Sodium-Glucose Cotransporter 2 (SGLT-2) Inhibitors: Delving Into the Potential Benefits of Cardiorenal Protection Beyond the Treatment of Type-2 Diabetes Mellitus.
TL;DR: In this article, the authors reviewed the mechanisms behind cardiac and renal involvement in type 2 diabetes and their inseparable interconnections and discussed the pharmacokinetic and pharmacodynamic profile of different SGLT2 inhibitors available in the market.
Abstract: Diabetes mellitus is a leading cause of morbidity and mortality and a significant risk factor for the early onset of chronic kidney disease and heart disease. Hyperglycemia and insulin resistance are key factors that play a role in the pathogenesis of type 2 diabetes. Renal glucose reabsorption is a critical component of glycemic regulation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, commonly known as gliflozins, lower blood sugar levels by inhibiting glucose absorption in the proximal tubule of the kidney. SGLT2 inhibitors are currently used primarily as antidiabetic medications; however, their advantages go well beyond just glycemic control. This article has reviewed the mechanisms behind cardiac and renal involvement in type 2 diabetes and their inseparable interconnections. This article has also discussed the pharmacokinetic and pharmacodynamic profile of different SGLT2 inhibitors available in the market. Finally, this review has provided a perspective on the outcome trials, which provide evidence supporting a potential benefit of SGLT2 inhibitors in reducing cardiovascular and renal risks and possible mechanisms that mediate the renal and cardiovascular protection conferred.
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TL;DR: The proposed hypothesis for hyperglycemia in COVID-19 include insulin resistance, critical illness hyperglyCEmia (stress- induced hyperglycesmia) secondary to high levels of hormones like cortisol and catecholamines that counteract insulin action, acute cytokine storm and pancreatic cell dysfunction.
Abstract: Hyperglycemia is commonly associated with adverse outcomes especially in patients requiring intensive care unit stay. Data from the corona virus disease 2019 (COVID-19) pandemic indicates that individuals with diabetes appear to be at similar risk for COVID-19 infection to those without diabetes but are more likely to experience increased morbidity and mortality. The proposed hypothesis for hyperglycemia in COVID-19 include insulin resistance, critical illness hyperglycemia (stress- induced hyperglycemia) secondary to high levels of hormones like cortisol and catecholamines that counteract insulin action, acute cytokine storm and pancreatic cell dysfunction. Diabetic patients are more likely to have severe hyperglycemic complications including diabetic ketoacidosis and hyperosmolar hyperglycemic state. Management of hyperglycemia in COVID-19 is often complicated by use of steroids, prolonged total parenteral or enteral nutrition, frequent acute hyperglycemic events, and restrictions with fluid management due to acute respiratory distress syndrome. While managing hyperglycemia special attention should be paid to mode of insulin delivery, frequency of glucose monitoring based on patient and caregiver safety thereby minimizing exposure and conserving personal protective equipment. In this article we describe the pathophysiology of hyperglycemia, challenges encountered in managing hyperglycemia, and review some potential solutions to address them.
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TL;DR: In this paper , the specific mechanisms of action, potential side effects, and cardiorenal benefits of GLP-1RA and SGLT-2i therapies are discussed to fully understand their roles in combating type 2 diabetes mellitus.
Abstract: Diabetes mellitus is a metabolic disorder characterized by increased serum glucose due to errors in insulin production or response. The prevalence of diabetes mellitus has continued to rise globally over the years, with roughly 7079 persons per 100,000 expected to be impacted by 2030. A vast number of patients with diabetes mellitus experience unfavorable side effects such as weight gain, hypoglycemia, and hepatorenal toxicity from the several diabetic medications available. These adverse effects may result in life-threatening consequences with a high likelihood of occurrence; therefore, ongoing efforts continue to develop medications with improved tolerability and better glycemic control. Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are examples of new innovative targeted therapies to manage diabetes mellitus and potentially improve cardiorenal conditions. This review article details the specific mechanisms of action, potential side effects, and cardiorenal benefits of GLP-1RA and SGLT-2i therapies to fully understand their roles in combating type 2 diabetes mellitus (T2D).
TL;DR: In this article , the association between cardiac adverse events (CAEs) and SGLT2i was investigated and 2,330 CAEs were associated with type 2 diabetic patients and 81 were used for heart failure.
Abstract: BACKGROUND
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective in reducing the risk of heart failure (HF) in type 2 diabetic patients. We systematically examined the association between cardiac adverse events (CAEs) and SGLT2i.
RESEARCH DESIGN AND METHODS
We analyzed CAEs in the FDA Adverse Event Reporting System between January 2013 and March 2021. The CAEs were classified into four major groups according to their preferred terms. Disproportionality and Bayesian analyses were performed to detect signals using reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and empirical Bayesian geometric mean (EBGM). Case seriousness was also described.
RESULTS
There were 2,330 CAEs associated with SGLT2i, and 81 were used for HFs. The SGLT2i were not associated with over-reporting frequencies of CAE based on ROR (ROR=0.97, 95% confidence interval [CI]: 0.93, 1.01), PRR (PRR=0.97, 95% CI: 0.94, 1.01), Bayesian confidence propagation neural network (IC= -0.04, IC025: N.A.), and multi-item gamma Poisson shrinker (EBGM = 0.97, EBGM05:0.94), unless further restricted to myocardial infarction (ROR = 2.03, 95% CI = 1.89, 2.17). Additionally, SGLT2i-associated CAEs are associated with 11.33% fatality and 51.25% hospitalization.
CONCLUSIONS
SGLT2i present a favorable cardiac safety profile; however, concerns should be raised regarding their potential association with specific events.
TL;DR: In this paper, the authors described the risk factors, pathogenesis, diagnostic criteria, prevention strategies, and management of post-transplant diabetes mellitus (PTDM) in kidney transplant patients.
Abstract: Kidney transplant recipients are a unique subgroup of chronic kidney disease patients due to their single functioning kidney, immunosuppressive agent usage, and long-term complications related to transplantation. Post-transplant diabetes mellitus (PTDM) has a significant adverse effect on renal outcomes in particular. As transplantations enable people to live longer, cardiovascular morbidity and mortality become more prevalent, and PTDM is a key risk factor for these complications. Although PTDM results from similar risk factors to those of type 2 diabetes, the conditions differ in their pathophysiology and clinical features. Transplantation itself is a risk factor for diabetes due to chronic exposure to immunosuppressive agents. Considering current evidence, this article describes the risk factors, pathogenesis, diagnostic criteria, prevention strategies, and management of PTDM. The therapeutic options are discussed regarding their safety and potential drug–drug interactions with immunosuppressive agents.
TL;DR: For instance, the authors showed that glucagon-like peptide 1 receptor agonists, which are widely used in the treatment of T2DM, were shown to slow down, or even prevent, neuronal degeneration.
Abstract: From an epidemiological and pathophysiological point of view, Alzheimer's disease (AD) and type 2 diabetes (T2DM) should be considered 'sister' diseases. T2DM significantly increases the risk of developing AD, and the mechanisms of neuronal degeneration themselves worsen peripheral glucose metabolism in multiple ways. The pathophysiological links between the two diseases, particularly cerebral insulin resistance, which causes neuronal degeneration, are so close that AD is sometimes referred to as 'type 3 diabetes'. Although the latest news on the therapeutic front for AD is encouraging, no treatment has been shown to halt disease progression permanently. At best, the treatments slow down the progression; at worst, they are inactive, or cause worrying side effects, preventing their use on a larger scale. Therefore, it appears logical that optimizing the metabolic milieu through preventive or curative measures can also slow down the cerebral degeneration that characterizes AD. Among the different classes of hypoglycaemic drugs, glucagon-like peptide 1 receptor agonists, which are widely used in the treatment of T2DM, were shown to slow down, or even prevent, neuronal degeneration. Data from animal, preclinical, clinical phase II, cohort and large cardiovascular outcomes studies are encouraging. Of course, randomized clinical phase III studies, which are on-going, will be essential to verify this hypothesis. Thus, for once, there is hope for slowing down the neurodegenerative processes associated with diabetes, and that hope is the focus of this review.
References
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TL;DR: Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care.
Abstract: BACKGROUND The effects of empagliflozin, an inhibitor of sodium–glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known. METHODS We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina. RESULTS A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P = 0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P = 0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events. CONCLUSIONS Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.)
7,705 citations
TL;DR: Diabetes prevalence, deaths attributable to diabetes, and health expenditure due to diabetes continue to rise across the globe with important social, financial and health system implications.
5,474 citations
TL;DR: Patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal.
Abstract: BackgroundCanagliflozin is a sodium–glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. MethodsThe CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. ResultsThe mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% c...
4,842 citations
TL;DR: The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium–glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined.
Abstract: Background The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium–glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined. Methods We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause. Results We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, ...
3,430 citations
Royal North Shore Hospital1, The George Institute for Global Health2, Concord Repatriation General Hospital3, Imperial College London4, University of Sydney5, Harvard University6, New York University7, Janssen Pharmaceutica8, Indiana University – Purdue University Indianapolis9, Veterans Health Administration10, University of Chicago11, Kolling Institute of Medical Research12, Utah System of Higher Education13, University of British Columbia14, University College London15, Peking University16, Lunenfeld-Tanenbaum Research Institute17, Stanford University18
TL;DR: In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years.
Abstract: Background Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium...
3,233 citations