Long-term impact of mediterranean diet on cardiovascular disease prevention: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Dietary modification plays a pivotal role in the prevention of cardiovascular disease (CVD), with particular emphasis on the potential benefits associated with adopting a Mediterranean diet (MedDiet). Numerous observational studies have explored the impact of the MedDiet on CVD prevention, addressing both primary and secondary prevention. However, a substantial portion of the primary evidence comes from specific Randomized Controlled Trials (RCTs), such as the Lyon Diet Heart Study, the Indo-Mediterranean Diet Heart Study, the PREDIMED Study, and the recent CORDIOPREV Study. To provide a comprehensive assessment of the long-term clinical effects, we conducted a meta-analysis, systematically synthesizing findings from RCTs to better understand the preventive impact of MedDiet on cardiovascular health. METHODS: We searched for RCTs exploring the efficacy of MedDiet on CVD prevention from inception until January 2024, utilizing databases such as MEDLINE (via PubMed), Google Scholar, the Cochrane Library, ClinicalTrials.gov, and the ScienceDirect portal. Statistical analysis used RevMan 5.4 with a random-effects model, presenting dichotomous outcomes as odds ratios (OR) with a 95 % confidence interval (CI) and assessing heterogeneity using the I2 test. RESULTS: Our analysis incorporated four RCTs involving a total of 10,054 participants, with an average age of 57 years and a mean follow-up duration ranging from 2 to 7 years. In our pooled analysis, the composite endpoint of major adverse cardiovascular events (MACE) demonstrated a statistically significant reduction in incidence in participants on MedDiet versus control diet with an OR of 0.52 (95 % CI: 0.32 to 0.84, p = 0.008; I2 = 87 %). Additionally, our study revealed a notable decrease in the incidence of cardiovascular events, both myocardial infarction (MI) and stroke in the the MedDiet group, with an OR of 0.62 (95 % CI: 0.41 to 0.92, p = 0.02; I2 = 56 %) and 0.63 (95 % CI: 0.48 to 0.87, p = 0.002; I2 = 0 %), respectively. However, no statistically significant change in the rate of revascularization was observed, with an OR of 0.74 (95 % CI: 0.30 to 1.27, p = 0.06; I2 = 16 %). Concerning mortality rates, MedDiet significantly reduced the risk of cardiovascular death with an OR of 0.54 (95 % CI: 0.31 to 0.94, p = 0.03; I2 = 55 %), while no significant change was noted in all-cause mortality, with an OR of 0.77 (95 % CI: 0.51 to 1.15, p = 0.20; I2 = 58 %). CONCLUSION: MedDiet serves as an effective intervention for both primary and secondary prevention of CVD, demonstrating a substantial and long-term impact in reducing the incidence of MACE, MI, stroke, and cardiovascular-related mortality while showing no observed effect on all-cause mortality. Nevertheless, it is essential to acknowledge the current limitations in available clinical trial evidence, emphasizing the need for additional trials to substantiate and strengthen these findings.

Supervised exercise training in heart failure with preserved ejection fraction: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) represents a prevalent and increasingly common condition. Recognized for its high incidence, there is a growing interest in exploring effective interventions, with exercise emerging as a critical component in the rehabilitation of HFpEF patients. We aim to update evidence on the impact of supervised exercise training on exercise capacity, diastolic function, arterial stiffness, and health-related quality of life (QoL) of individuals diagnosed with HFpEF. METHODS: We systematically reviewed the literature, searching from inception to December 2023, utilizing databases such as MEDLINE (via PubMed), Google Scholar, the Cochrane Library, ClinicalTrials.gov, and the ScienceDirect portal. Statistical analyses utilized RevMan 5.4 with a random-effects model. Outcomes were presented as the weighted mean difference (WMD) alongside corresponding 95 % confidence intervals (CI), and heterogeneity was assessed using the I2 test. RESULTS: Our final analysis included 7 randomized controlled trials (RCTs) of 346 participants, with an exercise follow-up duration of 12 to 48 weeks. In our pooled analysis, diastolic function, measured by E/A (WMD 0.01, 95 % CI: -0.04 to 0.05, p = 0.79; I2 = 0 %) and E/e' (WMD 0.87, 95 % CI: -11.09 to 12.83, p = 0.89; I2 = 69 %), showed no significant change post-exercise training. However, exercise capacity, measured by peak V̇o2 significantly improved (WMD 2.57, 95 % CI: 1.38 to 3.75, p < 0.0001; I2= 14 %). The QoL assessed by the Minnesota Living with Heart Failure (MLWHF) score remained unchanged (WMD -3.12, 95 % CI: -8.73 to 2.50, p = 0.28; I2 = 0 %), but the SF-36 physical functioning scale indicated significant improvement (WMD 9.84, 95 % CI: 2.94 to 16.73, p < 0.005; I2 = 0 %). Arterial stiffness and vascular function remained unaffected, as evidenced by arterial elastance (WMD -0.13, 95 % CI: -0.36 to 0.10, p = 0.26; I2 = 0 %) and total arterial compliance (WMD 0.12, 95 % CI: -0.26 to 0.49, p = 0.54; I2 = 0 %). CONCLUSION: Exercise training is safe and significantly enhances exercise capacity and QoL in HFpEF, with no significant impact on diastolic function, arterial stiffness, or vascular function.

Cardiovascular disease risk communication: Strategies, impact, and future directions.

Cardiovascular disease (CVD) prevails as the leading cause of global mortality, claiming the lives of an estimated 17.9 million individuals in 2019, representing a substantial portion of worldwide mortality. Research indicates that individuals with a deeper understanding of their cardiovascular health are more inclined to adhere to preventive measures, potentially leading to improved outcomes. Moreover, inadequate communication may undermine confidence in healthcare professionals, fostering anxiety and other adverse consequences. CVD risk communication serves as a powerful tool in enhancing comprehension and supporting informed decisions regarding the clinical management of CVD. This review examines the impact of CVD risk communication on cardiovascular outcomes, exploring diverse strategies for conveying information about cardiovascular risks and preventive measures. The effectiveness of these strategies in influencing patient behavior and health outcomes is thoroughly assessed. Furthermore, gaps in current approaches are discussed, and future directions are proposed for enhancing CVD risk communication and improving patient education, engagement, and overall cardiovascular health.

Heart Failure: Recent Advances and Breakthroughs.

Heart failure (HF) is a common clinical condition encountered in various healthcare settings with a vast socioeconomic impact. Recent advancements in pharmacotherapy have led to the evolution of novel therapeutic agents with a decrease in hospitalization and mortality rates in HF with reduced left ventricular ejection fraction (HFrEF). Lately, the introduction of artificial intelligence (AI) to construct decision-making models for the early detection of HF has played a vital role in optimizing cardiovascular disease outcomes. In this review, we examine the newer therapies and evidence behind goal-directed medical therapy (GDMT) for managing HF. We also explore the application of AI and machine learning (ML) in HF, including early diagnosis and risk stratification for HFrEF.

Tachy-brady syndrome: Electrophysiology and evolving principles of management.

Sudden alterations in the heart rate may be associated with diverse symptoms. Sinus node dysfunction (SND), also known as sick sinus syndrome, is a sinoatrial (SA) node disorder. SND is primarily caused by the dysfunction of the pacemaker, as well as impaired impulse transmission resulting in a multitude of abnormalities in the heart rhythms, such as bradycardia-tachycardia, atrial bradyarrhythmias, and atrial tachyarrhythmias. The transition from bradycardia to tachycardia is generally referred to as "tachy-brady syndrome" (TBS). Although TBS is etiologically variable, the manifestations remain consistent throughout. Abnormal heart rhythms have the propensity to limit tissue perfusion resulting in palpitations, fatigue, lightheadedness, presyncope, and syncope. In this review, we examine the physiology of tachy-brady syndrome, the practical approach to its diagnosis and management, and the role of adenosine in treating SND.

Factors influencing the quality of life in inflammatory bowel disease: A comprehensive review.

Inflammatory bowel disease (IBD) is a group of chronic relapsing disorders, including Crohn's disease (CD) and ulcerative colitis (UC), which affects an increasing number of people worldwide. In the last few decades, the scientific world has witnessed many developments in IBD management by controlling debilitating symptoms and remaining in remission for more protracted periods. Even so, we still have a large population suffering from active IBD. An individual's quality of life (QoL) can be severely affected by IBD, like any other chronic illness. In this article, we have reviewed factors influencing the QoL in IBD patients, including chronic pain, diet, physical activity, and psychological factors like depression, anxiety, and stress symptoms. We also discussed the mechanisms of diet-microbial-immune system interaction, currently available dietary therapies for active CD and UC, and early psycho-social interventions that can reduce the disease burden and improve QoL in IBD patients.

Ethnic Disparities in the Burden of Cardiovascular Disease Among Immigrants in Canada.

Canada has the highest level of immigration, with one in four Canadians being immigrants. And little is known about the ethnic differences and cardiovascular disease (CVD) risk in the Canadian immigrant population. The high level of immigration has resulted in significant ethnic diversity in Canada, with each presenting a CVD risk profile unique to their ethnicity and country of birth. A better understanding of the ethnic differences in the risk of CVD could help navigate effective health promotion and targeted interventions, which can mitigate the burden of morbidity and mortality associated with the disease.

Cardiovascular-Kidney-Metabolic (CKM) syndrome: A state-of-the-art review.

The correlation between obesity, type 2 diabetes mellitus (DM), cardiovascular disease (CVD), and chronic kidney disease (CKD) is an escalating and widely acknowledged epidemic in industrialized nations. Recently, this complex web of interrelated health conditions has been collectively defined as the Cardiovascular-Kidney-Metabolic (CKM) syndrome by the American Heart Association (AHA). The molecular mechanisms underlying CKM disease contain a spectrum of interconnected factors, including hyperglycemia, insulin resistance, heightened activity of the renin-angiotensin-aldosterone system (RAAS), the generation of advanced glycation end-products, oxidative stress, lipotoxicity, endoplasmic reticulum stress, abnormalities in calcium handling, malfunctioning of mitochondria and impaired energy production, as well as persistent chronic inflammation. Addressing their prevention, management, and treatment is of paramount importance to promote better patient health outcomes. The objective of this review is to provide a comprehensive and critical examination of the current state-of-the-art regarding the recently defined CKM syndrome. This includes an exploration of epidemiological evidence establishing connections between cardio-renal-metabolic diseases, an examination of the underlying pathophysiological mechanisms, and a comprehensive overview of existing treatment modalities.

Usefulness of Carotid Ultrasound Screening in Primary Cardiovascular Prevention: A Systematic Review.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, and its prevention is more cost-effective than the treatment of its complications. Although cardiovascular (CV) risk assessment based on conventional risk factors is the general recommendation, a significant percentage of the population, irrespective of these risk factors, present with subclinical atherosclerosis during carotid Doppler ultrasound (US) imaging. Subclinical atherosclerotic lesions at the carotid bifurcations may be related to the incidence of future CV events and occult atherosclerotic coronary disease. Such patients might benefit from preventive measures if the carotid Doppler US is allowed as a screening tool to detect the extent of carotid stenosis. We aimed to conduct a comprehensive and systematic evaluation of the impact of carotid US screening on CV risk stratification. METHODS: We searched PubMed, Scopus, and ScienceDirect from inception until July 2023. We included literature that examined the impact of carotid US screening on cardiovascular risk factor (CVRF) prevention, CV events, and mortality in adults of all age groups free of symptomatic carotid artery disease. RESULTS: We identified 2 randomized controlled trials (RCTs) and 9 observational studies, including 21,046 participants. The mean age of the participants was 49, and 53% were female. Two RCTs, with 7,064 participants, examined the impact of pictorial knowledge about subclinical carotid atherosclerosis using carotid US versus traditional CVD risk evaluation without any US evidence in primary cardiovascular prevention. Both studies reported remarkable improvement in medication adherence at 1 to 3-year follow-up after carotid US screening with a decrease in Framingham risk score (FRS). Nine observational studies with 13, 982 participants analyzed the evidence of atherosclerosis on carotid US screening and demonstrated that it is a beneficial tool in the early identification of subclinical atherosclerosis and effective therapeutic intervention. CONCLUSION: This systematic review found that pictorial presentation of silent atherosclerosis using carotid US screening has a contributory role in CV risk stratification and prevention of CVD.

Metabolic surgery in improving arterial health in obese individuals.

PURPOSE: Arterial stiffness has gained recognition as a stand-alone risk factor for cardiovascular disease (CVD). Obesity is intricately linked to elevated arterial stiffness, the development of left ventricular (LV) hypertrophy, and the emergence of diastolic dysfunction, all of which collectively contribute substantially to an unfavorable prognosis. Weight loss has become a standard recommendation for all patients with CVD concurrent with morbid obesity; however, randomized evidence to support this recommendation was limited earlier. The latest scientific studies revealed dynamic changes in aortic stiffness after substantial weight loss by bariatric surgery, also known as metabolic surgery, in patients with obesity. There is also a favorable evolution in LV hypertrophy and a significant impact on arterial hypertension and other promising cardiovascular outcomes in obese people after bariatric surgery. METHODS/RESULTS: We aimed to examine the cardiovascular effects of various metabolic surgeries in morbidly obese individuals, especially their role in improving arterial health, the potential impact on surrogate markers of atherosclerotic vascular disease, and consequently reducing the likelihood of cardiovascular events. CONCLUSION: In conclusion, metabolic surgery is associated with a significant decrease in the occurrence of major adverse cardiovascular events (MACE) and all-cause mortality among obese individuals, alongside remarkable enhancement of arterial health. These findings underscore the critical importance of implementing strategies to combat obesity and reduce adiposity within the general population.

Narrative Review of Probiotic Use on the Recovery of Postoperative Patients with Esophageal Cancer.

PURPOSE OF REVIEW: This narrative review discusses the significance of probiotic therapy in the postoperative care of patients with esophageal cancer and its role as an adjunct therapy to other treatment modalities for esophageal cancer. RECENT FINDINGS: As such, there is an emerging need to address any malnutrition and gastrointestinal problems occurring in these patients which tend to have a strong negative impact on their prognosis. Probiotic effects on esophageal cancer biomarkers suggest that there is a positive correlation between these two factors. However, the beneficial effects remain controversial and warrant further investigation. Probiotics, now being widely utilized as postoperative therapy in some carcinomas of the gastrointestinal tract such as gastric cancer and colorectal cancer, have been shown in some clinical studies to positively impact the nutritional status of patients with esophageal cancer. Postoperative care among patients suffering from esophageal cancer is a very crucial aspect in the survival of these patients.

Aficamten: A Breakthrough Therapy for Symptomatic Obstructive Hypertrophic Cardiomyopathy.

Aficamten is a novel cardiac myosin inhibitor that has demonstrated its ability to safely lower left ventricular outflow tract (LVOT) gradients and improve heart failure symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM). Based on the REDWOOD-HCM open label extension (OLE) study, participants receiving aficamten had significantly reduced resting and Valsalva LVOT gradient within 2 weeks after initiating treatment, with ongoing improvements over 24 weeks, and recent evidence suggests effects can sustain up to 48 weeks. While beta-blockers, calcium channel blockers, and disopyramide have shown some benefits in managing HCM, they have limited direct impact on the underlying disease process in patients with obstructive HCM. Aficamten achieves its therapeutic effect by reducing hypercontractility and improving diastolic function in obstructive HCM. Mavacamten was the first cardiac myosin inhibitor approved for symptomatic obstructive HCM. However, aficamten has a shorter human half-life (t1/2) and fewer drug-drug interactions, making it a preferable treatment option. This review evaluates the long-term clinical value and safety of aficamten in patients with obstructive HCM based on available data from completed and ongoing clinical trials. Additionally, the molecular basis of sarcomere-targeted therapy in reducing LVOT gradients is explored, and its potential in managing obstructive HCM is discussed.

Recurrent syncopal episodes in a pregnant patient with neurocysticercosis.

Neurocysticercosis (NCC) is the most common parasitic infection of the nervous system and acquired epilepsy in low-resource settings due to the pork tapeworm, Taenia solium. Humans contract the intestinal infection of the adult tapeworm (taeniasis) through the fecal-oral route after consuming undercooked food, particularly pork or water, contaminated with tapeworm eggs. When the larvae invades the central nervous system (CNS), the infection causes NCC, which often manifests as late-onset seizures, chronic headaches, and intracranial hypertension. We describe a 31-year-old Hispanic multigravida woman from Guatemala, at 33 weeks of gestation, who presented with multiple syncopal and hypotensive episodes prompting a Computed tomography (CT) image of the head revealing multiple small cerebral calcifications indicating NCC. In this article, we highlight the significance of early symptom recognition and diagnostic workup for NCC in areas with diverse immigrant populations. We also discuss the epidemiology, clinical manifestations, and current treatment modalities available for NCC.

Precision Medicine and Cardiac Channelopathies: Human iPSCs Take the Lead.

Sudden cardiac death (SCD) is one of the leading causes of death worldwide, usually involving young people. SCD remains a critical public health problem accounting for 185,000-450,000 deaths annually, representing around 7%-18% of all deaths globally. As per evidence, ∼2%-54% of sudden unexpected deaths in people under the age of 35 years fail to show evidence of structural cardiac abnormalities at autopsy, making ion channelopathies the probable causes in such cases. The most generally recognized cardiac ion channelopathies with genetic testing are long QT syndrome (LQTS), Brugada syndrome (BrS), short QT syndrome (SQTS), and catecholaminergic polymorphic ventricular tachycardia (CPVT). The substantial progress in understanding the genetics of ion channelopathies in the last 2 decades has obliged the early diagnosis and prevention of SCD to a certain extent. In this review, we analyze the critical challenges and recent advancements in the identification, risk stratification, and clinical management of potentially fatal cardiac ion channel disorders. We also emphasize the application of precision medicine (PM) and artificial intelligence (AI) for comprehending the underlying genetic mechanisms, especially the role of human induced pluripotent stem cell (iPSC) based platforms to unravel the primary refractory clinical problems associated with channelopathies.

Glucocorticoid Receptor Antagonism and Cardiomyocyte Regeneration Following Myocardial Infarction: A Systematic Review.

Myocardial regeneration has been a topic of interest in literature and research in recent years. An evolving approach reported is glucocorticoid (GC) receptor antagonism and its role in the regeneration of cardiomyocytes. The authors of this study aim to explore the reported literature on GC receptor antagonism and its effects on cardiomyocyte remodeling, hypertrophy, scar formation, and ongoing cardiomyocyte death following cardiac injury. This article overviews cellular biology, mechanisms of action, clinical implications, challenges, and future considerations. The authors of this study conducted a systematic review utilizing the Cochrane methodology and PRISMA guidelines. This study includes data collected and interpreted from 30 peer-reviewed articles from 3 databases with the topic of interest. The mammalian heart has regenerative potential during its embryonic and fetal phases which is lost during its developmental processes. The microenvironment, intrinsic molecular mechanisms, and systemic and external factors impact cardiac regeneration. GCs influence these aspects in some cases. Consequently, GC receptor antagonism is emerging as a promising potential target for stimulating endogenous cardiomyocyte proliferation, aiding in cardiomyocyte regeneration following a cardiac injury such as a myocardial infarction (MI). Experimental studies on neonatal mice and zebrafish have shown promising results with GC receptor ablation (or brief pharmacological antagonism) promoting the survival of myocardial cells, re-entry into the cell cycle, and cellular division, resulting in cardiac muscle regeneration and diminished scar formation. Transient GC receptor antagonism has the potential to stimulate cardiomyocyte regeneration and help prevent the dreaded complications of MI. More trials based on human populations are encouraged to justify their applications and weigh the risk-benefit ratio.

Gene Editing as the Future of Cardiac Amyloidosis Therapeutics.

Cardiac Amyloidosis (CA) is a manifestation of a systemic disorder resulting from the deposition of transthyretin (TTR) in the myocardium. This leads to a myriad of manifestations ranging from conduction defects to heart failure. Previously CA was considered a rare disease, but recent advances in diagnostics and therapeutics have revealed the prevalence to be higher than estimated. There are two major classes of treatments for TTR cardiac amyloidosis (ATTR-CA): TTR stabilizers, such as tafamidis and AG10, and RNA interference (siRNA), such as patisiran and vutrisiran. Clustered regularly interspaced short palindromic repeats of genetic information-Cas9 endonuclease (CRISPR-Cas9) utilizes an RNA-guided endonuclease to target specific locations in the genome. Until recently, CRISPR-Cas9 was studied in small animal models for its ability to decrease extracellular deposition and accumulation of amyloid in tissues. Gene editing has demonstrated some early clinical promise as an emerging therapeutic modality in the treatment of CA. In an introductory human trial involving 12 subjects with TTR amyloidosis and amyloid cardiomyopathy (ATTR-CM), CRISPR-Cas9 therapy has demonstrated a reduction in approximately 90% of serum TTR proteins after 28 days. In this article, the authors review the current literature on therapeutic gene editing as a prospective curative treatment modality for CA.

Colonic diverticular bleeding: An update on pathogenesis and management.

Colonic diverticular bleeding is the most common cause of lower gastrointestinal (GI) bleeding, which can be life-threatening and frequently recurrent. In recent years, the prevalence of diverticulosis has increased in developed countries, with a documented incidence of 50% in patients older than 60 years. Based on the evidence, the use of anticoagulants and/or antiplatelets in the elderly population has resulted in an increased incidence of acute diverticular bleeding. According to the literature, about 50% of patients with diverticular bleeding require a blood transfusion, and 18% - 53% need emergency surgery. Although endoscopic identification of the culprit diverticula and appropriate intervention is a challenge, the newer treatment modality, over-the-scope clip method (OTSC) has been demonstrated to be an effective endoscopic hemostatic method in severe diverticular bleeding, especially in cases of rebleeding after first-line conventional endoscopic procedures. In this review, we summarize the pathophysiology of colonic diverticulosis and diverticular bleeding, recent evidence in its management, and existing theories on various preventive strategies to control diverticular bleeding. We also discuss the efficacy and treatment outcome of the OTSC technique in controlling diverticular bleeding.

Isolated sixth nerve palsy as the first manifestation of preeclampsia.

Preeclampsia constitutes one of the leading causes of maternal morbidity and mortality in the United States. Preeclampsia-related neurological disorders are well-established and associated with a broad spectrum of manifestations, including headaches, visual symptoms like blurred vision, photopsia, field defects, and other major clinical events. However, cranial nerve disorders are rare in preeclampsia, which is inadequately researched. Here, we present a 26-year-old primigravida woman with an isolated abducens nerve palsy as the first sign of preeclampsia at 35 weeks of gestation.

Spontaneous atraumatic heparin-induced hemarthrosis in a patient treated for non-ST-elevation myocardial infarction.

Hemarthrosis secondary to heparin use is a scarce event, especially in patients with no underlying thrombophilia or platelet disorders. Although previously associated with thrombophilia, platelet disorders, or secondary to fibrinolytic therapy, to date, there are very few reported cases in contemporary literature for heparin-induced hemarthrosis. In this article, we report a case of left shoulder joint inferior subluxation secondary to heparin-induced hemarthrosis in an 81-year-old male with an extensive cardiac history and multiple comorbidities. This case report depicts a rare event and discusses its clinical implications aiding healthcare professionals in an early diagnosis and timely management.

Insulin analogs in the treatment of type II diabetes and future perspectives.

The discovery of insulin by Banting and Best marked 100 years in 2021, and it was a life-saving treatment modality for type II diabetes mellitus (T2DM). Insulin is a natural hormone that has been used extensively in T2DM patients since its discovery. Currently, insulin analogs are also available in different formulations for T2DM management, overcoming the limitations of human insulin with better safety and side effect profiles. The insulin analogs like the rapid-acting analogs (Aspart, lispro, glulisine), the long-acting basal analogs (Glargine, detemir), the ultra-long acting (Insulin degludec), and the premixed insulin analog formulations (75% Neutral protamine lispro, 25% lispro; 50% neutral protamine lispro, 50% lispro; 70% protamine aspart, 30% aspart) have been prepared through genetic engineering while preserving the basic insulin profile. A large number of studies have demonstrated their clinical effects on glycated hemoglobin test (HbA1c) in achieving glycemic control and thereby lowering the microvascular and macrovascular complications of T2DM with less traditional side effects of regular human insulin, mainly the risk of hypoglycemia, postprandial glycemic excursions, and weight gain. This review explores the currently available insulin analogs, their clinical implications, pharmacokinetics (PK), pharmacodynamics (PD), safety profile, and cost-effectiveness. We also discuss the future developments in the management of T2DM, especially the scientific advancements surrounding the novel insulin formulations, including the biosimilar insulin, and the innovative insulin delivery methods, such as oral and inhaled insulin.