Sodium-glucose cotransporter inhibitors in type 2 diabetes: thinking beyond glucose lowering.
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ABSTRACT:
SUBMITTER: Neuen BL
PROVIDER: S-EPMC6791785 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
Publications
Sodium-glucose cotransporter inhibitors in type 2 diabetes: thinking beyond glucose lowering.
Neuen Brendon L BL Cherney David Z DZ Jardine Meg J MJ Perkovic Vlado V
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 20191001 41
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Project description:Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class initially designed and approved for treatment of diabetes mellitus, have been shown to exert pleiotropic metabolic and direct cardioprotective and nephroprotective effects that extend beyond their glucose-lowering action. These properties prompted their use in two frequently intertwined conditions, heart failure and chronic kidney disease. Their unique mechanism of action makes SGLT2i an attractive option also to lower the rate of cardiac events and improve overall survival of oncological patients with preexisting cardiovascular risk and/or candidate to receive cardiotoxic therapies. This review will cover biological foundations and clinical evidence for SGLT2i modulating myocardial function and metabolism, with a focus on their possible use as cardioprotective agents in the cardio-oncology settings. Furthermore, we will explore recently emerged SGLT2i effects on hematopoiesis and immune system, carrying the potential of attenuating tumor growth and chemotherapy-induced cytopenias.
| S-EPMC11790819 | biostudies-literature
Project description:Diabetes and heart failure (HF) are closely linked, with one causing a worse prognosis in the other. The majority of anti-hyperglycaemic agents primarily reduce risk of ischaemic microvascular events without targeting the mechanisms involved for diabetes cardiomyopathy and HF. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a novel class of glucose-lowering agents that have consistently reduced HF hospitalisations, unlike other agents. The authors discuss the current evidence and highlight possible future directions for the role of SGLT2 inhibitors in HF prevention.
| S-EPMC6848945 | biostudies-literature
Project description:Revelations of the multifactorial pathogenesis of type 2 diabetes mellitus (T2DM) that extend beyond the role of insulin and glucose utilization have been crucial in redefining the treatment paradigm. The focus of treatment is currently directed towards achieving wide-ranging targets encompassing the management of cardiovascular comorbidities that have been evidenced as indispensable aspects of T2DM. While most currently prescribed antihyperglycemic agents have little or no effect on reducing cardiovascular risks, some have been associated with undesirable effects on common risk factors such as weight gain and cardiovascular sequelae. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are newer additions to the array of therapeutic agents for T2DM that have demonstrated robust glycemic control as mono and add-on therapies. Their unique renal mode of action, independent of insulin modulation, confers complementary metabolic benefits. By virtue of these effects, SGLT2i may have a distinct role in the revised treatment recommendations by established working groups such as the American Diabetes Association and the American Association of Clinical Endocrinologists that advocate a more comprehensive management of T2DM, not restricting to glycemic targets. The current review gives an overview of the changing treatment needs for T2DM and discusses the nonglycemic effects of SGLT2i. It provides an updated summary on the efficacy of canagliflozin, dapagliflozin, and empagliflozin in promoting weight loss, stabilizing blood pressure, and other favorable metabolic effects.
| S-EPMC5729683 | biostudies-other
Project description:Aims/introductionSodium-glucose cotransporter 2 inhibitors (SGLT2i) are used worldwide because of their multiple benefits for patients with type 2 diabetes. The purpose of this study was to determine the efficacy and safety of SGLT2i in patients with type 1 diabetes.Materials and methodsPatients with type 1 diabetes who had been treated with SGLT2i for >12 weeks were included in this retrospective observation study. We recorded the changes in body mass, insulin dose, blood and urine test data, and adverse events. The changes in day-to-day glucose variability, as the primary end-point, was evaluated using the interquartile range (P25/P75) of the ambulatory glucose data obtained using continuous glucose monitoring.ResultsA total of 51 patients (37 women; mean age 52.7 years) were included. Glycated hemoglobin and body mass significantly decreased by 0.4% and 1.6 kg, respectively. The total required insulin dose decreased by 9.4% (42.7 ± 26.6-38.7 ± 24.3 units/day). Continuous glucose monitoring data were obtained from 30 patients. P25/P75 decreased by 17.6 ± 20.7% during SGLT2i treatment (P < 0.001). The percentage of time per day within the target glucose range of 70-180 mg/dL significantly increased (from 42.2 to 55.5%, P < 0.001), without an increase in the percentage of time spent in the hypoglycemic range (<70 mg/dL). Urinary ketone bodies were detected in four patients (7.8%), but none developed ketoacidosis.ConclusionsSGLT2i improved day-to-day glucose variability and time in the target glucose range, without increasing frequency of hypoglycemia, in patients with type 1 diabetes, and reduced glycated hemoglobin, body mass and the required insulin dose.
| S-EPMC7858126 | biostudies-literature
Project description:Type 2 diabetes mellitus (T2DM) is a chronic, complex metabolic disease characterized by chronic hyperglycemia causing from insufficient insulin signaling because of insulin resistance or defective insulin secretion, and may induce severe complications and premature death. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are oral drugs used to reduce hyperglycemia in patients with T2DM, including empagliflozin, ertugliflozin, dapagliflozin and canagliflozin. The primary objective of this article is to examine the clinical benefit, safety, and tolerability of the four SGLT2 inhibitors approved by the US FDA. SGLT2 inhibitors increase urinary glucose excretion via inhibiting SGLT2 to decrease renal reabsorption of filtered glucose and reduce the renal threshold for glucose. Rather than stimulating insulin release, SGLT2 inhibitors improve β-cell function by improving glucotoxicity, as well as reduce insulin resistance and increase insulin sensitivity. Early clinical trials have confirmed the beneficial effects of SGLT2 in T2DM with acceptable safety and excellent tolerability. In recent years, SGLT2 inhibitors has been successively approved by the FDA to decrease cardiovascular death and decrease the risk of stroke and cardiac attack in T2DM adults who have been diagnosed with cardiovascular disease, treating heart failure (HF) with reduced ejection fraction and HF with preserved ejection fraction, and treat diabetic kidney disease (DKD), decrease the risk of hospitalization for HF in T2DM and DKD patients. SGLT2 inhibitors are expected to be an effective treatment for T2DM patients with non alcoholic fatty liver disease. SGLT2 inhibitors have a similar safety profile to placebo or other active control groups, with major adverse events such as Ketoacidosis or hypotension and genital or urinary tract infections.
| S-EPMC9134641 | biostudies-literature
Project description:ImportanceDiabetic nephropathy and diabetic retinopathy share many similarities in pathophysiological processes. Preclinical studies have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) have a protective role in the risk of diabetic retinopathy.ObjectiveTo compare the risk of sight-threatening retinopathy associated with SGLT2is and other second-line glucose-lowering medications (including pioglitazone, sulfonylureas, and dipeptidyl peptidase-4 inhibitors [DPP-4is]) in patients with type 2 diabetes (T2D).Design, setting, and participantsThis cohort study in Taiwan applied a new-user and active-comparator design. Patient demographic and clinical data were obtained from the National Health Insurance Research Database. Adult patients with newly diagnosed T2D from January 1, 2009, to December 31, 2019, were recruited and followed up until December 31, 2020. Propensity score matching was used to identify pairs of patients treated with SGLT2i vs DPP-4i, SGLT2i vs pioglitazone, and SGLT2i vs sulfonylurea from January 1, 2016, to December 31, 2019. Data were analyzed between August 18, 2022, and May 5, 2023.ExposuresTreatment with SGLT2i, DPP-4i, pioglitazone, and sulfonylureas starting on January 1, 2016.Main outcomes and measuresThe main outcome was sight-threatening retinopathy in participants. Cox proportional hazards regression models were used to assess relative hazards of sight-threatening retinopathy between the matched case and control groups.ResultsA total of 3 544 383 patients with newly diagnosed T2D were identified. After 1:1 propensity score matching, 65 930 pairs of patients treated with SGLT2i vs DPP-4i, 93 760 pairs treated with SGLT2i vs pioglitazone, and 42 121 pairs treated with SGLT2i vs sulfonylurea were identified. These matched patients included 236 574 males (58.6%), with a mean (SD) age of 56.9 (11.8) years. In the matched cohorts, SGLT2i had a significantly lower risk of sight-threatening retinopathy than DPP-4i (adjusted hazard ratio [AHR], 0.57; 95% CI, 0.51-0.63), pioglitazone (AHR, 0.75; 95% CI, 0.69-0.81), and sulfonylureas (AHR, 0.62; 95% CI, 0.53-0.71). The Kaplan-Meier curves showed that SGLT2i was associated with a significantly lower cumulative incidence of sight-threatening retinopathy than DPP-4i (3.52 vs 6.13; P < .001), pioglitazone (4.32 vs 5.76; P < .001), and sulfonylureas (2.94 vs 4.67; P < .001).Conclusions and relevanceThis cohort study found that SGLT2i was associated with a lower risk of sight-threatening retinopathy compared with DPP-4i, pioglitazone, and sulfonylureas. This finding suggests that SGLT2i may play a role not only in reduced risk of diabetic nephropathy but also in the slow progression of diabetic retinopathy in patients with T2D.
| S-EPMC10733799 | biostudies-literature
Project description:Cardiorenal syndrome (CRS) in people with type 2 diabetes mellitus (T2DM) illustrates the bidirectional link between the heart and the kidneys, with acute or chronic dysfunction of one organ adversely impacting the function of the other. Of the five subtypes identified, type 1 and 2 CRS occur because of the adverse impact of cardiac conditions on the kidneys. Type 3 and 4 occur when renal conditions affect the heart, and in type 5, systemic conditions impact the heart and kidneys concurrently. The cardiovascular and renoprotective benefits evidenced with sodium-glucose cotransporter-2 (SGLT2) inhibitors make them a potential choice in the management of CRS. Cardiovascular protection is mediated by a reduction in cardiac workload, blood pressure, and body weight; with improvement in lipid profile, uric acid levels, and adaptive ketogenesis process. Renoprotection is facilitated by reduction in albuminuria and hypoxic stress, and restoration of tubuloglomerular feedback. The favourable effect on cardiovascular complications and death, as well as renal complications and progression to end-stage kidney disease, has been confirmed in clinical trials. Guidelines endorse first-line use of SGLT2 inhibitors after metformin in patients with T2DM with high cardiovascular risk, chronic kidney disease or both. Since most trials with SGLT2 inhibitors excluded subjects with acute illness, patients with CRS subtypes 1 and 3 have not been studied adequately, making SGLT2 initiation in clinical practice challenging. Ongoing trials may provide evidence for SGLT2 inhibitor use in CRS. This review aims to enhance understanding of CRS and provide guidance for judicious use of SGLT2 inhibitors in T2DM.
| S-EPMC7572171 | biostudies-literature
Project description:Type 2 diabetes (T2D) is associated with an increased risk of macro- and microvascular complications, including cardiovascular disease (CVD), heart failure (HF), and chronic kidney disease (CKD). Of the currently available glucose-lowering therapies, sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are the only class to target the pathophysiologic increase in renal glucose reabsorption in patients with T2D. In CV outcomes trials of SGLT-2is in patients with T2D and established CVD or varying levels of CV risk, empagliflozin, canagliflozin, and dapagliflozin were associated with significant improvements in the risk of composite CV and renal outcomes compared with placebo that extended beyond their glycemic effects. Real-world observational studies have also reported improvements in CV outcomes with SGLT-2is compared with other glucose-lowering therapy in routine clinical practice. This review describes the pleiotropic effects of SGLT-2is and discusses the potential mechanisms for these effects as well as how they potentially provide benefits beyond glycemic control in patients with T2D. These favorable nonglycemic effects indicate that SGLT-2is may be of particular benefit in patients with diabetic complications, such as CVD, HF, or CKD. Ongoing large randomized trials in specific patient populations, including those with CVD, HF, or CKD (with or without T2D), may help to confirm the benefits of SGLT-2is in these patients and further elucidate the potential mechanisms of their pleiotropic effects. FUNDING: AstraZeneca.
| S-EPMC6778563 | biostudies-literature
Project description:Despite the availability of established treatments, heart failure (HF) is associated with a poor prognosis and its management is suboptimal, highlighting the need for new options for treatment and prevention. Patients with type 2 diabetes (T2D) often experience cardiovascular (CV) complications, with HF being one of the most frequent. Consequently, several CV outcome trials have focused on glucose-lowering therapies and their impact on CV outcomes. An established treatment for T2D, sodium-glucose cotransporter-2 inhibitors (SGLT-2is; canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) have demonstrated beneficial effects on CV outcomes in long-term studies of patients with T2D with established CV disease and/or a broad range of CV risk factors. Recent studies have extended these findings to patients with HF, with and without T2D, finding that SGLT-2is (particularly dapagliflozin and empagliflozin) are effective therapeutic interventions for the treatment and prevention of HF. This narrative review article discusses the use of SGLT-2is in the treatment and prevention of HF in patients with and without T2D. Dapagliflozin was the first SGLT-2i to receive US Food and Drug Administration (FDA) approval for treatment of HF, to reduce the risk of CV death and hospitalization for HF in adults with HF with reduced ejection fraction (HFrEF) with and without T2D. Recently, the FDA also approved empagliflozin for this indication. Given the new HFrEF indications for dapagliflozin and empagliflozin, and the likelihood of similar approvals for other SGLT-2is, cardiology guidelines are beginning to integrate SGLT-2is into a standard-of-care treatment regimen for patients with HFrEF. The utility of SGLT-2is in HF with preserved EF (HFpEF) shows promise based on data from the EMPEROR-Preserved study of empagliflozin in patients with HFpEF. Further clinical trial evidence may lead to more widespread use and further integration of SGLT-2is into standard-of-care regimens for the treatment and management of HF in patients with and without T2D.
| S-EPMC8866261 | biostudies-literature
Project description:The efficacy of the sodium-glucose cotransporter 2 (SGLT2) inhibitors canagliflozin, dapagliflozin, and empagliflozin in reducing hyperglycemia in patients with type 2 diabetes is well documented. In addition, positive effects have been observed with these agents on nonglycemic variables, such as reductions in body weight and blood pressure, which may confer additional health benefits. SGLT2 inhibitors are also associated with evidence of renal-protecting benefits. Furthermore, during the landmark Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial, a substantial reduction in major adverse cardiovascular outcomes was demonstrated with empagliflozin therapy. In view of the complex pathogenesis of cardiovascular disease in patients with diabetes, a pharmacologic intervention for type 2 diabetes that produces a multifaceted reduction in cardiovascular disease risk, separate from glycemic control alone, would be advantageous. Although SGLT2 inhibitors are generally well tolerated, they are associated with an increased risk of genital mycotic infections, as well as the potential risk for serious adverse events such as dehydration, development of diabetic ketoacidosis, serious urinary tract infections, and bone fractures. The findings of ongoing research will help to determine the magnitude and clinical importance of these adverse events and whether the findings of EMPA-REG OUTCOME represent a class effect for SGLT2 inhibition or are specific to empagliflozin and will further elucidate the future role of SGLT2 inhibitors in the individualized management of patients with type 2 diabetes. In this article, we discuss the nonglycemic outcomes associated with SGLT2 inhibitor therapy in patients with type 2 diabetes as well as the clinical implications of these agents.
| S-EPMC5412678 | biostudies-literature