Browsing by Author "Rizzo, Manfredi"

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The effect of sodium-glucose co-transporter-2 inhibitors on markers of subclinical atherosclerosis
(2023-12) Rizzo, Manfredi
Abstract: Background: Despite the widespread use of classical cholesterol-lowering drugs to mitigate the adverse impacts of dyslipidaemia on atherosclerosis, many patients still face a substantial residual risk of developing atherosclerotic cardiovascular disease (CVD). This risk is partially attributed to non-traditional pathophysiological pathways. Latest evidence suggests that sodium glucose co-transporter-2 (SGLT2) inhibitors are beneficial for patients suffering from type 2 diabetes mellitus (T2DM) or established CVD by reducing morbidity and mortality. However, the underlying mechanisms of this benefit have not been clearly elucidated. It has been hypothesized that one possible mechanism could be the attenuation of subclinical atherosclerosis (SA) progression. Aim: The objective of this narrative review is to examine the present evidence concerning the impact of SGLT2 inhibitors on markers of SA. Results: The current evidence on the efficacy of SGLT2 on SA, endothelial function and arterial stiffness remains controversial. Findings from observational and randomized studies are quite heterogeneous; however, they converge that the antiatherosclerotic activity of SGLT2 inhibitors is not strong enough to be widely used for prevention of atherosclerosis progression in patients with or without T2DM. Conclusions: Further research is needed to investigate the underlying mechanisms and the possible beneficial impact of SGLT2i on primary and secondary CVD prevention through attenuation of premature atherosclerosis progression.
The Effect of Sodium-Glucose Cotransporter Inhibitors on Renal Function as Adjunctive to Insulin in Adults with Type 1 Diabetes: An Updated Multilevel Meta-analysis of Randomized Controlled Trials
(2024-01) Rizzo, Manfredi
Abstract: Introduction: This systematic review aimed to summarize the existing evidence from published randomized controlled trials (RCTs) on the impact of sodium-glucose cotransporter (SGLT) inhibitors on albuminuria levels and renal function in patients with type 1 diabetes mellitus (T1D). Methods: The literature search was performed through Medline (via PubMed), Cochrane Library, and Scopus until November 11, 2023. Double-independent study selection, data extraction, and quality assessment were performed. Evidence was pooled with three-level mixed-effects meta-analysis. Results: In total, 5221 participants with T1D among 11 RCTs were analyzed. All RCTs had low risk of bias according to the Cochrane Collaboration tool (RoB 2). SGLT inhibitors were associated with a significantly greater reduction in urine albumin-to-creatinine ratio (UACR) compared to controls (MD = - 23.13%; 95% CI = [- 33.69, - 12.57]; P < 0.001; level of evidence high). On the basis of subgroup analysis, this effect was consistent across all available SGLT inhibitors, irrespective of the dosage. Finally, a neutral class effect was observed on the estimated glomerular filtration rate (eGFR, MD = - 1.03 mL/min/1.73 m2; 95% CI = [- 2.26, 0.19]; P = 0.1; level of evidence moderate). Only empagliflozin was associated with a significant reduction in eGFR compared to placebo (MD = - 2.23 mL/min/1.73 m2; 95% CI = [- 3.62, - 0.84]; P = 0.002). Conclusion: Our findings suggest that adjunctive therapy with SGLT inhibitors results in a significant reduction in albuminuria, while their use is associated with a neutral effect on creatinine clearance, as a measure of renal function. Future renal outcome trials are needed to assess SGLT inhibitors' role in the pharmacological armamentarium against diabetic nephropathy in T1D.
Efficient Generation of Chondrocytes From Bone Marrow–Derived Mesenchymal Stem Cells in a 3D Culture System: Protocol for a Practical Model for Assessing Anti-Inflammatory Therapies
(2023) Patnaik, Rajashree; Jannati, Shirin; Rizzo, Manfredi; Naidoo, Nerissa; Banerjee, Yajnavalka
Background: Chondrocytes are the primary cells responsible for maintaining cartilage integrity and function. Their role in cartilage homeostasis and response to inflammation is crucial for understanding the progression and potential therapeutic interventions for various cartilage-related disorders. Developing an accessible and cost-effective model to generate viable chondrocytes and to assess their response to different bioactive compounds can significantly advance our knowledge of cartilage biology and contribute to the discovery of novel therapeutic approaches. Objective: We developed a novel, streamlined protocol for generating chondrocytes from bone marrow–derived mesenchymal stem cells (BMSCs) in a 3D culture system that offers significant implications for the study of cartilage biology and the discovery of potential therapeutic interventions for cartilage-related and associated disorders. Methods: We developed a streamlined protocol for generating chondrocytes from BMSCs in a 3D culture system using an “in-tube” culture approach. This simple pellet-based 3D culture system allows for cell aggregation and spheroid formation, facilitating cell-cell and cell–extracellular matrix interactions that better mimic the in vivo cellular environment compared with 2D monolayer cultures. A proinflammatory chondrocyte model was created by treating the chondrocytes with lipopolysaccharide and was subsequently used to evaluate the anti-inflammatory effects of vitamin D, curcumin, and resveratrol. Results: The established protocol successfully generated a large quantity of viable chondrocytes, characterized by alcian blue and toluidine blue staining, and demonstrated versatility in assessing the anti-inflammatory effects of various bioactive compounds. The chondrocytes exhibited reduced inflammation, as evidenced by the decreased tumor necrosis factor-α levels, in response to vitamin D, curcumin, and resveratrol treatment. Conclusions: Our novel protocol offers an accessible and cost-effective approach for generating chondrocytes from BMSCs and for evaluating potential therapeutic leads in the context of inflammatory chondrocyte–related diseases. Although our approach has several advantages, further investigation is required to address its limitations, such as the potential differences between chondrocytes generated using our protocol and those derived from other established methods, and to refine the model for broader applicability and clinical translation.
Efficient Generation of Chondrocytes From Bone Marrow–Derived Mesenchymal Stem Cells in a 3D Culture System: Protocol for a Practical Model for Assessing Anti-Inflammatory Therapies
(2023) Patnaik, Rajashree; Jannati, Shirin; Rizzo, Manfredi; Naidoo, Nerissa; Banerjee, Yajnavalka
Background: Chondrocytes are the primary cells responsible for maintaining cartilage integrity and function. Their role in cartilage homeostasis and response to inflammation is crucial for understanding the progression and potential therapeutic interventions for various cartilage-related disorders. Developing an accessible and cost-effective model to generate viable chondrocytes and to assess their response to different bioactive compounds can significantly advance our knowledge of cartilage biology and contribute to the discovery of novel therapeutic approaches. Objective: We developed a novel, streamlined protocol for generating chondrocytes from bone marrow–derived mesenchymal stem cells (BMSCs) in a 3D culture system that offers significant implications for the study of cartilage biology and the discovery of potential therapeutic interventions for cartilage-related and associated disorders. Methods: We developed a streamlined protocol for generating chondrocytes from BMSCs in a 3D culture system using an “in-tube” culture approach. This simple pellet-based 3D culture system allows for cell aggregation and spheroid formation, facilitating cell-cell and cell–extracellular matrix interactions that better mimic the in vivo cellular environment compared with 2D monolayer cultures. A proinflammatory chondrocyte model was created by treating the chondrocytes with lipopolysaccharide and was subsequently used to evaluate the anti-inflammatory effects of vitamin D, curcumin, and resveratrol. Results: The established protocol successfully generated a large quantity of viable chondrocytes, characterized by alcian blue and toluidine blue staining, and demonstrated versatility in assessing the anti-inflammatory effects of various bioactive compounds. The chondrocytes exhibited reduced inflammation, as evidenced by the decreased tumor necrosis factor-α levels, in response to vitamin D, curcumin, and resveratrol treatment. Conclusions: Our novel protocol offers an accessible and cost-effective approach for generating chondrocytes from BMSCs and for evaluating potential therapeutic leads in the context of inflammatory chondrocyte–related diseases. Although our approach has several advantages, further investigation is required to address its limitations, such as the potential differences between chondrocytes generated using our protocol and those derived from other established methods, and to refine the model for broader applicability and clinical translation.
Ferroptosis and iron metabolism in diabetes: Pathogenesis, associated complications, and therapeutic implications
(2024-08) Rizzo, Manfredi
Abstract Diabetes mellitus is a complex chronic disease, considered as one of the most common metabolic disorders worldwide, posing a major threat to global public health. Ferroptosis emerges as a novel mechanism of programmed cell death, distinct from apoptosis, necrosis, and autophagy, driven by iron-dependent lipid peroxidation accumulation and GPx4 downregulation. A mounting body of evidence highlights the interconnection between iron metabolism, ferroptosis, and diabetes pathogenesis, encompassing complications like diabetic nephropathy, cardiomyopathy, and neuropathy. Moreover, ferroptosis inhibitors hold promise as potential pharmacological targets for mitigating diabetes-related complications. A better understanding of the role of ferroptosis in diabetes may lead to an improvement in global diabetes management. In this review, we delve into the intricate relationship between ferroptosis and diabetes development, exploring associated complications and current pharmacological treatments.
GLP-1 and dual GIP/GLP-1 receptor agonists in overweight/obese patients for atherosclerotic cardiovascular disease prevention: Where are we now?
(2023) Rizzo, Manfredi
Introduction: Obesity is a highly prevalent chronic disease characterized by an increase of body fat stores.1 Increased adiposity (body fat), particularly abdominal/visceral fat, plays a role in altering immune and inflammatory function, developing insulin resistance (IR) and contributing to downstream metabolic risk factors (RFs) such as hyperglycemia, dyslipidemia, systemic adrenergic activity, hypertension, atherosclerosis and finally, cardiovascular (CV) disease (CVD).2 Furthermore, visceral fat is strongly associated with increased atherosclerotic burden and the risk of recurrent atherosclerotic CVD (ASCVD), residual CV risk, and CVD mortality.
Glucagon-Like Peptide-1 Receptor Agonists and Dual Glucose-Dependent Insulinotropic Polypeptide/Glucagon-Like Peptide-1 Receptor Agonists in the Treatment of Obesity/Metabolic Syndrome, Prediabetes/Diabetes and Non-Alcoholic Fatty Liver Disease-Current Evidence
(2022-12) Mikhailidis, Dimitri P; Rizzo, Manfredi
Abstract: The obesity pandemic is accompanied by increased risk of developing metabolic syndrome (MetS) and related conditions: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease (CVD). Lifestyle, as well as an imbalance of energy intake/expenditure, genetic predisposition, and epigenetics could lead to a dysmetabolic milieu, which is the cornerstone for the development of cardiometabolic complications. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs promote positive effects on most components of the "cardiometabolic continuum" and consequently help reduce the need for polypharmacy. In this review, we highlight the main pathophysiological mechanisms and risk factors (RFs), that could be controlled by GLP-1 and dual GIP/GLP-1 RAs independently or through synergism or differences in their mode of action. We also address the evidence on the use of GLP-1 and dual GIP/GLP-1 RAs in the treatment of obesity, MetS and its related conditions (prediabetes, T2DM and NAFLD/NASH). In conclusion, GLP-1 RAs have already been established for the treatment of T2DM, obesity and cardioprotection in T2DM patients, while dual GIP/GLP-1 RAs appear to have the potential to possibly surpass them for the same indications. However, their use in the prevention of T2DM and the treatment of complex cardiometabolic metabolic diseases, such as NAFLD/NASH or other metabolic disorders, would benefit from more evidence and a thorough clinical patient-centered approach. There is a need to identify those patients in whom the metabolic component predominates, and whether the benefits outweigh any potential harm.
New Onset Diabetes Mellitus in COVID-19: A Scoping Review
(2024) Banerjee, Yajnavalka; Mikhailidis, Dimitri P.; Rizzo, Manfredi
Background: Higher education institutions need to put change management as a pivotal part of their strategy. The challenge is to effectively contextualize existing change management models to the respective work environment. Failing to properly adapt existing models to match the intricacies of the environment could lead to plenty of setbacks. For such a contextualization to take place, gauging employees’ engagement and satisfaction becomes of paramount importance. As such, the overall purpose of the current study is to explore the perception of employees of a medical and health sciences university in Middle East and North Africa (MENA) region, in relation to change management and agility, and to showcase how the captured perspectives can be systemically interpreted to inform decision-making in the context of the study. Method: This research study relied on a sequential mixed methods design, which started with an exploration of the perception of Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU) leaders. Qualitative data was collected through a focus group session and was inductively analysed (based on constructivist epistemology). The output of the qualitative analysis contributed to the development of the quantitative data collection tool. The quantitative data was analysed by SPSS-version-27. Findings: The qualitative analysis generated three key themes: Trigger, Execution, and Results, along with a thorough outline of lessons learned and opportunities for improvement. The Cronbach’s Alpha reliability score was 92.8%. The percentage of the total average of agreement was 72.3%, and it appeared that 83.2% of the variance can be explained by the instrument (p<0.001). Conclusion: The current study generated a novel conceptual framework that can be leveraged by educational leadership and administration to reinforce their decisions and optimize their agility in terms of managing change. The study also introduces a data collection tool which captures the perception of higher education stakeholders regarding the way their respective institutions handle change. This tool proved to be reliable and valid in the context of the study.
Obesity and nonalcoholic fatty liver disease in type 1 diabetes mellitus patients
(2022-11) Rizzo, Manfredi; Mikhailidis, Dimitri P
Introduction: Assessed the prevalence of nonalcoholic fatty liver disease (NAFLD) in children with type 1 diabetes mellitus (T1DM). They included 15 children with T1DM and obesity, 34 children with T1DM but no obesity and 28 obese children without T1DM. The authors1 found that age and body mass index (BMI)-matched obese children with or without T1DM share similar clinical, biochemical, and liver FibroScan features. Obesity was the main risk factor for NAFLD in pediatric T1DM. Tas et al.1 also provide cut-off values for BMI, high density lipoprotein cholesterol (HDL–C) and BMI:HDL-C ratio, that may help clinicians decide which children may benefit from further investigation to establish the presence or absence of NAFLD. The authors describe the limitations of their study (including imaging techniques) and of the previous literature.1 It may be premature to eliminate a role for T1DM in the etiology of childhood NAFLD because of the limitations of the present study.1 Nevertheless, we agree with the authors1 that their study makes a valuable contribution to the limited evidence that is currently available in this field.
Personalized management of dyslipidemias in patients with diabetes-it is time for a new approach (2022)
(2022) Rizzo, Manfredi
Abstract: Dyslipidemia in patients with type 2 diabetes (DMT2) is one of the worst controlled worldwide, with only about 1/4 of patients being on the low-density lipoprotein cholesterol (LDL-C) target. There are many reasons of this, including physicians' inertia, including diabetologists and cardiologists, therapy nonadherence, but also underusage and underdosing of lipid lowering drugs due to unsuitable cardiovascular (CV) risk stratification. In the last several years there is a big debate on the risk stratification of DMT2 patients, with the strong indications that all patients with diabetes should be at least at high cardiovascular disease (CVD) risk. Moreover, we have finally lipid lowering drugs, that not only allow for the effective reduction of LDL-C and do not increase the risk of new onset diabetes (NOD), and/or glucose impairment; in the opposite, some of them might effectively improve glucose control. One of the most interesting is pitavastatin, which is now available in Europe, with the best metabolic profile within statins (no risk of NOD, improvement of fasting blood glucose, HOMA-IR, HbA1c), bempedoic acid (with the potential for the reduction of NOD risk), innovative therapies-PCSK9 inhibitors and inclisiran with no DMT2 risk increase, and new forthcoming therapies, including apabetalone and obicetrapib-for the latter one with the possibility of even decreasing the number of patients diagnosed with prediabetes and DMT2. Altogether, nowadays we have possibility to individualize lipid lowering therapy in DMT2 patients and increase the number of patients on LDL-C goal without any risk of new onset diabetes and/or diabetes control worsening, and in consequence to reduce the risk of CVD complications due to progression of atherosclerosis in this patients' group.
The role of atherogenic lipoproteins in diabetes: Molecular aspects and clinical significance
(2023) Banerjee, Yajnavalka; Vichithran, Suhina; Faisal, Shemima; Rizzo, Manfredi
Abstract: Dyslipidaemia plays a prominent role in the genesis of atherosclerotic plaque and the increased cardiovascular risk in diabetes. Macrophages readily take up atherogenic lipoproteins, transforming into foam cells and amplifying vascular damage in the presence of endothelial dysfunction. We discuss the importance of distinct lipoprotein subclasses in atherogenic diabetic dyslipidaemia as well as the effects of novel anti-diabetic agents on lipoprotein fractions and ultimately on cardiovascular risk prevention. In patients with diabetes, lipid abnormalities should be aggressively identified and treated in conjunction with therapeutical agents used to prevent cardiovascular disease. The use of drugs that improve diabetic dyslipidaemia plays a prominent role in conferring cardiovascular benefit in individuals with diabetes.
Telemedicine for diabetes management during COVID-19: what we have learnt, what and how to implement
(2023) Banerjee, Yajnavalka; Rizzo, Manfredi
Abstract: The past two decades have witnessed telemedicine becoming a crucial part of health care as a method to facilitate doctor-patient interaction. Due to technological developments and the incremental acquisition of experience in its use, telemedicine’s advantages and cost-effectiveness has led to it being recognised as specifically relevant to diabetology. However, the pandemic created new challenges for healthcare systems and the rate of development of digital services started to grow exponentially. It was soon discovered that COVID-19-infected patients with diabetes had an increased risk of both mortality and debilitating sequelae. In addition, it was observed that this higher risk could be attenuated primarily by maintaining optimal control of the patient’s glucose metabolism. As opportunities for actual physical doctor-patient visits became restricted, telemedicine provided the most convenient opportunity to communicate with patients and maintain delivery of care. The wide range of experiences of health care provision during the pandemic has led to the development of several excellent strategies regarding the applicability of telemedicine across the whole spectrum of diabetes care. The continuation of these strategies is likely to benefit clinical practice even after the pandemic crisis is over.
Understanding the mechanisms mediating cardi-renal benefit of empagliflozin in type 2 diabetes mellitus
(2023-11) Rizzo, Manfredi
Abstract: In a recently published, post-hoc analysis of the hallmark EMPA-REG OUTCOME trial, Kramer ¨ et al.1 assessed whether changes in cardiac and haemodynamic markers achieved with empagliflozin in subjects with type 2 diabetes mellitus (T2DM) may mediate its significant benefits across a number of surrogate cardiovascular and kidney outcomes. They have demonstrated that empagliflozin treatment resulted in a significant decrease in pulse pressure (PP), mean arterial pressure (MAP) and cardiac workload, compared with placebo; at week 12, placebo-adjusted mean changes from baseline were − 2.5 mmHg for PP, − 2.2 mmHg for MAP and − 315 mmHg x beats per minute (bpm) for cardiac workload (p < 0.0001 for all). They have also found that such benefits were present for both empagliflozin groups (10 mg and 25 mg) combined, while treatment differences were maintained throughout to week 164.1