Efficacy and safety of dapagliflozin monotherapy in people with Type 2 diabetes: a randomized double-blind placebo-controlled 102-week trial.

AIMS: To assess initial pharmacotherapy of Type 2 diabetes with the sodium-glucose cotransporter-2 inhibitor dapagliflozin. METHODS: This double-blind, placebo-controlled trial, randomly allocated people with Type 2 diabetes aged 18-77 years and inadequate glycaemic control on diet and exercise [HbA1c 53-86 mmol/mol (7.0-10.0%)] to receive placebo (n = 75) or dapagliflozin monotherapy 2.5 mg (n = 65), 5 mg (n = 64) or 10 mg (n = 70) once daily in the morning. After 24 weeks, low-dose double-blind metformin 500 mg/day was added to the placebo group regimen (placebo+low-dose metformin group). Changes in HbA1c level, fasting plasma glucose and body weight, as well as adverse events, were assessed over 102 weeks. RESULTS: Of the 274 participants randomized, 167 completed the study (60.9%). At 102 weeks, significant differences vs placebo+low-dose metformin with dapagliflozin 5 and 10 mg were observed for HbA1c (-5.8 mmol/mol [-0.53%], P = 0.018; and -4.8 mmol/mol [-0.44%], P = 0.048), respectively); and for FPG (-0.69 mmol/L, P = 0.044; and -1.12 mmol/l, P = 0.001, respectively). For body weight, the difference between the dapagliflozin 10-mg group and the placebo+low-dose metformin group was significant (-2.60 kg; P = 0.016). Hypoglycaemic events were uncommon, with rates of 5.3% for placebo+low-dose metformin group and 0-4.6% for the dapagliflozin groups. Genital infections and urinary tract infections were more common in the dapagliflozin groups than in the placebo+low-dose metformin group. CONCLUSIONS: Dapagliflozin as monotherapy in treatment-naïve people with early Type 2 diabetes improved glycaemic control and reduced weight without increasing hypoglycaemia over 102 weeks. Dapagliflozin may provide an alternative initial pharmacotherapy in such people.

PCSK9 and LDLR The Yin-Yang in the Cellular Uptake of Cholesterol.

The intracellular concentration of cholesterol is a vital constant influenced by the uptake, metabolism and excretion of cholesterol. The synthesis and expression of the PCSK9-LDLR duo is one of the most important mechanisms to regulate this constant; in a physiological state, the yin-yang balance between PCSK9 and LDLR regulates the entry of cholesterol into the cell to keep the intracellular cholesterol concentration stable. The mapping of the human gene encoding the serine protease PCSK9, located at 1p32-3, has allowed the identification of mutations with "gain" and "loss" of protease functions. Gain of function mutations causes decreased LDLR resulting in increased LDL-C and increased incidence of cardiovascular events. Loss of function mutations have opposite effect, increased LDLR, decreased LDL-C and decreased incidence of cardiovascular events. The identification of human mutations with PCSK9 "loss" of function demostrated the benefit of decreased PCSK9 and opened the door to developing new anti-PCSK9 therapies. The goal of this research area is to reduce the incidence of cardiovascular events beyond statins; the strategy is to mimic the state of PCSK9 "loss" of function by tactics as oligonucleotide therapies targeting PCSK9 mRNA and/or biological therapies with human monoclonal antibodies targeting PCSK9. This chapter reviews, the characteristics of the PCSK9, the physiological significance of the PCSK9-LDLR duo, and the therapeutic implications of the human genetic models of PCSK9 "loss" of function. The phase I-II clinical trial data of two promising monoclonal antibodies to PCSK9, Alirocumab formerly SAR236553/REGN727and AMG145 will be presented.

Coronary Atherosclerosis The Implications of Being a Woman.

The profile of ischemic heart disease by coronary atherosclerosis has been developed based on clinical, paraclinical and angiographic grounds inherent to the male gender. A man in his 40s - 50s with "classical" cardiovascular risk factors, angina pectoris and hemodynamically significant myocardial ischemia associated with angiographic stenosis (≥ 50% endovascular diameter reduction equivalent to ≥ 75% endovascular area reduction and determining a trans-stenotic pressure gradient) is the prototype over which guidelines for prevention, diagnosis and treatment of this disease are structured. However, this "male" pattern of coronary atherosclerosis is not the rule in female gender. Therefore, in women, the frequent lack of a clinical, paraclinical and angiographic profile, classically masculine, results in a suboptimal medical approach, characterized by low implementation of the guidelines for prevention, diagnosis and treatment of ischemic heart disease. The final consequence of this cycle, favored by other gender, social and environmental circumstances, is a high morbidity and mortality caused by this pathology in the female gender. In this chapter, which concludes with a review of the state-of-the-art knowledge of atheroma in females, the current concepts on the physiological level of c-LDL, oxidized c-LDL "a mimicked pathogen" and atherogenesis will be reviewed in sequence for didactic purposes.

Dyslipidemia, Hypertension and Diabetes Metaflammation. A Unique Mechanism for 3 Risk Factors.

The main current threat to the human race is the correlation and synergy between two determining triumvirates of atherosclerosis, cardiovascular disease and death. The first triumvirate is constituted by obesity, metaflammation and insulin resistance; the second triumvirate is constituted by atherogenic dyslipidemia, hypertension and type 2 diabetes mellitus. The etiopathogenic driving force for both triumvirates is the global epidemic of obesity. Metaflammation and insulin resistance are associated with obesity; in turn, insulin resistance determines a high risk for the development of atherogenic dyslipidemia, hypertension and type 2 diabetes mellitus, the three of them being factors responsible for vascular endothelial injury and substrates involved in the genesis of atherosclerosis, cardiovascular disease and death. The present chapter will address both triumvirates. Firstly, the current concepts of obesity, metaflammation and insulin resistance will be reviewed; emphasizing the second (metaflammation) for being a concept that has revolutionized and integrated our understanding of the harmful effects of obesity. Secondly, the impact of insulin resistance in the regulation of intermediary metabolism and endothelial function will be addressed; this will facilitate the understanding of the inextricable link between atherogenic dyslipidemia, hypertension and type 2 diabetes mellitus. Thus, this chapter aims to present to the clinician the best knowledge to link epidemics of obesity and cardiovascular death, through the sequence of metaflammation, insulin resistance and cardiovascular risk factors (mixed dyslipidemia, hypertension and type 2 diabetes mellitus).

[Electroechocardiography correlation in the diagnosis of left ventricular hypertrophy in patients with systemic arterial hypertension]. / Correlación electroecocardiográfica en el diagnóstico de hipertrofia ventricular izquierda en pacientes con hipertensión arterial sistémica.

To evaluate the surface (12 derivations) electrocardiogram in its possibility to predict left ventricular hypertrophy, the diastolic thickness of the posterior wall of the left ventricle was determined by M mode echocardiography in 12 normal persons and 47 hypertensive patients. In all cases the echocardiographic findings concerning diastolic thickness of the free wall of the left ventricle were studied as well as their relation ship to several electrocardiographic criteria mentioned in literature as indicative of left ventricle hypertrophy. The sensitivity, specificity and precision were calculated for each EKG criterion. The electrocardiographic criteria in general are little sensitive, highly specific and very variable in its accuracy. The most sensitive criteria found as indicative of left ventricle hypertrophy were the T positive wave in V1 higher than the T in V6 and the intrinsecoid deflection time inscription higher than 0.04 sec.

[Asymptomatic myocardial ischemia]. / Isquemia miocárdica asintomática.

The concept, physiopathology, epidemiology, diagnostic procedures, prognosis and treatment of asymptomatic myocardial ischemia are reviewed. Hypotheses given to explain the absence of pain in the presence of myocardial ischemia are analyzed; Cohn's classification of asymptomatic myocardial ischemia is described and complemented with other clinical entities of painless myocardial ischemia. Prevalence of asymptomatic myocardial ischemia in different groups of patients is also discussed as well as the most important characteristics of diagnostic procedures. Finally the prognosis of asymptomatic myocardial ischemia is analyzed and the present therapeutic possibilities are discussed.