucose cotransporter 2 inhibitors such as ertugliflozin depends on glucose filtration through the kidney. This phase 1, open‐label study evaluated the effect of renal impairment on the pharmacokinetics, pharmacodynamics, and tolerability of ertugliflozin (15 mg) in type 2 diabetes mellitus and healthy subjects with normal renal function (estimated glomerular filtration rate not normalized for body surface area ≥90 mL/min) and type 2 diabetes mellitus subjects with mild (60‐89 mL/min), moderate (30‐59 mL/min), or severe (<30 mL/min) renal impairment (n = 36). Blood and urine samples were collected predose and over 96 hours postdose for pharmacokinetic evaluation and measurement of urinary glucose excretion over 24 hours. Log‐linear regression analyses indicated predicted mean area under the concentration‐time curve values for mild, moderate, and severe renal function groups that were ≤70% higher relative to subjects with normal renal function. Generally consistent results were obtained with categorical analysis based on analysis of variance. The increase in ertugliflozin exposure in subjects with renal impairment is not expected to be clinically meaningful. Regression analysis of change from baseline in urinary glucose excretion over 24 hours vs estimated glomerular filtration rate showed a decrease in urinary glucose excretion with declining renal function. A single 15‐mg dose of ertugliflozin was well tolerated in all groups.

Evaluation of Methods for Improving Precision of Blood Pressure Measurements in Phase I Clinical Trials

Small sample sizes are typically incorporated in early Phase I clinical studies, which may lead to insignificant changes in safety parameters such as blood pressure. Therefore, it is paramount to identify an optimal, noninvasive method of accurately measuring blood pressure and an appropriate analysis strategy yielding the smallest variability. The goals of this study were (1) to compare the variability between automated and manual blood pressure measurements, (2) to determine whether triplicate blood pressure measurements were independent of one another, and (3) to assess how the number of blood pressure readings affects variability and study sample size. Twenty healthy volunteers were enrolled in this randomized, two‐way crossover study. Each subject received three incremental infusions of phenylephrine or normal saline on separate days to simulate blood pressure variability. The mean systolic blood pressure readings with the automated device were consistently higher than the manual device by 3 to 5 mmHg. Conversely, the mean diastolic blood pressure readings with the automated device were consistently 3 to 5 mmHg lower than the manual device. However, the variability and absolute change in blood pressure were essentially identical with manual and automated methods. No systematic order effects such as the first blood pressure reading always being higher were detected, suggesting that the triplicate readings were independent of one another and that an interval of 2 minutes between readings is adequate. Compared to a single measurement, collecting blood pressure in triplicate results in a 40% lower sample size needed to detect a 5‐mmHg difference in systolic blood pressure.