Sodium-glucose Cotransporter 2 Inhibitor Group Research Articles

Clinical Outcomes in Type 2 Diabetes Patients After Acute Myocardial Infarction: AComparison of Sodium-Glucose Cotransporter 2 Inhibitors vs. Non-Users.

To compare clinical outcomes in patients with type 2 diabetes (T2D) after acute myocardial infarction (AMI) using sodium-glucose cotransporter-2 inhibitors (SGLT2i) vs. non-use of SGLT2i. A national cohort study based on the Taiwan National Health Insurance Research Database enrolled 944 patients with T2D who had experienced AMI and were treated with SGLT2i and 8,941 patients who did not receive SGLT2i, respectively, from May 1, 2016, to December 31, 2019. We used propensity score matching to balance covariates across study groups. The follow-up period was from the index date to the independent occurrence of the study outcomes, discontinuation of the index drug, or the end of the study period (December 31, 2020), whichever occurred first. The SGLT2i group exhibited a significantly lower incidence of cardiovascular death (0.865% per year vs. 2.048% per year; hazard ratio (HR): 0.42; 95% confidence interval (CI): 0.24-0.76; P = 0.0042), heart failure hospitalization (1.987% per year vs. 3.395% per year; HR: 0.59; 95% CI: 0.39-0.89; P = 0.0126), and all-cause mortality (3.406% per year vs. 4.981% per year, HR: 0.69; 95% CI: 0.50-0.95; P = 0.0225) compared with the non-SGLT2i group. There were no significant differences between the two groups in the incidence of AMI, ischemic stroke, coronary revascularization, major adverse cardiovascular events, composite renal outcomes, or lower limb amputation. These findings suggest that the use of SGLT2i may have favorable effects on clinical outcomes in patients with T2D after AMI.

Cardioprotective effect of SGLT2 inhibitor in diabetic kidney transplant recipients: A multicenter propensity score matched study

BackgroundKidney transplantation improves the cardiovascular outcomes of patients with end-stage kidney disease. However, cardiovascular disease remains the leading cause of premature death and graft loss in kidney transplant recipients (KTRs) with diabetes. We evaluated the cardioprotective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in KTRs with diabetes. MethodsA total of 750 KTRs with diabetes were enrolled from six tertiary hospitals. Among them, 129 (17.2%) patients were prescribed SGLT2i. The primary outcome was the incidence of major adverse cardiovascular events (MACE), which comprised of myocardial infarction (MI), death from cardiovascular causes, hospitalization for heart failure, and stroke. Multivariable Cox regression analysis and propensity score matching were used to investigate the effect of SGLT2i on clinical outcomes. ResultsIn the matched cohort, MACE occurred in 5 (3.9%) patients in the SGLT2i group and 15 (11.8%) patients in the non-SGLT2i group, out of 127 patients in each group over 55.3 months. The incidence of MACE and MI was lower in the SGLT2i group than in the non-SGLT2i group (P=0.036 and 0.008, respectively). In multivariate analysis, the SGLT2i group had a lower risk of MACE and MI than the non-SGLT2i group (adjusted hazard ratio, 0.30 and 0.04; 95% confidence interval, 0.10–0.88 and 0.004–0.40; P=0.028 and 0.006, respectively). There was no difference in the incidence of urinary tract infection between the two groups. ConclusionsSGLT2i significantly decreased the risk of cardiovascular events in KTRs with diabetes, particularly lowering the incidence of MI and death from cardiovascular causes. Therefore, SGLT2i can be used to reduce the burden of cardiovascular disease in KTRs with diabetes.

Risks of carpal tunnel syndrome and carpal tunnel release surgery in users of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists: a target trial emulation study

AimPreclinical studies have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) have a neuroprotective effect. This study compared the risks of carpal tunnel syndrome and carpal tunnel release surgery between new users of SGLT2is and new users of glucagon-like peptide-1 receptor agonists (GLP-1RAs). MethodsA retrospective new-user active comparator cohort study with a target trial design was conducted by using the TriNetX platform. Patients with type 2 diabetes mellitus prescribed SGLT2is or GLP-1RAs were identified. Covariates were balanced using propensity score matching to form 2 homogenous treatment groups. Outcomes were the risk of carpal tunnel syndrome and the risk of carpal tunnel release surgery. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using the TriNetX platform. ResultsThe crude cohort included 86188 and 100244 patients in the SGLT2is group and GLP-1RAs group, respectively. After matching, each group included 65464 patients. The SGLT2is group had an average age of 59.6 years, and 46% were women. The GLP-1RAs group had an average age of 59.5 years, and 45.9% were women. The incidences of carpal tunnel syndrome (HR: 0.928; 95% CI: 0.869 to 0.991) and carpal tunnel release surgery (HR: 0.840; 95% CI: 0.726 to 0.971) were significantly lower in the SGLT2is group than in the GLP-1RAs group. ConclusionIn patients with type 2 diabetes mellitus, SGLT2is seem to decrease the risk of carpal tunnel syndrome and the need for carpal tunnel release surgery. Prospective studies are required to confirm our results.

The effect of sodium-glucose transporter 2 inhibitors on stroke in patients with type 2 diabetes: A meta-analysis

ObjectivesTo provide an update on the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on stroke in patients with type 2 diabetes (T2D). MethodsPubMed, Embase, and Cochrane Library were systematically searched for randomized controlled trials (RCTs) comparing SGLT2 inhibitors versus placebo or other therapies in patients with T2D and reporting stroke endpoint. We computed the risk ratios (RRs) to binary endpoints, with 95 % confidence intervals (CIs). ResultsA total of 71 RCTs and 105,914 patients were included, of whom 62,488 (59 %) were randomized to the SGLT2 inhibitors group. The follow-up ranged from 12 weeks to 4.2 years. There were no significant differences between groups in all types of stroke (RR 0.96; 95 % CI 0.89-1.04), ischemic stroke (RR 0.89; 95 % CI 0.76-1.04), and transient ischemic attack (RR 0.96; 95 % CI 0.79-1.16). Patients on SGLT2 inhibitors experienced lower rates of hemorrhagic stroke (RR 0.62; 95 % CI 0.39-0.98). In the subgroup analysis of the type of drug, sotagliflozin significantly reduced all types of stroke (RR 0.74; 95 % CI 0.56-0.97). ConclusionIn this meta-analysis of 71 RCTs comprising 105,914 patients with T2D, SGLT2 inhibitors were not associated with a reduced risk of stroke and transient ischemic attack compared to placebo or other therapies; however, there was a trend toward reduced risk of hemorrhagic stroke. Among all SGLT2 inhibitors, sotagliflozin significantly reduced the risk of stroke.

The Effectiveness of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors on Cardiovascular Outcomes and All-Cause Mortality in Patients With Acute Coronary Syndrome: A Systematic Review and Meta-Analysis.

The aim of this systematic review and meta-analysis was to investigate the impact of early sodium-glucose cotransporter-2 (SGLT2) initiation on long-term cardiovascular outcomes and all-cause mortality among patients with acute coronary syndrome (ACS).For this study, we adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guideline. Two researchers independently performed a comprehensive literature search on PubMed, Embase, and the Cochrane Library, spanning from the inception of each database to February 24, 2023, without language limitations. The outcomes examined in this meta-analysis comprised major adverse cardiovascular events (MACE) (as defined by individual studies), all-cause mortality, cardiovascular mortality, stroke (ischemic and hemorrhagic), recurrent ACS, and hospitalization due to heart failure (HF). A total of nine studies were included in this meta-analysis.The pooled analysis of nine studies revealed a significant reduction in the risk of MACE, all-cause mortality, cardiovascular mortality, and cardiovascular-related hospitalizations among patients receiving SGLT2 inhibitors (SGLT2i) compared to those in the control group. Additionally, there was a trend towarda lower risk of recurrent ACS in the SGLT2i group, although this difference did not reach statistical significance. The findings of this study suggest a promising therapeutic effect of SGLT2 inhibitors in this population. Further research, particularly focusing on myocardial infarction (MI) patients, is warranted to validate these results and potentially revolutionize ACS management.

A Study to Evaluate the Effect of Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors on Oxidative Stress Parameters in Type 2 Diabetes Mellitus Patients.

Introduction Diabetes mellitus (DM) is a global health issue with 50 million diabetics currently residing in India. Hyperglycemia causes tissue damage due to mitochondrial overproduction of reactive oxygen species. Sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) have shown a decrease in oxidative stress by either amelioration of free-radical generation or potentiation of cellular antioxidative capacity in preclinical studies. However, there is a paucity of published clinical studies. Hence, this study was undertaken to evaluate the effect of co-administration of SGLT2i with other drugs on oxidative stress in type 2 DM (T2DM) patients. Methods A prospective, parallel, open-label study in T2DM patients attending endocrinology OPDwas conducted for a period of 12 months. At the clinician's discretion, patients were grouped as SGLT2i as an add-on to standard drugs vs standard drugs alone. Blood samples were collected at baseline and at the end of 12 weeks to estimate malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH) levels. Secondary parameters - glycemic indices and lipid profile - were estimated every four weeks. Results A total of 32 patients were enrolled in the study (16 per group). There was a significant decrease in MDA (p < 0.05) and NO (p < 0.01) and a highly significant increase in GSH (p < 0.001) at 12 weeks from baseline in the SGLT2i group. A reduction in fasting blood sugar (FBS) and post-prandial blood sugar (PPBS) and a 0.56% difference in HbA1c were also noted in the SGLT2i group.Significant lowering of low-density lipoprotein (LDL, p < 0.05) and elevation in HDL levels (p < 0.05) from baseline was seen in the SGLT2i group. Conclusion Co-administration of SGLT2i with antidiabetic drugs demonstrated a significant effect in improving oxidative stress biomarkers and glycemic and lipid profiles among T2DM patients.

Increased risk of erythrocytosis in men with type 2 diabetes treated with combined sodium-glucose cotransporter-2 inhibitor and testosterone replacement therapy.

In clinical trials, sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and testosterone replacement therapy (TRT) were shown to stimulate red blood cell production. Little is known if combination therapy poses risk of erythrocytosis in real world clinical practice. This was a retrospective nationwide cohort study of US Veterans with type 2 diabetes (T2D) and baseline hematocrit between 38 and 50% who were prescribed SGLT-2i and/or TRT between 3/2013 and 10/2022 and had adequate adherence based on the proportion of days covered > 80%. Patients were divided into 3 groups: SGLT-2i only, TRT only, or combination therapy. Odds Ratio (OR) of new erythrocytosis defined as hematocrit level > 54% within 365days of therapy initiation was calculated by logistic regression model adjusted for baseline hematocrit, age, BMI, obstructive sleep apnea, diuretic use, and smoking status. Of the entire cohort of 53,971 people with T2D, total of 756 (1.4%) patients developed erythrocytosis. In unadjusted analyses, the OR of new onset erythrocytosis was higher in the combined SGLT-2i and TRT group compared with the SGLT-2i or TRT group alone (4.99, 95% CI (3.10-7.71) and 2.91, 95% CI (1.87-4.31), respectively). In the models adjusted for baseline characteristics, patients on combination therapy had significantly higher odds of erythrocytosis compared to those on SGLT-2i (OR 3.80, 95% CI (2.27-6.11)) or TRT alone (OR 2.49, 95% CI (1.51-3.59)). Testosterone delivery route (topical vs injectable) did not modify increased odds of erythrocytosis. For the first time, we demonstrated that in large cohort of patients combined therapy with SGLT-2i and TRT is associated with increased erythrocytosis risk compared with either treatment alone. Given rising prevalence of SGLT-2i use, providers should consider periodic hematocrit assessment in persons receiving both SGLT-2i and TRT.

Sodium-glucose cotransporter 2 inhibitors and cancer: a systematic review and meta-analysis.

The effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cancer has yet to be fully elucidated. This systematic review and meta-analysis investigated the effects of SGLT2 inhibitors on cancer. We searched the PubMed and ClinicalTrials.gov databases up to July 15, 2023, to identify eligible randomized, double-blind, placebo-controlled trials that lasted at least ≥24weeks. The primary outcome was the overall cancer incidence, and the secondary outcomes were the incidences of various types of cancer. We used the Mantel-Haenszel method, fixed effects model, risk ratio (RR) and 95% confidence interval (CI) to analyze dichotomous variables. Subgroup analysis was performed based on the SGLT2 inhibitor type, baseline conditions, and follow-up duration. All meta-analyses were performed using RevMan5.4.1 and Stata MP 16.0. A total of 58 publications (59 trials) were included, comprising 113,909 participants with type 2 diabetes mellitus and/or chronic kidney disease and/or high cardiovascular risk and/or heart failure (SGLT2 inhibitor group, 63864; placebo group, 50045). Compared to the placebo SGLT2 inhibitors did not significantly increase the overall incidence of cancer (RR 1.01; 95% CI 0.94-1.08; p = 0.82). However, ertugliflozin did significantly increase the overall incidence of cancer (RR 1.29; 95% CI 1.01-1.64; p = 0.04). SGLT2 inhibitors did not increase the risks of bladder or breast cancer. However, dapagliflozin did significantly reduce the risk of bladder cancer by 47% (RR 0.53; 95% CI 0.35-0.81; p = 0.003). SGLT2 inhibitors had no significant effect on the risks of gastrointestinal, thyroid, skin, respiratory, prostate, uterine/endometrial, hepatic and pancreatic cancers. Dapagliflozin reduced the risk of respiratory cancer by 26% (RR 0.74; 95% CI 0.55-1.00; p = 0.05). SGLT2 inhibitors (particularly mediated by dapagliflozin and ertugliflozin but not statistically significant) were associated with a greater risk of renal cancer than the placebo (RR 1.39; 95% CI 1.04-1.87; p = 0.03). SGLT2 inhibitors did not significantly increase the overall risk of cancer or the risks of bladder and breast cancers. However, the higher risk of renal cancer associated with SGLT2 inhibitors warrants concern.

Association of sodium-glucose cotransporter 2 inhibitors with risk of major adverse cardiovascular events in type 2 diabetes patients with acute coronary syndrome: a propensity score‑matched analysis

BackgroundThis study aimed to investigate the association of sodium-glucose cotransporter 2 inhibitors (SGLT2i) use with cardiovascular (CV) clinical outcomes in type 2 diabetes (T2D) patients with acute coronary syndrome (ACS).MethodsData of T2D patients hospitalized for ACS at Civil Aviation General Hospital from January 2019 to December 2022 were collected. Based on SGLT2i use or not, patients were stratified as SGLT2i group and SGLT2i-free group. A 1:1 nearest-neighbor propensity score-matched (PSM) was performed to adjust for the confounding factors and facilitate the robust comparisons between groups. The first occurrence of major adverse cardiovascular events (MACE) with 1 year follow-up, which consisted of CV death, all cause death, non-fatal myocardial infarction or stroke, coronary revascularization or heart failure readmission, was assessed. Kaplan–Meier analysis and Cox regressions were conducted to evaluate the prognostic significance of SGLT2i use. Subgroup analyses were performed to assess the interaction between subgroups and SGLT2i use.ResultsA total of 925 patients were included, and the SGLT2i use increased from 9.9% in 2019 to 43.8% in 2022. 226 pairs were finally matched using the PSM model. During 1 year follow-up period, a total of 110 patients experienced MACE in the matched cohort, with a rate of 24.3%. Survival analyses showed cumulative incidence of MACE, CV death, and heart failure readmission in the SGLT2i group were significantly lower than the SGLT2i-free group. Additionally, the adjusted Cox analyses demonstrated that SGLT2i was associated with a 34.1% lower risk of MACE (HR 0.659, 95% CI 0.487–0.892, P = 0.007), which was primarily driven by a decrease in the risk of CV death by 12.0% (HR 0.880, 95% CI 0.7830.990, P = 0.033), and heart failure readmission by 45.5% (HR 0.545, 95% CI 0.332–0.893, P = 0.016). This MACE preventive benefit was consistent across different subgroups (P interaction > 0.05 for all comparisons).ConclusionsIn T2D patients with ACS, there was a clear increasing trend in SGLT2i use. SGLT2i was associated with a significantly lower risk of MACE, driven by the decrease in the risk of CV death, and heart failure readmission. Our study confirmed real-world use and efficacy of SGLT2i in a general T2D population with ACS.

Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure with Malnutrition, Frailty, Sarcopenia, or Cachexia.

(1) Background: In patients with heart failure (HF) and impaired nutritional status or decreased muscle mass, sodium-glucose cotransporter-2 inhibitors (SGLT2is) may worsen these conditions and result in poor prognosis, especially worsening of frailty. We aimed to investigate the relationship between SGLT2is and clinical outcomes, including frailty-related events, in patients with HF and malnutrition, frailty, sarcopenia, or cachexia. (2) Methods: In this retrospective observational cohort study, a global federated health research network provided data on patients with HF and malnutrition, frailty, sarcopenia, or cachexia from January 2016 to December 2021. We investigated the incidence of the composite endpoint of death or frailty-related events within one year. (3) Results: Among 214,778 patients included in the analysis, 4715 were treated with SGLT2is. After propensity score matching, 4697 patients in the SGLT2is group were matched with 4697 patients in the non-SGLT2is groups. The incidence of the composite endpoint, mortality, and frailty-related events was lower in the SGLT2is group than in the non-SGLT2is group (composite endpoint, 65.6% versus 77.6%, p < 0.001; mortality, 17.4% vs. 35.5%, p < 0.001; frailty-related events, 59.4% vs. 64.3%, p < 0.001). (4) Conclusions: Patients with HF and malnutrition, frailty, sarcopenia, or cachexia had a high incidence of death and frailty-related events. SGLT2is were associated with a lower incidence of these events.

Inhibition of sodium-glucose cotransporter-2 and liver-related complications in individuals with diabetes: a Mendelian randomization and population-based cohort study.

No medication has been found to reduce liver-related events. We evaluated the effect of sodium-glucose cotransporter-2 inhibitor (SGLT2i) on liver-related outcomes. Single nucleotide polymorphisms associated with SGLT2 inhibition were identified, and a genetic risk score (GRS) was computed using the UK Biobank data (n=337,138). Two-sample Mendelian randomization (MR) was conducted using the FinnGen (n=218,792) database and the UK Biobank data. In parallel, a nationwide population-based study using the Korean National Health Insurance Service (NHIS) database was conducted. The development of liver-related complications (ie, hepatic decompensation, HCC, liver transplantation, and death) was compared between individuals with type 2 diabetes mellitus and steatotic liver diseases treated with SGLT2i (n=13,208) and propensity score-matched individuals treated with dipeptidyl peptidase-4 inhibitor (n=70,342). After computing GRS with 6 single nucleotide polymorphisms (rs4488457, rs80577326, rs11865835, rs9930811, rs34497199, and rs35445454), GRS-based MR showed that SGLT2 inhibition (per 1 SD increase of GRS, 0.1% lowering of HbA1c) was negatively associated with cirrhosis development (adjusted odds ratio=0.83, 95% CI=0.70-0.98, p =0.03) and this was consistent in the 2-sample MR (OR=0.73, 95% CI=0.60-0.90, p =0.003). In the Korean NHIS database, the risk of liver-related complications was significantly lower in the SGLT2i group than in the dipeptidyl peptidase-4 inhibitor group (adjusted hazard ratio=0.88, 95% CI=0.79-0.97, p =0.01), and this difference remained significant (adjusted hazard ratio=0.72-0.89, all p <0.05) across various sensitivity analyses. Both MRs using 2 European cohorts and a Korean nationwide population-based cohort study suggest that SGLT2 inhibition is associated with a lower risk of liver-related events.

Association between sodium-glucose cotransporter-2 inhibitors and arrhythmic outcomes in patients with diabetes and pre-existing atrial fibrillation.

Prior studies suggest that sodium-glucose cotransporter-2 inhibitors (SGLT2is) may decrease the incidence of atrial fibrillation (AF). However, it is unknown whether SGLT2i can attenuate the disease course of AF among patients with pre-existing AF and Type II diabetes mellitus (DM). In this study, our objective was to examine the association between SGLT2i prescription and arrhythmic outcomes among patients with DM and pre-existing AF. We conducted a population-based cohort study of adults with DM and AF between 2014 and 2019. Using a prevalent new-user design, individuals prescribed SGLT2i were matched 1:1 to those prescribed dipeptidyl peptidase-4 inhibitors (DPP4is) based on time-conditional propensity scores. The primary endpoint was a composite of AF-related healthcare utilization (i.e. hospitalization, emergency department visits, electrical cardioversion, or catheter ablation). Secondary outcome measures included all-cause mortality, heart failure (HF) hospitalization, and ischaemic stroke or transient ischaemic attack (TIA). Cox proportional hazard models were used to examine the association of SGLT2i with the study endpoint. Among 2242 patients with DM and AF followed for an average of 3.0 years, the primary endpoint occurred in 8.7% (n = 97) of patients in the SGLT2i group vs. 10.0% (n = 112) of patients in the DPP4i group [adjusted hazard ratio 0.73 (95% confidence interval 0.55-0.96; P = 0.03)]. Sodium-glucose cotransporter-2 inhibitors were associated with significant reductions in all-cause mortality and HF hospitalization, but there was no difference in the risk of ischaemic stroke/TIA. Among patients with DM and pre-existing AF, SGLT2is are associated with decreased AF-related health resource utilization and improved arrhythmic outcomes compared with DPP4is.

Cardiovascular Outcomes With Empagliflozin and Dapagliflozin in Patients Without Diabetes

While the cardiovascular (CV) benefits with sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with diabetes mellitus (DM) are well known, their effects in patients without DM continue to be explored. We provide a meta-analysis of the available evidence. Online databases were searched for randomized controlled trials (RCTs) comparing SGLT2i to placebo/control in patients without DM. The endpoints of interest were composite CV death/hospitalization for heart failure (HF) with individual components, all cause death, major adverse CV events (MACE) and serious adverse events. Subgroup analysis was performed according to the type of SGLT2i. Pooled odds ratios (OR) and 95% confidence intervals (CI) were generated via a random-effects model. A total of 6 RCTs with 12,984 patients (6,501 in the SGLT2i group and 6,483 in the placebo group) were included, followed over a mean duration of 17.7 months. Four RCTs had patients with HF, 1 with chronic kidney disease (CKD) and 1 with myocardial infarction (MI). The mean age was 64 years, 72% patients were men and mean HbA1C was 5.7%. As compared to placebo, SGLT2i treatment was associated with significant reduction in composite CV death or hospitalization for HF (OR 0.77, 95% CI 0.68 - 0.87, p < 0.0001), primarily due to decrease in hospitalization for HF (OR 0.70, 95% CI 0.60 - 0.81, p < 0.00001). No significant differences were found pertaining to CV death (OR 0.86, 95% CI 0.74 - 1.01, p = 0.06), all cause death (OR 0.89, 95% CI 0.71 - 1.11, p = 0.29) and MACE (OR 0.95, 95% CI 0.68 - 1.32, p = 0.75). Serious adverse events were lower with use of empagliflozin vs placebo. In conclusion, this study shows significant CV benefits in terms of reduction in CV death or hospitalization for HF in non-diabetic patients treated with SGLT2i as compared to placebo. The underlying heterogeneity of patients in terms of comorbidities (HF, CKD or MI) needs to be considered while interpreting the results.

Effects of SGLT2 Inhibitors with and without Metformin in High-Risk, Treatment-Naïve Patients with Diabetes.

Background: Contemporary evidence supports the cardiovascular and renal benefits of sodium-glucose co-transporter-2 inhibitors (SGLT2is) in patients with diabetes. While metformin has traditionally been recommended as a first-line treatment, its exact role in improving cardiovascular outcomes remains uncertain. This study aims to evaluate the impact of combination therapy with metformin on the cardiovascular and renal outcomes in high-risk, treatment-naïve diabetic patients who have undergone SGLT2i therapy. Methods: Using the National Health Insurance Research Database in Taiwan, a retrospective cohort study was conducted. Treatment-naïve patients with diabetes and established atherosclerotic cardiovascular disease (ASCVD) undertaking SGLT2i therapy from 1 January 2016 to 31 December 2021 were included. Patients were categorized based on the concomitant use of metformin. Propensity score matching was employed to minimize confounding factors. The primary outcome was major adverse cardiovascular events (MACEs), with secondary outcomes including cardiovascular death, hospitalization for heart failure, and renal outcomes. Results: In total, 10,151 treatment-naïve diabetic patients with ASCVD were identified, with 2570 in the only SGLT2i therapy group and 7581 in the SGLT2i plus metformin group. In total, 2262 pairs were analyzed after propensity score adjustment. The risk of MACEs (36.6 vs. 42.1 events per 1000 person-years; hazard ratio 0.87, 95% confidence interval 0.70-1.09) and other outcomes did not significantly differ between the two treatment groups. Conclusions: In high-risk, treatment-naïve diabetic patients, initiating SGLT2i therapy alone or in combination with metformin resulted in comparable cardiovascular and renal outcomes. These findings suggest that metformin might not be mandatory as a first-line treatment for achieving cardiovascular benefits in such patients.

Renal outcomes with sodium-glucose cotransporter 2 inhibitors in Japanese people with grade 3 chronic kidney disease and type 2 diabetes: Analysis of medical administrative databases.

To evaluate whether sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy is associated with a reduction of renal events compared with other glucose-lowering drugs (oGLDs) among Japanese people with type 2 diabetes (T2D) and grade 3 (G3) chronic kidney disease (CKD) in a real-world clinical practice setting. People with T2D who were newly prescribed an SGLT2i or an oGLD from April 2014 to November 2021 (without prior use of index drugs for ≥ 1 year prior to index date) and G3 CKD (estimated glomerular filtration rate [eGFR] ≥ 30 to < 60 mL/min/1.73 m2) were selected from the Medical Data Vision database (MDV-DB) and the Real-World Data database (RWD-DB). SGLT2i and oGLD users were matched (1:1) using propensity score on patient background characteristics. The primary endpoint was a composite of the development of end-stage kidney disease or a sustained decline in eGFR of 50% or more. Hazard ratios (HRs) were estimated using the Cox proportional hazards model. Overall, 3190 (1595 per group) patients in the MDV-DB and 2572 (1286 per group) patients in the RWD-DB were included in the analyses. The composite outcome was significantly lower in the SGLT2i group than in the oGLD group in the MDV-DB (HR 0.49, 95% confidence interval [CI] 0.33 to 0.74, P < 0.001) and in the RWD-DB (HR 0.57, 95% CI 0.37 to 0.88, P = 0.011). Japanese people with T2D and G3 CKD initiating an SGLT2i had a lower risk of renal events than people initiating an oGLD.

Effects of SGLT2 Inhibitors and DPP-4 Inhibitors on Advanced Glycation End Products.

Clinical trials have revealed that sodium glucose cotransporter 2 (SGLT2) inhibitors suppress the onset of heart failure and cardiovascular death in diabetic patients. On the other hand, few reports have been published concerning such effects of dipeptidyl peptidase-4 (DPP-4) inhibitors. We undertook the present study to evaluate the effects of SGLT2 inhibitors and DPP-4 inhibitors on the advanced glycation end products (AGEs), well known as a risk factor for the development of cardiovascular disorders.Type 2 diabetes mellitus were divided into two groups and treated with either SGLT2 inhibitors or DPP-4 inhibitors for 3 months. Before and after the 3-month treatment period with each drug, the AGEs and diabetes-related parameters were measured. Methylglyoxal-derived hydroimidazolone-1 (MG-H1) was measured as one of the AGEs.In the SGLT2 inhibitor group, both the blood HbA1c and MG-H1 levels decreased significantly after the 3-month treatment period. In the DPP-4 inhibitor group, only the blood HbA1c level decreased significantly, with no significant change of the blood MG-H1 level.SGLT2 inhibitor reduced both the blood levels of HbA1c and AGEs (MG-H1). Considering that the blood levels of AGEs are associated with the risk of heart failure and cardiovascular disorders, the results of the present study suggest that the effect of SGLT2 inhibitors in suppressing cardiovascular death might be mediated by the reduction in the blood levels of AGEs induced by this class of drugs. DPP-4 inhibitors showed no significant effects on the blood levels of AGEs.

The Effect of Sodium-Glucose Cotransporter-2 Inhibitors on COVID-19 Patients with Type 2 Diabetes Mellitus: A Retrospective Cohort Study Using the Common Data Model.

There is no clinical evidence about the effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors on diabetic patients who have been diagnosed with coronavirus disease 19 (COVID-19). The dataset is based on insurance benefit claims sent to the Health Insurance Review and Assessment Service of Korea from January, 2018 to April, 2022. Among 9,822,577 patients who were involved in the claims, diabetic patients were divided into two groups based on whether they had a prescription for an SGLT2 inhibitor. The primary outcome was major adverse cardiac and cerebrovascular events (MACCEs), which were a composite of all-cause mortality, myocardial infarction, stroke, and revascularization over 90 days. A total of 172,682 patients was analyzed. In the propensity score-matched analysis, the rate of MACCE was lower in the SGLT2 inhibitor group compared to the non-SGLT2 inhibitor group (0.89% vs. 1.31%; hazard ratio, 0.71; 95% confidence interval, 0.53-0.94; p =0.020). Each of the MACCEs showed no differences between the two groups. The rate of pneumonia was similar between the two groups (4.45% vs. 4.39%; hazard ratio, 1.06; 95% confidence interval, 0.91-1.16; p = 0.620). In the diabetic patients who were diagnosed with COVID-19, SGLT2 inhibitors were associated with improved clinical outcomes in terms of MACCEs. SGLT2 inhibitors might be considered for prescription to diabetic patients in the current context of long COVID-19.

Sodium-glucose co-transporter-2 inhibitors in patients treated with immune checkpoint inhibitors

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized the prognosis of cancer. Diabetes mellitus (DM) has been shown to have a negative effect on patients treated with ICIs. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective antidiabetic therapies associated with reduced all-cause mortality and cardiovascular (CV) outcomes.ObjectiveTo evaluate the prognostic value of SGLT2i on all-cause mortality and cardiotoxicity among patients treated with ICIs.MethodsWe performed a retrospective analysis of patients diagnosed with cancer and type 2 DM (DM2) and treated with ICIs at our center. Patients were divided into two groups according to baseline treatment with or without SGLT2i. The primary endpoint was all-cause mortality and the secondary endpoint was MACE, including myocarditis, acute coronary syndrome, heart failure, and arrhythmia.ResultsThe cohort included 119 patients, with 24 (20%) patients assigned to the SGLT2i group. Both groups exhibited a comparable prevalence of cardiac risk factors, although the SGLT2i group displayed a higher incidence of ischemic heart disease. Over a median follow-up of 28 months, 61 (51%) patients died, with a significantly lower all-cause mortality rate in the SGLT2i group (21% vs. 59%, p = 0.002). While there were no significant differences in MACE, we observed zero cases of myocarditis and atrial fibrillation in the SGLT2i, compared to 2 and 6 cases in the non-SGLT2i group.ConclusionsSGLT2i therapy was associated with a lower all-cause mortality rate in patients diagnosed with cancer and DM2 and treated with ICIs. Further studies are needed to understand the mechanism and evaluate its benefit on cardiotoxicity.Graphical

Combined effects of sodium-glucose cotransporter 2 inhibitor and angiotensin receptor-neprilysin inhibitor on renal function in cardiovascular disease patients with type 2 diabetes mellitus: a retrospective cohort study.

Angiotensin receptor/neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) have shown a significant protective role against cardiovascular diseases and type 2 diabetes mellitus (T2DM), and there is a growing proportion of patients who are undergoing combined therapy with the two drugs. However, the effect of this combination treatment on renal function has not yet been determined. This study included 539 patients who were diagnosed with cardiovascular disease combined with T2DM. According to the use of SGLT2i and ARNI, patients were divided into the combination treatment group, SGLT2i group, ARNI group and control group. Primary outcomes were serum creatinine (Scr) and estimated glomerular filtration rate (eGFR) changes in the 6th month and 12th month. In the ARNI group, no significant changes in Scr or eGFR were observed during the follow-up period, while the above indicators showed a trend of deterioration in the other three groups. The univariate analysis results showed that at 6 months of follow-up, the renal function indicators of patients treated with ARNI (either alone or in combination) were better than those treated with SGLT2i alone. After 12 months of follow-up, the Scr results were the same as before, while the difference in eGFR between groups disappeared. After multivariate analysis, in terms of delaying the progression of Scr, the ARNI group was superior to the other groups at the end of follow-up. No significant difference in eGFR was observed between groups during follow-up. In patients with cardiovascular disease and T2DM, combination therapy with ARNI and SGLT2i did not show an advantage over monotherapy in delaying renal insufficiency progression, and renal function seems to be better preserved in patients treated with ARNI alone. clinicaltrials.gov, identifier NCT05922852.

Safety and tolerability of sodium-glucose cotransporter-2 inhibitors in children and young adults: a systematic review and meta-analysis.

Sodium glucose cotransporter-2 inhibitors (SGLT2i) have been evaluated in children with type 2 diabetes mellitus (T2DM), type 1 diabetes mellitus (T1DM), and several other nondiabetic conditions. Potential tolerability issues have prevented the routine use of SGLT2i in children with diabetes. However, no meta-analysis to date has evaluated the safety and tolerability of SGLT2i in children. This systematic review and meta-analysis aimed to address this knowledge gap. Databases were searched for randomized controlled trials (RCTs), case control, and cohort studies involving children receiving SGLT2i in the intervention-arm. Primary outcome was occurrence of treatment emergent adverse events (TAEs). Secondary outcomes were evaluation of glycemic efficacy and occurrence of severe adverse events (SAEs), hypoglycemia, ketosis, genital or urinary infections, and any other adverse events. From the 27 articles initially screened, data from 4 RCTs (258 children) were analyzed. In children with T2DM, occurrence of TAEs (odds ratio [OR], 1.77; 95% confidence interval [CI], 0.93-3.36; P=0.08; I2=0%), SAEs (OR, 0.45; 95% CI, 0.08-2.54; P=0.37; I2=0%), ketoacidosis (OR, 0.33; 95% CI, 0.01-8.37; P=0.50), urinary tract infections (OR, 2.34; 95% CI, 0.44-12.50; P=0.32; I2=0%), and severe hypoglycemia (OR, 4.47; 95% CI, 0.21-96.40; P=0.34) were comparable among the SGLTi group and placebo. Compared to placebo, T2DM children receiving SGLTi had significantly lower glycosylated hemoglobin at 24-26 weeks (mean difference [MD], -0.79%; 95% CI, -1.33 to -0.26; P=0.004; I2=0%). In T1DM children, β-hydroxybutyrate levels were significantly higher in the SGLTi group than the placebo group (MD, 0.11 mmol/L; 95% CI, 0.05-0.17; P=0.0005; I2=53%). In T1DM, there was not a single report of an SAE, ketoacidosis, or severe hypoglycemia in either the placebo or treatment groups, but time-in-range was considerably greater in the SGLT2i group than the placebo group (68%±6% vs. 50%±13%, P<0.001). SGLT2i use in children and young adults appears to be both safe and tolerable based on our meta-analyses and review of the literature.