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Background: Real-world data on the implementation and prognostic impact of glucose-lowering drugs with proven cardiovascular benefits in patients with type 2 diabetes (T2D) following acute coronary syndrome (ACS) are limited. We investigated the utilization and treatment patterns of sodium–glucose contrasporter-2 inhibitors (SGLT2Is) and glucagon-like peptide-1 recepto-agonists (GLP1RAs) in patients with T2D experiencing ACS and analyzed their association with mortality and major adverse cardiovascular events (MACEs) including recurrent ACS, acute revascularization, heart failure, or ischemic stroke. Methods: We carried out a retrospective analysis of 9756 patients with T2D from a nationwide healthcare organization in Israel who were hospitalized with ACS between 01/2019 and 01/2022. Drug prescriptions were estimated pre-hospitalization, 90 days, and 1 year following hospitalization. The association between SGLT2I and/or GLP1RA treatment with MACE and mortality was investigated using a time-dependent Cox regression analysis with multivariable adjustment. Results: The prescription rates (pre-hospitalization, 90 days, and 1 year post-hospitalization) of GLP1RAs were 13%, 13.2%, and 18%, and those of SGLT2Is were 23.9%, 33.6%, and 42.7%, respectively. At 1 year, 13.9% of patients were prescribed both treatments. The use of SGLT2Is and/or GLP1RAs was higher in younger age groups and increased from 2019 to 2021 (38.1% to 59.2%). The adjusted hazard ratio for the association of pre- or post-hospitalization SGLT2I and/or GLP1RA treatment with mortality and MACE was 0.724 (0.654–0.801) and 0.974 (0.909–1.043), respectively. Conclusions: In the real-world practice of treating patients with T2D experiencing ACS, the implementation of SGLT2Is, particularly GLP1RAs, was suboptimal when prescribed both early and 1 year following hospitalization, emphasizing the need to improve medical care. Treatment with SGLT2Is and/or GLP1RAs was associated with a favorable impact on mortality but not MACE. [ABSTRACT FROM AUTHOR]

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is common in type 2 diabetes mellitus (T2D), leading to high morbidity and mortality. Managing HFpEF in diabetic patients is challenging with limited treatments. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) have shown potential cardiovascular benefits. This meta-analysis compares the effects of GLP1-RA and SGLT2 inhibitors on HFpEF in T2D patients. Methods We conducted a meta-analysis of randomized controlled trials (RCTs) and observational studies evaluating GLP1-RA and SGLT2 inhibitors’ impact on HFpEF in T2D patients. Databases searched included PubMed, MEDLINE, and Cochrane Library up to July 2024. Primary outcomes were changes in left ventricular ejection fraction (LVEF), myocardial fibrosis (extracellular volume fraction, ECV), and functional capacity (6-minute walk test, 6MWT). Secondary outcomes included HbA1c, body weight, and systolic blood pressure (SBP). Results Twelve studies with 3,428 patients (GLP1-RA: 1,654; SGLT2 inhibitors: 1,774) were included. Both GLP1-RA and SGLT2 inhibitors significantly improved LVEF compared to placebo (GLP1-RA: mean difference [MD] 2.8%, 95% confidence interval [CI] 1.5 to 4.1, p

Abstract Tirzepatide is a new drug targeting glucagon-like peptide 1(GLP1) and gastric inhibitory polypeptide (GIP) receptors. This drug has demonstrated great potential in improving the clinical outcomes of patients with type 2 diabetes. It can lead to weight loss, better glycemic control, and reduced cardiometabolic risk factors. GLP1 receptor agonists have been proven effective antidiabetic medications with possible cardiovascular benefits. Even though they have been proven to reduce the risk of major adverse cardiovascular events, their effectiveness in treating heart failure is unknown. Unlike traditional GLP1 receptor agonists, tirzepatide is more selective for the GIP receptor, resulting in a more balanced activation of these receptors. This review article discusses the possible mechanisms tirzepatide may use to improve cardiovascular health. That includes the anti-inflammatory effect, the ability to reduce cell death and promote autophagy, and also its indirect effects through blood pressure, obesity, and glucose/lipid metabolism. Additionally, tirzepatide may benefit atherosclerosis and lower the risk of major adverse cardiac events. Currently, clinical trials are underway to evaluate the safety and efficacy of tirzepatide in patients with heart failure. Overall, tirzepatide’s dual agonism of GLP1 and GIP receptors appears to provide encouraging cardiovascular benefits beyond glycemic control, offering a potential new therapeutic option for treating cardiovascular diseases and heart failure. Graphical abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is common in type 2 diabetes mellitus (T2D), leading to high morbidity and mortality. Managing HFpEF in diabetic patients is challenging with limited treatments. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) have shown potential cardiovascular benefits. This meta-analysis compares the effects of GLP1-RA and SGLT2 inhibitors on HFpEF in T2D patients. Methods: We conducted a meta-analysis of randomized controlled trials (RCTs) and observational studies evaluating GLP1-RA and SGLT2 inhibitors' impact on HFpEF in T2D patients. Databases searched included PubMed, MEDLINE, and Cochrane Library up to July 2024. Primary outcomes were changes in left ventricular ejection fraction (LVEF), myocardial fibrosis (extracellular volume fraction, ECV), and functional capacity (6-minute walk test, 6MWT). Secondary outcomes included HbA1c, body weight, and systolic blood pressure (SBP). Results: Twelve studies with 3,428 patients (GLP1-RA: 1,654; SGLT2 inhibitors: 1,774) were included. Both GLP1-RA and SGLT2 inhibitors significantly improved LVEF compared to placebo (GLP1-RA: mean difference [MD] 2.8%, 95% confidence interval [CI] 1.5 to 4.1, p < 0.001; SGLT2 inhibitors: MD 3.2%, 95% CI 2.0 to 4.4, p < 0.001). SGLT2 inhibitors significantly reduced myocardial fibrosis (MD -3.5%, 95% CI -4.2 to -2.8, p < 0.001) more than GLP1-RA (MD -2.3%, 95% CI -3.0 to -1.6, p < 0.001). Functional capacity improved significantly with both treatments (GLP1-RA: MD 45 m, 95% CI 30 to 60, p < 0.001; SGLT2 inhibitors: MD 50 m, 95% CI 35 to 65, p < 0.001). Secondary outcomes showed reductions in HbA1c (GLP1-RA: MD -1.1%, 95% CI -1.4 to -0.8, p < 0.001; SGLT2 inhibitors: MD -1.0%, 95% CI -1.3 to -0.7, p < 0.001) and body weight (GLP1-RA: MD -2.5 kg, 95% CI -3.1 to -1.9, p < 0.001; SGLT2 inhibitors: MD -2.0 kg, 95% CI -2.6 to -1.4, p < 0.001). Both treatments significantly lowered SBP (GLP1-RA: MD -5.2 mmHg, 95% CI -6.5 to -3.9, p < 0.001; SGLT2 inhibitors: MD -4.8 mmHg, 95% CI -6.0 to -3.6, p < 0.001). Conclusions: GLP1-RA and SGLT2 inhibitors significantly benefit HFpEF management in T2D patients. SGLT2 inhibitors reduce myocardial fibrosis more effectively, while both improve LVEF, functional capacity, and metabolic parameters. These therapies should be integral to HFpEF management in diabetic patients. Further research is needed on long-term outcomes and potential combined therapy effects. [ABSTRACT FROM AUTHOR]

Tirzepatide is a new drug targeting glucagon-like peptide 1(GLP1) and gastric inhibitory polypeptide (GIP) receptors. This drug has demonstrated great potential in improving the clinical outcomes of patients with type 2 diabetes. It can lead to weight loss, better glycemic control, and reduced cardiometabolic risk factors. GLP1 receptor agonists have been proven effective antidiabetic medications with possible cardiovascular benefits. Even though they have been proven to reduce the risk of major adverse cardiovascular events, their effectiveness in treating heart failure is unknown. Unlike traditional GLP1 receptor agonists, tirzepatide is more selective for the GIP receptor, resulting in a more balanced activation of these receptors. This review article discusses the possible mechanisms tirzepatide may use to improve cardiovascular health. That includes the anti-inflammatory effect, the ability to reduce cell death and promote autophagy, and also its indirect effects through blood pressure, obesity, and glucose/lipid metabolism. Additionally, tirzepatide may benefit atherosclerosis and lower the risk of major adverse cardiac events. Currently, clinical trials are underway to evaluate the safety and efficacy of tirzepatide in patients with heart failure. Overall, tirzepatide's dual agonism of GLP1 and GIP receptors appears to provide encouraging cardiovascular benefits beyond glycemic control, offering a potential new therapeutic option for treating cardiovascular diseases and heart failure. [ABSTRACT FROM AUTHOR]

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent clinical condition associated with elevated morbidity and mortality rates. Patients with MASLD treated with semaglutide, a glucagon-like peptide-1 receptor agonist, demonstrate improvement in terms of liver damage. However, the mechanisms underlaying this beneficial effect are not yet fully elucidated. We investigated the efficacy of semaglutide in halting MASLD progression using a genetic mouse model of diabesity. Leptin-receptor-deficient mice with obesity and diabetes (BKS db/db) were either untreated or administered with semaglutide for 11 weeks. Changes in food and water intake, body weight and glycemia were monitored throughout the study. Body fat composition was assessed by dual-energy X-ray absorptiometry. Upon sacrifice, serum biochemical parameters, liver morphology, lipidomic profile and liver-lipid-related pathways were evaluated. The semaglutide-treated mice exhibited lower levels of glycemia, body weight, serum markers of liver dysfunction and total and percentage of fat mass compared to untreated db/db mice without a significant reduction in food intake. Histologically, semaglutide reduced hepatic steatosis, hepatocellular ballooning and intrahepatic triglycerides. Furthermore, the treatment ameliorated the hepatic expression of de novo lipogenesis markers and modified lipid composition by increasing the amount of polyunsaturated fatty acids. The administration of semaglutide to leptin-receptor-deficient, hyperphagic and diabetic mice resulted in the amelioration of MASLD, likely independently of daily caloric intake, suggesting a direct effect of semaglutide on the liver through modulation of the lipid profile. [ABSTRACT FROM AUTHOR]

Background: An FQHC in Denver, Colorado developed and implemented an interprofessional care model to collaboratively manage type 2 diabetes mellitus (T2DM). Utilizing the 340B program, the team protocolized ADA Guidelines to promote the early adoption of first-line medications, glucagon-like peptide1 receptor agonists (GLP1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) to improve patient outcomes. Objectives: To assess the impact of interprofessional collaborative management versus standard care on early initiation of a SGLT2i and/or GLP1 RA as first-line therapies to enhance (1) deprescribing of insulin, (2) reducing overbasalization of insulin through insulin de-escalation, and (3) effectively lowering A1C levels in adult primary care patients with T2DM. Methods: This was a retrospective chart review of adult patients with T2DM who were initiated on a GLP1 RA and/or a SGLT2i. To determine the effects of initiating GLP1 RA and/or SGLT2i therapy on insulin usage and glycemic control, the total daily dose (TDD) of insulin before initiation was compared with the most recent TDD post-initiation to evaluate deprescribing. To determine the impact on overbasalization, pre-initiation and post-initiation insulin doses were evaluated. The effectiveness of GLP1 RA and/or SGLT2i in lowering A1C levels was determined by comparing the A1C prior to initiation with the A1C postinitiation. To evaluate the influence of interprofessional collaborative care on insulin deprescribing, overbasalization, and diabetes control, relevant measures were compared between patients receiving collaborative care versus standard care. Results: Of the 60 total patients treated with insulin, 46.6% were deprescribed insulin, with a majority in the interprofessional collaborative group (93.1%) compared to standard care (6.9%). A total of 78.3% of patients benefited from a reduction in A1C following the initiation of a GLP1 RA and/or SGLT2i. The greatest A1C reduction was −2.9% in the group receiving metformin in addition to a GLP1 RA and a SGLT2i. Patients who received interprofessional collaborative care had an average A1c reduction of −2.9% compared to—1.1% with standard care. Conclusion: Most patients initially overbasalized on insulin experienced a reduction in overbasalization after initiating GLP1 RA and/or SGLT2i. There was a notable A1C reduction, de-escalation, and deprescribing of insulin in patients receiving interprofessional collaborative care. [ABSTRACT FROM AUTHOR]

Aims: The aim of the present study was to verify predictors of HbA1c reduction with Sodium‐GLucose Transporter‐2 (SGLT2) inhibitors and Glucagon‐Like Peptide 1 (GLP1) receptor agonists in routine clinical practice. Materials and Methods: A retrospective cohort study was performed, enrolling patients with type 2 diabetes aged ≥18 years who received a prescription of an SGLT2 inhibitor or a long‐acting GLP1 receptor agonist with at least 6 months of persistence in therapy. Therapeutic success was defined as HbA1c reduction >10 mmol/mol or attainment of the recommended HbA1c target. Results: Out of 236 patients receiving SGLT2 inhibitors, 148 were categorised as successes: successes had a mean lower age and higher estimated Glomerular Filtration Rate than failures, but only age retained statistical significance at multivariate analysis (Odds Ratio with 95% confidence interval: 0.94 [0.91–0.98], p = 0.006). In the GLP1 receptor agonists cohort (N = 214) there were 146 successes, showing a significantly shorter duration of diabetes even after adjusting for age, and baseline HbA1c (HR 0.96 [0.91–0.99], p = 0.02). Conclusions: The present study is a preliminary exploration of factors associated with HbA1c response to SGLT2 inhibitors and GLP1 receptor agonists. Differences in predictors of HbA1c changes across different classes of drugs could be useful in identifying the most suitable drug in individual patients. SGLT2 inhibitors seem to be associated with a greater reduction of HbA1c in younger subjects, and GLP1 agonists in those with a shorter duration of diabetes. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) and chronic kidney disease (CKD) are common in middle aged and older adult individuals. DM may accelerate the aging process, and the age-related declines in the estimated glomerular filtration rate (eGFR) can pose a challenge to diagnosing diabetic kidney disease (DKD) using standard diagnostic criteria especially with the absence of severe albuminuria among older adults. In the presence of CKD and DM, older adult patients may need multidisciplinary care due to susceptibility to various health issues, e.g., cognitive decline, auditory or visual impairment, various comorbidities, complex medical regimens, and increased sensitivity to medication adverse effects. As a result, it can be challenging to apply recent therapeutic advancements for the general population to older adults. We review the evidence that the benefits from these newer therapies apply equally to older and younger patients with CKD and diabetes type 2 and propose a comprehensive management. This framework will address nonpharmacological measures and pharmacological management with renin angiotensin system inhibitors (RASi), sodium glucose co-transporter 2 inhibitors (SGLT2i), non-steroidal mineralocorticoids receptor antagonists (MRAs), and glucagon like peptide 1 receptor agonists (GLP1-RAs). [ABSTRACT FROM AUTHOR]

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent clinical condition associated with elevated morbidity and mortality rates. Patients with MASLD treated with semaglutide, a glucagon-like peptide-1 receptor agonist, demonstrate improvement in terms of liver damage. However, the mechanisms underlaying this beneficial effect are not yet fully elucidated. We investigated the efficacy of semaglutide in halting MASLD progression using a genetic mouse model of diabesity. Leptin-receptor-deficient mice with obesity and diabetes (BKS db/db) were either untreated or administered with semaglutide for 11 weeks. Changes in food and water intake, body weight and glycemia were monitored throughout the study. Body fat composition was assessed by dual-energy X-ray absorptiometry. Upon sacrifice, serum biochemical parameters, liver morphology, lipidomic profile and liver-lipid-related pathways were evaluated. The semaglutide-treated mice exhibited lower levels of glycemia, body weight, serum markers of liver dysfunction and total and percentage of fat mass compared to untreated db/db mice without a significant reduction in food intake. Histologically, semaglutide reduced hepatic steatosis, hepatocellular ballooning and intrahepatic triglycerides. Furthermore, the treatment ameliorated the hepatic expression of de novo lipogenesis markers and modified lipid composition by increasing the amount of polyunsaturated fatty acids. The administration of semaglutide to leptin-receptor-deficient, hyperphagic and diabetic mice resulted in the amelioration of MASLD, likely independently of daily caloric intake, suggesting a direct effect of semaglutide on the liver through modulation of the lipid profile.

Chronic kidney disease (CKD) is associated with increased morbidity and mortality, especially from cardiovascular (CV) causes, and especially in people with diabetes mellitus (DM). Already the presence of DM increases CV risk and potentiates the risk of CKD. Therefore, besides glycemic control, prevention and treatment of CKD to slow its progression are of clinical importance. A significant nephroprotective effect of novel antidiabetic drugs, namely sodium-glucose cotransporter 2 inhibitors (SGLT2-I) and glucagon-like peptide 1 receptor agonists (GLP1-RA), has been shown on top of their glucose-lowering effects and was confirmed in cardiovascular outcome trials. GLP1-RA mainly reduced the risk of macroalbuminuria, whereas SGLT2-I were also associated with a lower risk of declining glomerular filtration rate (GFR) over time. The nephroprotective effects of SGLT2-I are also evident in people without DM. According to current guidelines, SGLT2-I and/or GLP1-RA are recommended for people with DM who have chronic kidney disease and/or increased cardiovascular risk. However, other antidiabetic drugs offer nephroprotective properties, which will also be discussed in this review. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease (ASCVD) commonly affects people with type 2 diabetes (T2D). Historically, traditional cardiovascular (CV) risk-lowering therapies in patients with T2D and ASCVD have included antiplatelet agents, blood pressure-lowering therapies, lipid-lowering therapies and healthy lifestyle modifications. In the past decade, multiple antihyperglycaemic agents have emerged as CV risk-lowering therapies in this population as well. This article provides a narrative review on the current non-glycaemic and glycaemic treatment options for CV risk reduction in patients with T2D and ASCVD. The FDA requirement that all new antihyperglycaemic agents undergo cardiovascular outcomes trials has demonstrated increasing evidence to support the role of glucagon-like peptide 1 (GLP1) receptor agonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors as first-line agents for both glycaemic control and CV risk reduction in this population.

Heart failure with preserved ejection fraction (HFpEF) is a common clinical syndrome frequently seen in elderly patients, the incidence of which is steadily increasing due to an ageing population and the increasing incidence of diseases, such as diabetes, hypertension, obesity, chronic renal failure, and so on. It is a multifactorial disease with different phenotypic aspects that share left ventricular diastolic dysfunction, and is the cause of about 50% of hospitalizations for heart failure in the Western world. Due to the complexity of the disease, no specific therapies have been identified for a long time. Sodium-Glucose Co-Transporter 2 Inhibitors (SGLT2-Is) and Glucagon-Like Peptide Receptor Agonists (GLP-1 RAs) are antidiabetic drugs that have been shown to positively affect heart and kidney diseases. For SGLT2-Is, there are precise data on their potential benefits in heart failure with reduced ejection fraction (HFrEF) as well as in HFpEF; however, insufficient evidence is available for GLP-1 RAs. This review addresses the current knowledge on the cardiac effects and potential benefits of combined therapy with SGLT2-Is and GLP-1RAs in patients with HFpEF. [ABSTRACT FROM AUTHOR]

Abstract The dramatic increase in overweight and obesity among children and adolescents has become a major public health problem. Obesity in children and young adults is associated with an increased prevalence of cardiometabolic risk factors. Obesity during adolescence represents a strong predictor of obesity and higher mortality in adulthood. Due to the serious implications of obesity in adolescents, effective treatments are urgently needed. Lifestyle interventions represent the recommended therapy. Nevertheless, real world data show that the majority of adolescents do not achieve weight loss in the long term, and are reluctant to participate in lifestyle interventions. Pharmacological treatment is recommended if a formal lifestyle modification program fails to limit weight gain or to improve comorbidities. However, until 2020 the European Medicines Agency (EMA) had not approved any pharmacotherapeutic agents for obesity in pediatric patients. On April 2021, EMA has authorized the use of Liraglutide, a glucagon-like peptide (GLP)-1 analog, for the treatment of obesity in adolescents (12–17 years). The efficacy and safety of Liraglutide were demonstrated in a randomized, double-blind trial, enrolling 251 adolescents. After 56 weeks, a reduction in BMI of at least 5% was observed in 43.3% of participants in the liraglutide group vs. 18.7% in the placebo group, and a reduction in BMI of at least 10% was observed in 26.1 and 8.1%, respectively. Gastrointestinal events were the events most frequently reported with liraglutide. Bariatric surgery represents another effective treatment for adolescents with severe obesity, with sustained benefits on weight loss and cardiometabolic risk factors. However, long-term safety and effectiveness data in adolescents are still scarce. Risks of bariatric surgery include the need for additional abdominal surgical procedures and specific micronutrient deficiencies. Hopefully, new pharmacological treatments in addition to lifestyle interventions will offer more chances of success.

The differential benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) in cardiovascular or renal outcomes have not been fully investigated. Patients with diabetes prescribed SGLT2i or GLP1RA were retrospectively identified. Patients treated with antihyperglycemic medications other than SGLT2i or GLP1RA were used as a control group. Primary outcomes were composite ischemic events (acute coronary syndrome, coronary revascularization, and stroke) and a composite of heart failure and renal events (hospitalization for heart failure, renal death, initiation of renal replacement therapy, and renal admission). During a median 38.7 months of follow-up, the incidence of composite ischemic events tended to be lower in the GLP1RA group (annualized rate 0.82% per person-year) than in the other groups (1.68% per person-year in the SGLT2i group and 1.36% per person-year in the control group). The risk of a composite of heart failure and renal outcomes was significantly lower in the SGLT2i group than in the GLP1RA and control groups (0.86% per person-year, 2.33% per person-year, and 1.48% per person-year, respectively). The SGLT2i group had a slower decline in renal function over time compared to that in other groups. SGLT2i showed more benefits in heart failure and renal outcomes, whereas GLP1RA tended to have more favorable ischemic outcomes. • Recent guidelines recommend SGLT2i and GLP1RA for diabetic patients at higher risk. • Direct comparison of SGLT2i and GLP1RA for clinical outcomes are not yet available. • We compared the differential benefits of SGLT2i and GLP1RA on CV and renal outcomes. • SGLT2i showed more benefits in HF and renal outcomes across various subgroups. • GLP1RA tended to have more favorable ischemic outcomes (coronary events and stroke). [ABSTRACT FROM AUTHOR]

Oxidative stress is characterized by excessive production of reactive oxygen species together with exhausted antioxidant defenses. This constitutes a main pathophysiologic process that is implicated in cardiovascular and renal diseases. In particular, enhanced oxidative stress may lead to low-density lipoprotein accumulation and oxidation, endothelial cell activation, adhesion molecule overexpression, macrophage activation, and foam cell formation, promoting the development and progression of atherosclerosis. The deleterious kidney effects of oxidative stress are numerous, including podocytopathy, mesangial enlargement, renal hypertrophy, tubulointerstitial fibrosis, and glomerulosclerosis. The prominent role of oxidative mechanisms in cardiorenal diseases may be counteracted by recently developed pharmacotherapies such as novel antidiabetic agents and finerenone. These agents have demonstrated significant antioxidant activity in preclinical and clinical studies. Moreover, the use of melatonin as a treatment in this field has been experimentally investigated, with large-scale clinical studies being awaited. Finally, clinical implications and future directions in this field are presented. [ABSTRACT FROM AUTHOR]

Copyright of Hungarian Medical Journal / Orvosi Hetilap is the property of Akademiai Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

After several years with no real therapeutic alternatives, the management of obesity is entering a new era with the development of new surgical and endoscopic bariatric techniques, digital therapeutics and the arrival of new classes of drugs. New medication treatments aim to reduce food intake, targeting the hypothalamic regulation of food intake and satiety. The mechanism of their action remains poorly understood but, combines weight reduction and amelioration of cardiometabolic risk factors with a favorable benefit-risk balance and known side effects, mainly digestive. The future will tell us how these drugs will find their place in the management of this chronic disease that is obesity. [ABSTRACT FROM AUTHOR]

The dramatic increase in overweight and obesity among children and adolescents has become a major public health problem. Obesity in children and young adults is associated with an increased prevalence of cardiometabolic risk factors. Obesity during adolescence represents a strong predictor of obesity and higher mortality in adulthood. Due to the serious implications of obesity in adolescents, effective treatments are urgently needed. Lifestyle interventions represent the recommended therapy. Nevertheless, real world data show that the majority of adolescents do not achieve weight loss in the long term, and are reluctant to participate in lifestyle interventions. Pharmacological treatment is recommended if a formal lifestyle modification program fails to limit weight gain or to improve comorbidities. However, until 2020 the European Medicines Agency (EMA) had not approved any pharmacotherapeutic agents for obesity in pediatric patients. On April 2021, EMA has authorized the use of Liraglutide, a glucagon-like peptide (GLP)-1 analog, for the treatment of obesity in adolescents (12–17 years). The efficacy and safety of Liraglutide were demonstrated in a randomized, double-blind trial, enrolling 251 adolescents. After 56 weeks, a reduction in BMI of at least 5% was observed in 43.3% of participants in the liraglutide group vs. 18.7% in the placebo group, and a reduction in BMI of at least 10% was observed in 26.1 and 8.1%, respectively. Gastrointestinal events were the events most frequently reported with liraglutide. Bariatric surgery represents another effective treatment for adolescents with severe obesity, with sustained benefits on weight loss and cardiometabolic risk factors. However, long-term safety and effectiveness data in adolescents are still scarce. Risks of bariatric surgery include the need for additional abdominal surgical procedures and specific micronutrient deficiencies. Hopefully, new pharmacological treatments in addition to lifestyle interventions will offer more chances of success. [ABSTRACT FROM AUTHOR]

Aims: Wolfram syndrome type 1 is a rare recessive monogenic form of insulin-dependent diabetes mellitus with progressive neurodegeneration, poor prognosis, and no cure. Based on preclinical evidence we hypothesized that liraglutide, a glucagon-like peptide-1 receptor agonist, may be repurposed for the off-label treatment of Wolfram Syndrome type 1. We initiated an off-label treatment to investigate the safety, tolerability, and efficacy of liraglutide in pediatric patients with Wolfram Syndrome type 1.Methods: Pediatric patients with genetically confirmed Wolfram Syndrome type 1 were offered off-label treatment approved by The Regional Network Coordination Center for Rare Diseases, Pharmacological Research IRCCS Mario Negri, and the internal ethics committee. Four patients were enrolled; none refused nor were excluded or lost during follow-up. Liraglutide was administered as a daily subcutaneous injection. Starting dose was 0.3 mg/day. The dose was progressively increased as tolerated, up to the maximum dose of 1.8 mg/day. The primary outcome was evaluating the safety, tolerability, and efficacy of liraglutide in Wolfram Syndrome type 1 patients. Secondary endpoints were stabilization or improvement of C-peptide secretion as assessed by the mixed meal tolerance test. Exploratory endpoints were stabilization of neurological and neuro-ophthalmological degeneration, assessed by optical coherence tomography, electroretinogram, visual evoked potentials, and magnetic resonance imaging.Results: Four patients aged between 10 and 14 years at baseline were treated with liraglutide for 8–27 months. Liraglutide was well-tolerated: all patients reached and maintained the maximum dose, and none withdrew from the study. Only minor transient gastrointestinal symptoms were reported. No alterations in pancreatic enzymes, calcitonin, or thyroid hormones were observed. At the latest follow-up, the C-peptide area under the curve ranged from 81 to 171% of baseline. Time in range improved in two patients. Neuro-ophthalmological and neurophysiological disease parameters remained stable at the latest follow-up.Conclusions: We report preliminary data on the safety, tolerability, and efficacy of liraglutide in four pediatric patients with Wolfram Syndrome type 1. The apparent benefits both in terms of residual C-peptide secretion and neuro-ophthalmological disease progression warrant further studies on the repurposing of glucagon-like peptide-1 receptor agonists as disease-modifying agents for Wolfram Syndrome type 1.

Heart failure with preserved ejection fraction (HFpEF) is a common clinical syndrome frequently seen in elderly patients, the incidence of which is steadily increasing due to an ageing population and the increasing incidence of diseases, such as diabetes, hypertension, obesity, chronic renal failure, and so on. It is a multifactorial disease with different phenotypic aspects that share left ventricular diastolic dysfunction, and is the cause of about 50% of hospitalizations for heart failure in the Western world. Due to the complexity of the disease, no specific therapies have been identified for a long time. Sodium-Glucose Co-Transporter 2 Inhibitors (SGLT2-Is) and Glucagon-Like Peptide Receptor Agonists (GLP-1 RAs) are antidiabetic drugs that have been shown to positively affect heart and kidney diseases. For SGLT2-Is, there are precise data on their potential benefits in heart failure with reduced ejection fraction (HFrEF) as well as in HFpEF; however, insufficient evidence is available for GLP-1 RAs. This review addresses the current knowledge on the cardiac effects and potential benefits of combined therapy with SGLT2-Is and GLP-1RAs in patients with HFpEF.

Oxidative stress is characterized by excessive production of reactive oxygen species together with exhausted antioxidant defenses. This constitutes a main pathophysiologic process that is implicated in cardiovascular and renal diseases. In particular, enhanced oxidative stress may lead to low-density lipoprotein accumulation and oxidation, endothelial cell activation, adhesion molecule overexpression, macrophage activation, and foam cell formation, promoting the development and progression of atherosclerosis. The deleterious kidney effects of oxidative stress are numerous, including podocytopathy, mesangial enlargement, renal hypertrophy, tubulointerstitial fibrosis, and glomerulosclerosis. The prominent role of oxidative mechanisms in cardiorenal diseases may be counteracted by recently developed pharmacotherapies such as novel antidiabetic agents and finerenone. These agents have demonstrated significant antioxidant activity in preclinical and clinical studies. Moreover, the use of melatonin as a treatment in this field has been experimentally investigated, with large-scale clinical studies being awaited. Finally, clinical implications and future directions in this field are presented.

Background: This study evaluated the real-world weight loss and glycemic outcomes of multidrug therapy (MDT) according to various combinations of metformin, sodium-glucose cotransporter -2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor analogs (GLP1a), and orlistat in diabesity. Methods: Data retrospectively captured from medical records of 2 different centers in New Delhi for patients >35 years-age having prediabetes/diabetes and on at least any one of the 4 above medications with >6-months follow-up was analyzed. Results: In total, 5,336 patient records were screened; 2,442 with prediabetes/diabetes were considered; 1,509 patients who fulfilled all criteria were analyzed. Use of metformin, SGLT2i, sulfonylureas, DPP4i, pioglitazone, orlistat, and GLP1a was 85.35%, 74.95%, 68.32%, 60%, 39.16%, 9.08%, and 4.17%, respectively. However, 365, 970, and 104 patients were on one of 4 concerned medications (Group-1; 24.18%), dual MDT (Group-2; 64.28%), and triple/quadruple MDT (Group-3; 6.89%). Metformin with SGLT2i was most commonly used dual MDT (94.12%). Analysis according to weight-loss quartiles from 558 patients showed 6.9 kg weight-loss in the highest quartile. People losing maximum weight were significantly younger; had higher use of metformin, SGLT2i, GLP1, orlistat, and lower pioglitazone use; greatest HbA1c reduction (–1.3 vs. –0.3; quartile-1 vs. quartile –4; P < 0.001); and significantly higher occurrence of HbA1c

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Purpose: The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial showed the cardiovascular disease (CVD) benefits of liraglutide therapy among patients with type 2 diabetes mellitus (T2DM). We applied this trial to US adults with T2DM in terms of eligibility and preventable CVD events. Methods: We included US adults with T2DM from the National Health and Nutrition Examination Survey (NHANES) 2007–2016. Eligibility criteria from LEADER primary and secondary prevention cohorts were applied to determine potentially eligible US adults. We estimated the number of primary composite and secondary CVD endpoints that would occur based on LEADER treated and placebo published event rates, with the difference indicating the number of preventable events. Results: Among 4672 (projected to 27.3 million [M]) adults we identified with T2DM, we estimated 800 (4.2 million) (15.4%) to fit LEADER eligibility criteria, including 205 (0.9 M) primary prevention 595 (3.3 M) secondary prevention subjects. Compared to LEADER trial participants, our sample had higher proportions of women and minorities, prior angina, chronic kidney disease, and lipid-lowering medication use. We estimated 21,209 primary composite CVD events, 29,691 extended CVD composite outcomes, 16,967 all-cause deaths, 16,967 cardiovascular deaths, 12,725 myocardial infarctions, and 12,725 microvascular events would be prevented annually if our eligible T2DM subjects were on liraglutide. Conclusion: Liraglutide may prevent many fatal and non-fatal CVD events if provided to US adults meeting LEADER eligibility criteria. More efforts are needed to educate the healthcare providers on the CVD benefits from newer diabetes therapies, including liraglutide. [ABSTRACT FROM AUTHOR]

Purpose Of Review: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in individuals with type 2 diabetes (T2D). Recent cardiovascular outcome trials (CVOTs) have established sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1 RA) as powerful medications that can lower glucose as well as reduce the risk of complications of CVD in many individuals with T2D. The combination of glycemic and cardiovascular benefits of SGLT2i and GLP1 RA has highlighted the importance of collaborative care of patients by diabetes and cardiovascular specialists. We review several models of cardiometabolic care for patients with diabetes and CVD and discuss practical ways in which diabetes and cardiovascular specialists can work together to improve cardiometabolic care.Recent Findings: CVOTs for SGLT2i and GLP1 RA have demonstrated a significant reduction in major adverse cardiovascular events in individuals with T2D and CVD, in addition to their beneficial effects on glucose lowering and weight loss. Additionally, several models of care, including population health screening models with or without a remote management intervention, multidisciplinary clinics, and combined cardiometabolic training, have been proposed to better facilitate the multifaceted care that individuals with diabetes and CVD require. Innovative models of cardiometabolic care have the potential to improve the quality of care that individuals with diabetes and CVD receive. Through collaboration and co-management, diabetes specialists, cardiovascular specialists, and primary care providers have the ability to optimize diabetes and cardiovascular care. [ABSTRACT FROM AUTHOR]

Recently reported cardiovascular outcome studies on empagliflozin (EMPA-REG) and liraglutide (LEADER) have spurred interest in this field of diabetology. This commentary compares and contrasts these studies with two equally important outcome trials conducted using blood pressure lowering agents. A comparison with MICROHOPE (using ramipril) and ADVANCE (using perindopril + indapamide) blood pressure arms throws up interesting facts. The degree of blood pressure lowering, dissociation between cardiovascular and cerebrovascular benefits, and discordance between renal and retinal outcomes are surprisingly similar in these trials, conducted using disparate molecules. The time taken to achieve such benefits is similar for all drugs except empagliflozin. Such discussion helps inform rational and evidence-based choice of therapy and forms the framework for future research.

Background: This study evaluated the real-world weight loss and glycemic outcomes of multidrug therapy (MDT) according to various combinations of metformin, sodium-glucose cotransporter -2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor analogs (GLP1a), and orlistat in diabesity. Methods: Data retrospectively captured from medical records of 2 different centers in New Delhi for patients >35 years-age having prediabetes/diabetes and on at least any one of the 4 above medications with >6-months follow-up was analyzed. Results: In total, 5,336 patient records were screened; 2,442 with prediabetes/diabetes were considered; 1,509 patients who fulfilled all criteria were analyzed. Use of metformin, SGLT2i, sulfonylureas, DPP4i, pioglitazone, orlistat, and GLP1a was 85.35%, 74.95%, 68.32%, 60%, 39.16%, 9.08%, and 4.17%, respectively. However, 365, 970, and 104 patients were on one of 4 concerned medications (Group-1; 24.18%), dual MDT (Group-2; 64.28%), and triple/quadruple MDT (Group-3; 6.89%). Metformin with SGLT2i was most commonly used dual MDT (94.12%). Analysis according to weight-loss quartiles from 558 patients showed 6.9 kg weight-loss in the highest quartile. People losing maximum weight were significantly younger; had higher use of metformin, SGLT2i, GLP1, orlistat, and lower pioglitazone use; greatest HbA1c reduction (–1.3 vs. –0.3; quartile-1 vs. quartile –4; P < 0.001); and significantly higher occurrence of HbA1c<5.7% (16.8% vs. 6.29%; quartile-1 vs. 4; P < 0.001). Patients in Group-3 had the highest baseline BMI and maximum weight loss with highest number of patients with HbA1c<5.7% (19.44% vs. 10.34%; Group-3 vs. Group-1; P < 0.001). Conclusion: Greater weight loss with HbA1c reduction along with a greater number of patients attaining HbA1c <5.7% highlights that MDT is the way forward to tackle diabesity in India. [ABSTRACT FROM AUTHOR]

Recently reported cardiovascular outcome studies on empagliflozin (EMPA-REG) and liraglutide (LEADER) have spurred interest in this field of diabetology. This commentary compares and contrasts these studies with two equally important outcome trials conducted using blood pressure lowering agents. A comparison with MICROHOPE (using ramipril) and ADVANCE (using perindopril + indapamide) blood pressure arms throws up interesting facts. The degree of blood pressure lowering, dissociation between cardiovascular and cerebrovascular benefits, and discordance between renal and retinal outcomes are surprisingly similar in these trials, conducted using disparate molecules. The time taken to achieve such benefits is similar for all drugs except empagliflozin. Such discussion helps inform rational and evidence-based choice of therapy and forms the framework for future research. [ABSTRACT FROM AUTHOR]

Globally, nearly 500 million adults currently have diabetes, which is expected to increase to approximately 700 million by 2040. Cardiovascular diseases (CVD), including coronary heart disease, stroke, heart failure, and peripheral arterial disease, are the principal causes of death in persons with diabetes. Key to the prevention of CVD is optimization of associated risk factors. However, few persons with diabetes are at recommended targets for key CVD risk factors including low-density lipoprotein-cholesterol (LDL-C), blood pressure, glycated hemoglobin, nonsmoking status, and body mass index. While lifestyle management forms the basis for the prevention and control of these risk factors, newer and existing pharmacologic approaches are available to optimize the potential for CVD risk reduction, particularly for the management of lipids, blood pressure, and blood glucose. For higher-risk patients, antiplatelet therapy is recommended. Medication for blood pressure, statins, and most recently, icosapent ethyl, have evidence for reducing CVD events in persons with diabetes. Newer medications for diabetes, including sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists, also reduce CVD and SGLT2 inhibitors in particular also reduce progression of kidney disease and reduce heart failure hospitalizations (HFHs). Most importantly, a multidisciplinary team is required to address the polypharmaceutical options to best reduce CVD risks persons with diabetes.

Glucagon-like peptide receptor-1 agonists have a key place in the hypoglycemic treatment of type 2 diabetes. The possibilities of their administration are now well outlined as well as their use in both the step-up and step-down an-tidiabetic therapy, the advantages and potential disadvantages of the already available oral version over the parenteral formulation, and the possible differentiation options for their basal insulin-combined variants. These issues are re-viewed in the article, but recent research on the drug group, monotherapeutic and combination products being under development are also briefly discussed. Attention is drawn on the importance of the early introduction of any of their long-acting derivates, the cardiorenal protective effect, powerful glycemic effect, weight loss promoting property and low hypoglycemic risk. It is important to keep doctors continuously informed about the latest results of this area as well as the correct patient education.

Atherosclerotic cardiovascular disease (ASCVD) commonly affects people with type 2 diabetes (T2D). Historically, traditional cardiovascular (CV) risk-lowering therapies in patients with T2D and ASCVD have included antiplatelet agents, blood pressure-lowering therapies, lipid-lowering therapies and healthy lifestyle modifications. In the past decade, multiple antihyperglycaemic agents have emerged as CV risk-lowering therapies in this population as well. This article provides a narrative review on the current non-glycaemic and glycaemic treatment options for CV risk reduction in patients with T2D and ASCVD. The FDA requirement that all new antihyperglycaemic agents undergo cardiovascular outcomes trials has demonstrated increasing evidence to support the role of glucagon-like peptide 1 (GLP1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors as first-line agents for both glycaemic control and CV risk reduction in this population., Competing Interests: Disclosure and potential conflicts of interest: The authors declare that they have no conflicts of interest relevant to this manuscript. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2022/01/dic.2021-10-1-COI.pdf, (Copyright © 2022 Anderson SL, Marrs JC.)

Dulaglutide is a frequently used GLP-1 analogue and one of the most potent antidiabetic drugs. Practical aspects of treatment with dulaglutide are presented in this article, together with new data from AWARD-11 study with higher concentrations of dulaglutide, especially the effects on diabetes control, body weight and side effects.

Diabetic kidney disease (DKD) is a frequent, potentially devastating complication of diabetes mellitus. Several factors are involved in its pathophysiology. At a cellular level, diabetic kidney disease is associated with many structural and functional alterations. Autophagy is a cellular mechanism that transports intracytoplasmic components to lysosomes to preserve cellular function and homeostasis. Autophagy integrity is essential for cell homeostasis, its alteration can drive to cell damage or death. Diabetic kidney disease is associated with profound autophagy dysregulation. Autophagy rate and flux alterations were described in several models of diabetic kidney disease. Some of them are closely linked with disease progression and severity. Some antidiabetic agents have shown significant effects on autophagy. A few of them have also demonstrated to modify disease progression and improved outcomes in affected patients. Other drugs also target autophagy and are being explored for clinical use in patients with diabetic kidney disease. The modulation of autophagy could be relevant for the pharmacological treatment and prevention of this disease in the future. Therefore, this is an evolving area that requires further experimental and clinical research. Here we discuss the relationship between autophagy and Diabetic kidney disease and the potential value of autophagy modulation as a target for pharmacological intervention. [ABSTRACT FROM AUTHOR]

Context Cardiovascular outcome trials (CVOT) of glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrated reduction of major adverse cardiovascular events (MACE), cardiovascular deaths (CVD), and renal outcomes. Objective Assist in the prescribing decision regarding severity of illness and risk for adverse events. Design Meta-analysis of the major CVOT and previous meta-analyses. Main Outcome Measures Six trials of GLP-1 RA (51 762 subjects) and 4 trials of SGLT2i (33 457 subjects) showed both drug classes reduced MACE and CVD versus controls, with neither class preferred (comparison GLP1-RA vs SGLT2i: relative rate [rr] MACE 1.09, 95% confidence interval [CI] 0.97, 1.22, P  = ns; rr CVD 1.04, 95% CI 0.87, 1.24, P  = ns). Hospitalization for heart failure (HHF) improved with SGLT2i (rr 0.68, CI 0.61, 0.76, P  < 0.001) but not with GLP-1 RA, (rr 0.93, CI 0.86,1.03, P  = ns). Meta-regression suggested benefits of the SGLT2i on CVD and HHF were accentuated with the underlying rate of MACE in the cohort (i.e., >10 events/1000pt*year). GLP-1 RA and SGLT2i showed reduction in renal outcomes (GLP-1 RA rr 0.83, CI 0.75, 0.91, p ≤ 0.001, SGLT2i rr 0.67, CI 0.57, 0.79, P  < 0.001) without a preferential difference (GLP-1 RA vs SGLT2i, rr 1.24, CI 0.95, 1.61, P  = ns; relative difference (rd) 0.005, CI -0.011, 0.021, P  = ns). Serious adverse events for SGLT2i were mycotic genital infections in women (number needed to harm [NNH] = 13 and diabetic ketoacidosis NNH = 595. Gastrointestinal intolerance was the serious adverse event in the GLP1-RA class (NNH = 35). Conclusion GLP-1 RA and SGLT2i classes showed similar reduction in MACE, CVD, and renal outcomes. SGLT2i have advantages over GLP-1 RA in reduction in HHF. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus represents one of the most common chronic-degenerative diseases in modern society and is the cause of innumerable micro- and macrovascular complications that weigh on the national health system. Until a few years ago, there was no anti-diabetic drug that, in addition to lowering blood sugar, had an impact on cardiovascular risk in these patients. In this report, we will analyse the characteristics, contraindications, and evidence in favour of the use of two innovative categories of molecules that aim, for the first time in history, at controlling blood sugar levels and simultaneously lower cardiovascular risk in diabetics individuals: the glucagon-like peptide receptor agonists and the sodium-glucose cotransporter 2 inhibitors., (Published on behalf of the European Society of Cardiology. © The Author(s) 2020.)

Patients with diabetes have been reported to have enhanced susceptibility to severe or fatal COVID-19 infections, including a high risk of being admitted to intensive care units with respiratory failure and septic complications. Given the global prevalence of diabetes, affecting over 450 million people worldwide and still on the rise, the emerging COVID-19 crisis poses a serious threat to an extremely large vulnerable population. However, the broad heterogeneity and complexity of this dysmetabolic condition, with reference to etiologic mechanisms, degree of glycemic derangement and comorbid associations, along with the extensive sexual dimorphism in immune responses, can hamper any patient generalization. Even more relevant, and irrespective of glucose-lowering activities, DPP4 inhibitors and GLP1 receptor agonists may have a favorable impact on the modulation of viral entry and overproduction of inflammatory cytokines during COVID-19 infection, although current evidence is limited and not univocal. Conversely, SGLT2 inhibitors may increase the likelihood of COVID-19-related ketoacidosis decompensation among patients with severe insulin deficiency. Mindful of their widespread popularity in the management of diabetes, addressing potential benefits and harms of novel antidiabetic drugs to clinical prognosis at the time of a COVID-19 pandemic deserves careful consideration.

Background: The treatment of type 2 diabetes mellitus (T2DM) is complex; only a few patients successfully attain glycemic targets with monotherapy, most requiring drug combination therapy., Methods: The goal of this review was to identify in PubMed the complimentary ways of action leading to clinical benefit (in lowering HbA1c, body weight, renal, and cardiac risk factors and events) of the combination of sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA)., Results: SGLT2i, an emerging class of antidiabetic agents with an insulin-independent mechanism of action, are suitable for use in combination with any other class of antidiabetics, including insulin. The use of SGLT2i causes a reduction in Cardiovascular Disease (CVD) morbidity (mainly heart failure-HF) as well as total and CVD mortality. Besides insulin, SGLT2i may also be combined with incretin-based therapies, such as GLP-1 RA. The latter appears to reduce the rate or the progression of both macrovascular (mainly myocardial infarction-MI and stroke) and microvascular complications of DM, having a beneficial effect on all-cause mortality and CVD mortality, as well as CVD events. SGLT2i and GLP-1 RA may have a synergic effect on glucose reduction, weight reduction, renal impairment (both an independent lethal disease and a CVD risk factor) improvement, and cardiac event reduction, because the first reduces HF and related events and the second decreases CVD risk (mainly MI and stroke). Both also reduce total mortality, especially when combined with a statin., Conclusion: The combination of metformin with SGLT2i, GLP-1 RA, and a potent statin, in high CVD risk patients with DM, is expected to substantially reduce CVD mortality and morbidity, improving the quality of life of patients with DM at the same time. Prospective studies are needed to confirm this finding., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)