Teplizumab Therapy to Delay the Onset of Type 1 Diabetes.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease that results in the destruction of insulin-producing pancreatic beta cells. The incidence and prevalence of T1DM are increasing, making this one of the most common diseases of childhood. The disease is associated with significant morbidity and mortality with patients experiencing reduced quality of life and decreased life expectancy compared with the general population. Patients become dependent on exogenous insulin which has been the primary treatment since its first clinical use over 100 years ago. Although there have been advancements in glucose monitoring technology and insulin delivery devices, most patients fail to meet glycemic targets. Research has therefore focused on different treatment options to delay or prevent disease progression. Monoclonal antibodies have previously been utilized to suppress the immune response following an organ transplant and were subsequently studied for their ability to treat autoimmune diseases. Teplizumab, a monoclonal antibody (manufactured by Provention Bio and marketed as Tzield), was recently approved by the Food and Drug Administration as the first preventative treatment for T1DM. The approval came after a 3-decade history of research and development. This article provides an overview of the discovery and mechanism of action of teplizumab, as well as the clinical trials that led to its approval.

Tirzepatide for Weight Loss: Can Medical Therapy "Outweigh" Bariatric Surgery?

The worldwide prevalence of obesity has been increasing progressively over the past few decades and is predicted to continue to rise in coming years. Unfortunately, this epidemic is also affecting increasing rates of children and adolescents, posing a serious global health concern. Increased adiposity is associated with various comorbidities and increased mortality risk. Conversely, weight loss and chronic weight management are associated with improvements in overall morbidity and mortality. The pathophysiology of obesity is multifactorial with complex interactions between genetic and environmental factors. The foundation of most weight loss plans is lifestyle modification including dietary change and exercise. However, lifestyle modification alone is often insufficient to achieve clinically meaningful weight loss due to physiological mechanisms that limit weight reduction and promote weight regain. Therefore, research has focused on adjunctive pharmacotherapy to enable patients to achieve greater weight loss and improved chronic weight maintenance compared to lifestyle modification alone. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin hormone analogs that have proven effective for the management of type 2 diabetes mellitus as well as obesity and overweight. Tirzepatide is a novel "twincretin" that functions as a dual glucose-dependent insulinotropic polypeptide and GLP-1 RA. Tirzepatide was recently approved by the Food and Drug Administration for the management of type 2 diabetes. Similar to previously approved GLP-1RAs, weight loss is a common side effect of tirzepatide which prompted research focused on its use as a primary weight loss therapy. Although this drug has not yet been approved as an antiobesity medication, there are several phase 3 clinical trials that have demonstrated superior weight loss efficacy compared with previously approved medications. This review article will discuss the discovery and mechanism of tirzepatide, as well as the completed and ongoing trials that may lead to its approval as an adjunctive pharmacotherapy for weight loss.

Semaglutide for Weight Loss: Was It Worth the Weight?

Obesity is a major public health issue with an increasing prevalence worldwide. Excess body fat is associated with various comorbidities, as well as increased overall mortality risk. The benefits of weight loss are evident by the reductions in morbidity and mortality. The foundation for most weight loss programs involves strict lifestyle modification, including dietary change and exercise. Unfortunately, many individuals struggle with weight loss and chronic weight management due to difficulty adhering to long-term lifestyle modification and the metabolic adaptations that promote weight regain. The use of adjunctive pharmacotherapy has been employed to help patients not only achieve greater weight loss than lifestyle modification alone but also to assist with long-term weight management. Historically, antiobesity drugs have produced only modest weight loss and required at least once daily administration. Glucagon-like peptide-1 (GLP-1), a hormone with significant effects on glycemic control and weight regulation, has been explored for use as adjunctive pharmacotherapy for weight loss. Semaglutide, a GLP-1 receptor agonist, was recently approved by the Food and Drug Administration for chronic weight management in adults with obesity or who are overweight. The approval came after the publication of the Semaglutide Treatment Effect in People with Obesity clinical trials. In these 68-week trials, semaglutide 2.4 mg was associated with significantly greater weight loss compared to placebo. Semaglutide differs from other GLP-1 receptor agonists by having a longer half-life and producing greater weight loss. This article provides an overview of the discovery and mechanism of action of semaglutide 2.4 mg, and the clinical trials that led to its approval.

Heart failure with preserved ejection fraction: key stumbling blocks for experimental drugs in clinical trials.

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) is a disease with a high prevalence. Accounting for more than 50% of all heart failure cases, it carries a significant mortality. There is a lack of therapeutic options that show improvement in morbidity and mortality. Certain novel therapies have shown a decrease in heart failure hospitalizations; however, this beneficial effect was more pronounced for heart failure patients with mildly reduced ejection fraction (EF). AREAS COVERED: This review summarizes the pathophysiology of the disease to help elucidate the differences between heart failure with reduced ejection fraction (HFrEF), and HFpEF, which could explain why therapies are successful in one (rather than the other). This review focuses on non-standardized nomenclature across major trials, the challenges of finding a therapeutic agent for such a heterogeneous population, and identification of specific phenotypes that have different outcomes and could be a target for future therapies. EXPERT OPINION: Lack of standardized diagnostic criteria, associated with population heterogeneity, might explain why trials have failed to improve outcomes for patients with HFpEF. Standardizing phenotypes, recapitulating these phenotypes in animal models, and understanding the mechanisms of the disease at the molecular level could be the first steps in identifying promising therapeutic options.

The Pivotal Role of Adipocyte-Na K peptide in Reversing Systemic Inflammation in Obesity and COVID-19 in the Development of Heart Failure.

This review summarizes data from several laboratories that have demonstrated a role of the Na/K-ATPase, specifically its α1 subunit, in the generation of reactive oxygen species (ROS) via the negative regulator of Src. Together with Src and other signaling proteins, the Na/K-ATPase forms an oxidant amplification loop (NKAL), amplifies ROS, and participates in cytokines storm in obesity. The development of a peptide fragment of the α1 subunit, NaKtide, has been shown to negatively regulate Src. Several groups showed that the systemic administration of the cell permeable modification of NaKtide (pNaKtide) or its selective delivery to fat tissue-adipocyte specific expression of NaKtide-ameliorate the systemic elevation of inflammatory cytokines seen in chronic obesity. Severe acute respiratory syndrome - coronavirus 2 (SARS-CoV-2), the RNA Coronavirus responsible for the COVID-19 global pandemic, invades cells via the angiotensin converting enzyme 2 (ACE-2) receptor (ACE2R) that is appended in inflamed fat tissue and exacerbates the formation of the cytokines storm. Both obesity and heart and renal failure are well known risks for adverse outcomes in patients infected with COVID-19. White adipocytes express ACE-2 receptors in high concentration, especially in obese patients. Once the virus invades the white adipocyte cell, it creates a COVID19-porphyrin complex which degrades and produces free porphyrin and iron and increases ROS. The increased formation of ROS and activation of the NKAL results in a further potentiated formation of ROS production, and ultimately, adipocyte generation of more inflammatory mediators, leading to systemic cytokines storm and heart failure. Moreover, chronic obesity also results in the reduction of antioxidant genes such as heme oxygenase-1 (HO-1), increasing adipocyte susceptibility to ROS and cytokines. It is the systemic inflammation and cytokine storm which is responsible for many of the adverse outcomes seen with COVID-19 infections in obese subjects, leading to heart failure and death. This review will also describe the potential antioxidant drugs and role of NaKtide and their demonstrated antioxidant effect used as a major strategy for improving obesity and epicardial fat mediated heart failure in the context of the COVID pandemic.