Benefits Of Sodium-glucose Cotransporter Research Articles

Effects of sodium-glucose cotransporter 2 inhibitors on cardiovascular and renal outcomes in people with diabetes and advanced chronic kidney disease.

Although the benefits of sodium-glucose cotransporter 2 inhibitor (SGLT2i) use in chronic kidney disease (CKD) are well established, the effects of these therapeutic agents in patients with advanced CKD are less certain. We hypothesised that the continued use of these drugs, even when renal function deteriorates to stage 4 CKD or worse, is safe and associated with improved cardiorenal survival. This is a retrospective cohort study utilising data from medical records from two institutions. All patients with type 2 diabetes mellitus who were prescribed an SGLT2i between 1 January 2016 and 31 December 2021, who subsequently had eGFR <30 ml/min per 1.73 m2 recorded on two occasions at least 90 days apart, were identified. The date on which the eGFR first reached any level less than 30 ml/min per 1.73 m2 was defined as the index date. Individuals were then categorised into the SGLT2i continuation group or the discontinuation group according to the use of SGLT2i after the index date. Inverse probability of treatment weighting (IPTW) was performed to minimise confounding. Outcomes of interest included heart failure outcomes, cardiovascular outcomes, renal outcomes and safety outcomes. According to the eligibility criteria, 337 patients in the continuation group and 358 in the discontinuation group were identified. After IPTW, continuation of SGLT2i use was associated with significantly lower risks of the composite of major adverse cardiovascular events compared with discontinuation of SGLT2i use (HR 0.65 [95% CI 0.43, 0.99]), largely driven by reduced risk of myocardial infarction during follow-up (subdistribution HR [SHR] 0.43 [95% CI 0.21, 0.89]). The incidences of an eGFR decline of 50% or more (SHR 0.58 [95% CI 0.42, 0.81]) and all-cause hospital admission (SHR 0.77 [95% CI 0.64, 0.94]) were also significantly lower in the continuation group. None of the studied safety outcomes were significantly different when comparing the two groups. Blood haemoglobin levels were significantly higher in the continuation group at the end of follow-up (114.6 g/l vs 110.4 g/l, with a difference of 4.12 g/l; p=0.047). In patients with CKD who were treated with an SGLT2i, continuation of SGLT2i use after eGFR declined to 30 ml/min per 1.73 m2 or less was associated with lower risks of cardiovascular and renal events compared with discontinuation of SGLT2i use. Continued use of SGLT2i throughout the course of CKD should be considered to optimise patient outcomes.

Abstract 50: Sodium-Glucose Cotransporter 2 Inhibitors Use in Diabetic Patients With Acute Ischemic Stroke is Linked to Favorable Neurological Outcomes

Background: The benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in acute ischemic stroke (AIS) have been demonstrated preclinically. Here, we evaluated the neurological effects of SGLT2i use after stroke in patients with diabetes and AIS. Methods: Using a prospective stroke registry, we reviewed consecutive diabetic patients with AIS. Patients with and without SGLT2i use were 1:4 propensity score-matched for clinical variables. Clinical outcomes, including early neurological deterioration (END) during admission, National Institutes of Health Stroke Scale (NIHSS) score at discharge, and modified Rankin Scale (mRS) scores at discharge and at 3 months, were compared. The impact of SGLT2i on metabolic activity of various organs was examined in another cohort using 18 F-fluorodeoxyglucose positron emission tomography post-stroke. Results: Among the 820 eligible patients, 90 (11.0%) were prescribed SGLT2i on admission, and 76 continued the prescription at discharge. Seventy-four patients with and 266 patients without SGLT2i use were propensity score-matched and analyzed. SGLT2i did not increase the END risk (adjusted odds ratio [aOR] 0.48, 95% confidence interval [CI] 0.20-1.19). There was no significant difference in clinical outcomes at discharge between the two groups (NIHSS: B [standard error] -1.321 [0.952], p=0.17; mRS: aOR for favorable mRS 1.47, 95% CI 0.93-2.32). SGLT2i demonstrated significant improvement in the 3-month mRS (aOR 1.73, 95% CI 1.10-2.74). The positron emission tomography cohort showed that SGLT2i prescription was associated with elevated brown and subcutaneous adipose tissue metabolism. Conclusions: SGLT2i may be a priority for diabetic patients with AIS because of its potential benefits on long-term outcomes.

Efficacy of empagliflozin in heart failure with preserved ejection fraction according to frailty status in EMPEROR-Preserved.

Frailty is a severe, common co-morbidity associated with heart failure (HF) with preserved ejection fraction (HFpEF). The impact of frailty on HFpEF outcomes may affect treatment choices in HFpEF. The impact of frailty on HFpEF patients and any impact on the clinical benefits of sodium glucose co-transporter 2 (SGLT2) inhibition in HFpEF have been described in only a limited number of trials. Whether the SGLT2 inhibitor empagliflozin would improve or worsen frailty status when given to HFpEF patients is also not known. The aims of this study were, therefore, to evaluate, in HFpEF patients enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), the impact of frailty on clinical outcomes, and on the effects of empagliflozin, as well as the effect of empagliflozin on frailty status during treatment period. We calculated a cumulative deficit-derived frailty index (FI) using 44 variables including clinical, laboratory and quality of life parameters recorded in EMPEROR-Preserved. Patients were classified into four groups: non-frail (FI<0.21), mild frailty (0.21 to <0.30), moderate frailty (0.30 to <0.40) and severe frailty (≥0.40). Clinical outcomes and health-related quality of life were evaluated according to baseline FI along with the effect of empagliflozin on chronological changes in FI (at 12, 32 and 52weeks). The patient distribution was 1514 (25.3%), 2100 (35.1%), 1501 (25.1%) and 873 (14.6%) in non-frail, mild frailty, moderate frailty and severe frailty, respectively. Severe frailty patients tended to be female and have low Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, more co-morbidities and more polypharmacy. Incidence rates of the primary outcome of cardiovascular death or HF hospitalization increased as frailty worsened (hazard ratio [HR] of each FI category compared with the non-frail group: 1.10 [95% confidence interval, CI, 0.89-1.35], 2.00 [1.63-2.47] and 2.61 [2.08-3.27] in the mild frailty, moderate frailty and severe frailty groups, respectively; P trend<0.001). Compared with placebo, empagliflozin reduced the risk for the primary outcome across the four FI categories, HR: 0.59 [95% CI 0.42-0.83], 0.79 [0.61-1.01], 0.77 [0.61-0.96] and 0.90 [0.69-1.16] in non-frail to severe frailty categories, respectively (P value for trend=0.097). Empagliflozin also improved other clinical outcomes and KCCQ score across frailty categories. Compared with placebo, empagliflozin-treated patients had a higher likelihood of being in a lower FI category at Weeks 12, 32 and 52 (P<0.05), odds ratio: 1.12 [95% CI 1.01-1.24] at Week 12, 1.21 [1.09-1.34] at Week 32 and 1.20 [1.09-1.33] at Week 52. Empagliflozin improved key efficacy outcomes with a possible diminution of effect in very frail patients. Empagliflozin also improved frailty status during follow-up.

The classification shifting and outcomes of DELIVER-type patients with acute heart failure and preserved ejection fraction

Abstract Background The DELIVER trial enrolled subjects with acute heart failure (AHF) and preserved ejection fraction (HFpEF) who had elevated biomarkers and cardiac structural abnormalities. Given the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in AHF, it is important to understand the differences between DELIVER-type and non-DELIVER-type patients and how their classification may shift over time. Method This study enrolled patients hospitalized for AHF with LVEF ≥ 50%. Patients with elevated N-terminal pro B-type natriuretic peptide (NT-proBNP ≥ 300 or 600 pg/mL, depending on cardiac rhythm) and cardiac structural abnormalities (enlarged left atrial volume or index, or left ventricular hypertrophy) were classified as DELIVER-type. Patients who did not meet these criteria were classified as non-DELIVER-type. Patients with estimated glomerular filtration rate ≤ 25 mL/min/1.73m2 and those receiving SGLT2i treatment were excluded. Echocardiographic variables were obtained pre-discharge and one year after the index day. All-cause mortality and heart failure hospitalization up to one year were determined by web-based electronic record. Result The study included 385 subjects with an average age of 83.7 ± 13.9 years, of whom 53.2% were men. The DELIVER-type group had a higher proportion of atrial fibrillation, larger left atrial volume, thicker left ventricular wall, higher levels of the ratio of early diastolic mitral inflow velocity to early diastolic medial mitral annulus velocity (medial mitral E/e'), and higher pulmonary artery systolic pressure (PASP), as well as more evident haemoconcentration and body weight reduction during hospitalization. Kaplan-Meier curve analysis revealed higher rates of all-cause mortality and hospitalization for heart failure at one year in patients with DELIVER-type (Figure 1). In Cox regression analysis, the DELIVER-type subjects had comparable clinical outcomes after accounting for factors such as age, gender, atrial fibrillation, haemoglobin levels, and estimated glomerular filtration rate, compared to non-DELIVER subjects (hazard ratio and 95% confidence interval of mortality [1.62 (0.81-3.25)]). In one-year follow-up, 41.7% of patients shifted from non-DELIVER type to DELIVER-type, but only 14.6% of DELIVER-type subjects had classification shifting. Conclusion Non-DELIVER-type subjects had modestly lower event rates compared to those with DELIVER-type. The high proportion of classification shifting from non-DELIVER-type to DELIVER-type suggested that eligibility could vary during follow-up and that these patients could benefit from SGLT2i therapy.Baseline characteristicsClass shifting in DELIVER type

Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure.

It is not known whether the benefits of sodium-glucose cotransporter 2 inhibitors in heart failure persist after years of therapy. In the EMPEROR-Reduced (Empagliflozin Outcome Trials in Chronic Heart Failure With Reduced Ejection Fraction) and EMPEROR-Preserved (Empagliflozin Outcome Trials in Chronic Heart Failure With Preserved Ejection Fraction) trials, patients with heart failure were randomly assigned (double-blind) to placebo or empagliflozin 10 mg/day for a median of 16 and 26 months, respectively. At the end of the trials, 6799 patients (placebo 3381, empagliflozin 3418) were prospectively withdrawn from treatment in a blinded manner, and, of these, 3981 patients (placebo 2020, empagliflozin 1961) underwent prespecified in-person assessments after ≈30 days off treatment. From 90 days from the start of closeout to the end of double-blind treatment, the annualized risk of cardiovascular death or hospitalization for heart failure was lower in empagliflozin-treated patients than in placebo-treated patients (10.7 [95% CI, 9.0-12.6] versus 13.5 [95% CI, 11.5-15.6] events per 100 patient-years, respectively; hazard ratio 0.76 [95% CI, 0.60-0.96]). When the study drugs were withdrawn for ≈30 days, the annualized risk of cardiovascular death or hospitalization for heart failure increased in patients withdrawn from empagliflozin but not in those withdrawn from placebo (17.0 [95% CI, 12.6-22.1] versus 14.1 [95% CI, 10.1-18.8] events per 100 patient-years for empagliflozin and placebo, respectively). The hazard ratio for the change in risk in the patients withdrawn from empagliflozin was 1.75 (95% CI, 1.20-2.54), P=0.0034, whereas the change in the risk in patients withdrawn from placebo was not significant (hazard ratio 1.12 [95% CI, 0.76-1.66]); time period-by-treatment interaction, P=0.068. After withdrawal, the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score declined by 1.6±0.4 in patients withdrawn from empagliflozin versus placebo (P<0.0001). Furthermore, withdrawal of empagliflozin was accompanied by increases in fasting glucose, body weight, systolic blood pressure, estimated glomerular filtration rate, N-terminal pro-hormone B-type natriuretic peptide, uric acid, and serum bicarbonate and decreases in hemoglobin and hematocrit (all P<0.01). These physiological and laboratory changes were the inverse of the effects of the drug seen at the start of the trials during the initiation of treatment (≈1-3 years earlier) in the same cohort of patients. These observations demonstrate a persistent effect of empagliflozin in patients with heart failure even after years of treatment, which dissipated rapidly after withdrawal of the drug. URL: https://www. gov; Unique identifiers: NCT03057977 and NCT03057951.

Abstract 15820: The Use of Sglt 2 Inhibitors During Hospitalization for Acute Decompensated Heart Failure: A Systematic Review and Meta-Analysis

Background: There continues to be emerging data about the benefits of Sodium-glucose co-transporter 2 inhibitor (SGLT2i) in patients with heart failure. This has led to the addition of this medication to guideline-directed medical therapy for heart failure with reduced ejection fraction. There is a discrepancy in whether the use of SGLT2i is beneficial in patients hospitalized for decompensated heart failure. Methods: In this study, a search was completed through PubMed, Scopus, Cochrane Library, ProQuest for randomized controlled trials from 2020 to 2022 that evaluated the impact of the use of SGLT-2 inhibitors (Empagliflozin, Sotagliflozin) in patients admitted with acute HF. After screening for our preset inclusion and exclusion criteria, three randomized controlled clinical trials were eligible for inclusion. We carried out a Meta-analysis of the relative odds on the basis of the random effect model using the Mantel-Haenszel method for the major outcome of the incidence of death from any cause, the number of heart failure events, rehospitalization for heart failure, and time to first heart failure event in the acute setting. Comprehensive Meta-analysis version 3 software was used for analysis. Results: A total of 2,532 patients from the EMPULSE, SOLOIST-WHF, EMPA-RESPONSE-AHF trials were included. After analysis, it was found that the P-value was 0.000, Z-value was -4.103, and the OR 0.508 (95% CI 0.368; 0.702) for the patients on either Empagliflozin or Sotagliflozin. Conclusions: The systematic review and meta-analysis we conducted show that patients who received SGLT-2i (Empagliflozin, Sotagliflozin) during hospitalization within 24 hours or more had a statistically significant decreased odds of all-cause of death, number of heart failure events, and rehospitalization for heart failure.

Comparison of cardiovascular and renal outcomes between dapagliflozin and empagliflozin in patients with type 2 diabetes without prior cardiovascular or renal disease.

BackgroundCardiovascular and renal benefits of sodium glucose co-transporter 2 inhibitors (SGLT2i) have been clearly demonstrated. However, studies comparing the effects of dapagliflozin and empagliflozin are scarce. In addition, relatively few studies have analyzed the effects of SGLT2i in diabetic patients without established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or heart failure (HF), and current guidelines recommend SGLT2i and other antidiabetic drugs equally in this population. Therefore, we aimed to compare the clinical outcomes between dapagliflozin, empagliflozin, and dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with type 2 diabetes without prior ASCVD, CKD, or HF.MethodsUsing a propensity-score matching method, we retrospectively analyzed 921 patients treated with dapagliflozin, 921 patients treated with empagliflozin, and 1842 patients treated with DPP4i (control group). Study outcomes comprised composite coronary events (acute coronary syndrome and coronary revascularization), composite ischemic events (coronary events and stroke), and composite heart failure and renal events.ResultsDuring follow up (median, 43.4 months), the incidence of composite coronary events was significantly lower in the SGLT2i groups than in the control group, and the incidence of composite ischemic events was lower in the dapagliflozin group than in the control group. Dapagliflozin and empagliflozin both demonstrated significant benefits in terms of HF and renal outcomes, supported by renoprotective effects, as assessed by the change in glomerular filtration rate. At 24–36 months of treatment, the empagliflozin group had higher low-density lipoprotein cholesterol levels, and lower glycated hemoglobin levels, compared to those in the dapagliflozin and control groups.ConclusionSGLT2i use was associated with a significantly reduced risk of ASCVD, HF hospitalization, and renal events, compared to that with DPP4i use among diabetic patients without prior ASCVD, CKD, or HF. There were no significant differences in clinical outcomes between dapagliflozin and empagliflozin, supporting a SGLT2i class effect.

Does Dapagliflozin influence arterial stiffness and levels of circulating anti-aging hormone soluble Klotho in people with type 2 diabetes and kidney disease? Results of a randomized parallel group clinical trial.

ObjectiveThe mechanisms that explain the cardio-renal benefits of sodium glucose co-transporter 2 (SGLT-2) inhibitors are unknown. The effect of SGLT-2 inhibitors on arterial aging, measured by Aortic Pulse Wave Velocity (Ao-PWV) and Soluble Klotho (s-Klotho), a circulating anti-aging biomarker of arterial health are also unclear.Design/SettingA 24-week single center randomized controlled trial (registry number/ EudraCT Number: 2013-004042-42) comparing Dapagliflozin and Ramipril (D+R) versus Ramipril (R) on the primary endpoint of urine albumin excretion rate (AER) and pre-specified secondary endpoints of Ao-PWV and biomarkers of arterial aging [s-Klotho and Fibroblast Growth Factor 23 (FGF-23)]. People with type 2 diabetes who had estimated glomerular filtration rate (eGFR) > 60 ml/min and residual microalbuminuria on maximum tolerated renin angiotensin system (RAS) inhibition were included in this study.ResultsIn total, 33 participants (male 73%) were randomized to either D+R (n = 17) or R (n = 16) arms. After 24 weeks of treatment, Ao-PWV (mean ± SD) did not change significantly from baseline D +R [9.06 ± 1.91 m/s to 9.13 ± 2.03 m/s], and R [9.88 ± 2.12 m/s to 10.0 ± 1.84 m/s]. AER fell significantly by 43.5% (95% CI: −57.36%, −29.56%; p < 0.01) in people in the D+ R arm only. We do not observe any significant changes in FGF-23 or s-Klotho. HbA1c and Angiotensin 1–7 fell significantly only in D + R arm.ConclusionsThe combination of Dapagliflozin and Ramipril had no effects on Ao-PWV and s-Klotho which are biomarkers of arterial aging and cardio-renal risk. Our data suggest that the early cardio-renal benefits observed with SGLT-2 inhibitors are unlikely to be related to an improvement in arterial aging.

The unexpected benefits of sodium glucose co-transporter 2 (SGLT2) Inhibitors.

The sodium glucose co-transporter 2 (SGLT2) inhibitor empagliflozin is currently funded in New Zealand for management of patients with type 2 diabetes who have an HbA1c >53mmol/mol and a high cardiovascular (CV) risk. Large clinical trials now provide strong evidence that SGLT2 inhibitors decrease the risk of cardiovascular death, heart failure, progressive kidney dysfunction, myocardial infarction, stroke and gout. Patients with or without diabetes who have a history of heart failure, including those with a preserved left ventricular ejection fraction and patients with chronic kidney impairment are likely to benefit most from treatment with an SGLT2 inhibitor. These findings make a strong case for extending funding of SGLT2 inhibitors to include patients with heart failure or kidney dysfunction without diabetes, so many more New Zealanders could benefit.

Seven suggestions for successful SGLT2i use in glomerular disease - a standalone CKD therapy?

Recent advances in the world of glomerular diseases have largely focussed on remission induction with immune modulating therapy. It is well recognised that even with the best available treatments, patients with glomerular diseases may have an increased risk of progressive renal and cardiovascular disease. The arrival of large trials looking at the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with chronic kidney disease (CKD) and diabetes or not has shifted the entire focus of current management and the shift needs to go further. This review summarises the background to these landmark trials and provides practical guidance for implementation of the results in a general nephrology clinic. In sub-group analyses of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) clinical trial, SGLT2i improved renal outcomes in patients with immunoglobulin A (IgA) nephropathy highlighting the potential for this drug class in glomerular disease. We also discuss where the gaps in evidence are and where future trials in glomerular diseases, be they primary or secondary, should be focussed. The renal community has never before had evidence of this strength upon which to base recommendations for patients with CKD and we should be grasping it with both hands.

Do the benefits of sodium-glucose cotransporter 2 inhibitors exceed the risks in patients with type 1 diabetes?

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are well-established means of improving glycemia and preventing cardio-renal events in patients with type 2 diabetes. However, their efficacy and safety have yet to be fully characterized in patients with type 1 diabetes (T1D). We studied patients with T1D who regularly attended one of five diabetes centers and treated with an SGLT2i (ipragliflozin or dapagliflozin) for >52 weeks, and the changes in HbA1c, body mass, insulin dose, and laboratory data were retrospectively evaluated and adverse events (AEs) recorded during December 2018 to April 2021. A total of 216 patients with T1D were enrolled during the period. Of these, 42 were excluded owing to short treatment periods and 15 discontinued their SGLT2i. The mean changes in glycated hemoglobin (HbA1c), body mass, and insulin dose were -0.4%, -2.1 kg, and -9.0%, respectively. The change in HbA1c was closely associated with the baseline HbA1c (p < 0.001), but not with the baseline body mass or renal function. The basal and bolus insulin doses decreased by 18.2% and 12.6%, respectively, in participants with a baseline HbA1c <8%. The most frequent AE was genital infection (2.8%), followed by diabetic ketoacidosis (DKA; 1.4%). None of the participants experienced severe hypoglycemic events. In conclusion, the administration of an SGLT2i in addition to intensive insulin treatment in patients with T1D improves glycemic control and body mass, without increasing the incidence of hypoglycemia or DKA.

Cost-Effectiveness of Empagliflozin in Patients With Diabetic Kidney Disease in the United States: Findings Based on the EMPA-REG OUTCOME Trial

Benefits of sodium-glucose cotransporter 2 inhibitors on kidney outcomes have been demonstrated in clinical trials. Among patients with type 2 diabetes and established cardiovascular (CV) disease enrolled in the EMPA-REG OUTCOME study (ClinicalTrials.gov identifier NCT01131676), empagliflozin added to standard of care (SOC) reduced the risk of incident or worsening nephropathy compared with SOC alone. This analysis evaluated the cost-effectiveness of empagliflozin versus SOC alone in the subpopulation with diabetic kidney disease (DKD) from the perspective of US commercial insurers and Medicare. Discrete event simulation model. Patients with DKD in a US health care system. Empagliflozin 10 or 25mg with SOC versus SOC alone. SOC included glucose-lowering therapies and medications to treat CV risk factors. Incremental cost-effectiveness ratios (2020 US dollars per quality-adjusted life-year [QALY] gained). Costs and QALYs were discounted 3.0% per year. Cost-effectiveness analysis, commercial insurers and Medicare perspective, lifetime horizon. The incremental cost-effectiveness ratio of empagliflozin with SOC versus SOC alone was $25,974 per QALY. Empagliflozin added 0.67 QALYs and $17,322 per patient over a lifetime horizon. Results were driven by fewer clinical events (including CV death, heart failure hospitalization, albuminuria progression, and a composite kidney outcome) experienced by patients receiving empagliflozin with SOC versus SOC alone. Results were sensitive to rates of CV death, nonfatal myocardial infarction, and heart failure hospitalization, as well as to drug costs and time horizon. Probabilistic sensitivity analyses indicated 91% of simulations at<$50,000 per QALY. The EMPA-REG OUTCOME study was not powered to assess treatment benefits in a subgroup and excluded patients with estimated glomerular filtration rate<30mL/min/1.73m2. Based on the EMPA-REG OUTCOME study, this cost-effectiveness analysis suggests that, for commercial insurers and Medicare, adding empagliflozin to SOC may be a cost-effective treatment option for patients with DKD.

Changing the way type 2 diabetes is managed

A number of well organised randomised control trials have demonstrated benefits of sodium-glucose cotransporter 2 Inhibitors and glucagon-like peptide 1 receptor agonists in reducing major adverse cardiac events. Secondary endpoints for SGLT-2is have also shown improvement in outcomes for those with heart failure with reduced ejection fraction and chronic kidney disease with albuminuria. These therapeutic advantages enable risk stratification and for treatment to be individualised depending on patient baseline characteristics. This article discusses the place of different therapeutic agents in the treatment of type 2 diabetes and describes why we should adopt a holistic approach in managing the cardio-renal risk associated with type 2 diabetes in light of the current best practice evidence.

Extrapolating Long-term Event-Free and Overall Survival With Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction

Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients. To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient's lifetime. Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months. Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy. The primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient's lifetime for the primary outcome and the secondary outcome of death from any cause. A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival. These findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF. ClinicalTrials.gov Identifier: NCT03036124.

The effects of sodium glucose co-transporter (SGLT) 2 inhibitors on hematocrit levels: a systematic review and meta-analysis of randomized controlled trials.

Previous studies have suggested benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors including improving glycemic control, lower body weight, uric acid-lowering effect and decreasing blood pressure. The aim of this study was to evaluate the effects of SGLT2 inhibitors on hematocrit (Hct) levels in patients with type 2 diabetes mellitus. Embase, CENTRAL, PubMed and other databases were searched from the establishment of the database through to July 2020. Randomized controlled trials (RCTs) involving patients with type 2 diabetes mellitus who were treated with SGLT2 inhibitors were analyzed using the random effects model. Stata 12.0 statistical software was used to estimate the weighted mean difference (WMD) and the 95% confidence intervals (CIs). A total of 40 RCTs were included, comprising 21,050 patients. SGLT2 inhibitors resulted in a significant increase in Hct levels compared to patients treated with a placebo (WMD 2.67%, 95% CI, 2.53 to 2.82; P<0.001). Treatment with 2.5, 5, and 10 mg of dapagliflozin significantly increased Hct levels (WMD 1.96%, 2.27%, and 2.47%, respectively; P<0.001). Administration of 100 and 300 mg of canagliflozin also resulted in a significant increase in Hct (WMD 2.91% and 2.94%, respectively; P<0.001). Similarly, empagliflozin, at concentrations of 10 and 25 mg, caused a significant increase in Hct (WMD 3.39% and 3.44%, respectively; P<0.001). However, treatment with ipragliflozin (12.5 and 50 mg) and ertugliflozin (5 and 15 mg) only resulted in a slight increase in patient Hct levels (WMD 1.26% and 1.98%, respectively for ipragliflozin, P>0.05; WMD 2.24% and 2.64%, respectively for ertugliflozin; P>0.05). SGLT2 inhibitors, as a class of drugs, increased Hct levels in patients with type 2 diabetes, and this increase was slightly more pronounced at higher doses compared to lower doses. The protocol of this study has been submitted to the PROSPERO platform (https://www.crd.york.ac.uk/PROSPERO/), and the registration number is CRD42020200699.

Effects of canagliflozin on myocardial infarction: a post hoc analysis of the CANVAS programme and CREDENCE trial.

Given the benefits of sodium glucose co-transporter 2 inhibition (SGLT2i) in protecting against heart failure in diabetic patients, we sought to explore the potential impact of SGLT2i on the clinical features of patients presenting with myocardial infarction (MI) through a post hoc analysis of CANVAS Programme and CREDENCE trial. Individuals with type 2 diabetes and history or high risk of cardiovascular disease (CANVAS Programme) or type 2 diabetes and chronic kidney disease (CREDENCE) were included. The intervention was canagliflozin 100 or 300mg (combined in the analysis) or placebo. MI events were adjudicated as ST-elevation myocardial infarction (STEMI), non-STEMI, and type 1 MI or type 2 MI. A total of 421 first MI events in the CANVAS Programme and 178 first MI events in the CREDENCE trial were recorded (83 fatal, 128 STEMI, 431 non-STEMI, and 40 unknown). No benefit of canagliflozin compared with placebo on time to first MI event was observed [hazard ratio (HR) 0.89; 95% confidence interval (CI) 0.75, 1.05]. Canagliflozin was associated with lower risk for non-STEMI (HR 0.78; 95% CI 0.65, 0.95) but suggested a possible increase in STEMI (HR 1.55; 95% CI 1.06, 2.27), with no difference in risk of type 1 or type 2 MI. There was no change in fatal MI (HR 1.22, 95% CI 0.78, 1.93). Canagliflozin was not associated with a reduction in overall MI in the pooled CANVAS Programme and CREDENCE trial population. The possible differential effect on STEMI and Non-STEMI observed in the CANVAS cohort warrants further investigation. ClinicalTrials.gov identifiers: NCT01032629, NCT01989754, and NCT02065791.

Kidney Disease in Type 2 Diabetes Mellitus and Benefits of Sodium-Glucose Cotransporter 2 Inhibitors: A Consensus Statement.

Diabetic kidney disease (DKD) occurs in approximately 20–40% of patients with type 2 diabetes mellitus. Patients with DKD have a higher risk of cardiovascular and all-cause mortality. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antihyperglycemic drugs form the mainstay of DKD management and aim to restrict progression to more severe stages of DKD. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) control hyperglycemia by blocking renal glucose reabsorption in addition to preventing inflammation, thereby improving endothelial function and reducing oxidative stress; consequently, this class of prescription medicines is emerging as an important addition to the therapeutic armamentarium. The EMPA-REG OUTCOME, DECLARE TIMI 58, and CANVAS trials demonstrated the renoprotective effects of SGLT2i, such as restricting decline in glomerular filtration rate, in the progression of albuminuria, and in death due to renal causes. The renoprotection provided by SGLT2i was further confirmed in the CREDENCE study, which showed a 30% reduction in progression of chronic kidney disease, and in the DELIGHT study, which demonstrated a reduction in albuminuria with dapagliflozin compared with placebo (− 21.0%, confidence interval [CI] − 34.1 to − 5.2, p = 0.011). Furthermore, a meta-analysis demonstrated a reduced risk of dialysis, transplantation, or death due to kidney disease (relative risk 0.67; 95% CI 0.52–0.86; p = 0.0019) and a 45% risk reduction in worsening of renal function, end-stage renal disease, or renal death (hazard ratio 0.55, CI 0.48–0.64, p < 0.0001) with SGLT2i, irrespective of baseline estimated glomerular filtration rate. Thus, there is emerging evidence that SGLT2i may be used to curb the mortality and improve the quality of life in patients with DKD. However, clinicians need to effectively select candidates for SGLT2i therapy. In this consensus statement, we have qualitatively synthesized evidence demonstrating the renal effects of SGLT2i and proposed recommendations for optimal use of SGLT2i to effectively manage and delay progression of DKD.

Potential mechanisms underlying the cardiovascular benefits of sodium glucose cotransporter 2 inhibitors: a systematic review of data from preclinical studies.

There is growing evidence from Phase III randomized clinical trials of the cardiovascular benefits of sodium glucose cotransporter 2 (SGLT2) inhibitors in patients with diabetes mellitus. It is hypothesized that these benefits are mediated by mechanisms other than glucose control. To address this, we performed a systematic review of data from preclinical studies examining the direct cardioprotective effects of SGLT2 inhibitors. Medline, EMBASE, CINAHL, and International Pharmaceutical Abstracts databases were searched for preclinical studies that examined the potential cardioprotective effects of SGLT2 inhibitors. Submission documents to the US Food and Drug Administration, European Medicines Agency, and Japanese Pharmaceutical and Medical Devices Agency for the registration of SGLT2 inhibitors were also reviewed. A total of 36 reports were included in the final analysis. The potential direct cardiovascular benefits of SGLT2 inhibitors include: augmentation of signal transducer and activator of transcription 3; inhibition of sodium hydrogen exchange; reduction of atherosclerosis; modulation of natriuretic peptides; vasodilation; modulation of sympathetic tone; and reduction of inflammation, oxidative stress, endoplasmic reticulum stress, and cardiac glucose uptake via down-regulation of SGLT1 expression. There are a number of mechanisms by which SGLT2 inhibitors may exert cardiovascular benefits beyond glycaemic control.

Making sense of newer treatment options for type 2 diabetes.

Over the past decade, several new medications have been developed to treat type 2 diabetes mellitus. Large-scale outcome trials have been performed with patients at high cardiovascular risk to assess the cardiovascular safety of these agents. These trials are changing the landscape of diabetes therapy with evidence beyond safety to cardiovascular benefits of sodium-glucose cotransporter 2 (SGLT-2) inhibitors and some glucagon-like peptide-1 receptor agonists. This review provides an overview of incretin-based therapies and SGLT-2 inhibitors with a particular focus on the results of published cardiovascular outcome trials, which have also provided unique opportunities to evaluate uncommon but potentially serious adverse events of these newer agents. The cardiovascular benefits of SGLT-2 inhibitors and some glucagon-like peptide-1 receptor agonists suggest that they may be the preferred choice, usually as an add-on to metformin, for patients with type 2 diabetes mellitus at high cardiovascular risk.

Sodium-glucose co-transporter 2 inhibitors and cardiovascular outcomes: A systematic review and meta-analysis.

Background The risks and benefits of sodium-glucose co-transporter 2 (SGLT2) inhibitors on cardiovascular outcomes have not been well established. We pooled evidence from all available clinical trials to assess the cardiovascular effects of this drug. Design A systematic review and meta-analysis of randomised controlled trials. Methods We queried electronic databases (MEDLINE, Scopus, CENTRAL and clinicaltrials.gov) from their inception to July 2017 for published and unpublished placebo controlled trials of SGLT2 inhibitors. Only studies with a follow-up period of at least 24 weeks and reporting at least one cardiovascular outcome were included. Results from trials were presented as odds ratios (ORs) with 95% confidence intervals (CIs) and were pooled using a random-effects model. Results Thirty-five eligible studies (canagliflozin, nine; empagliflozin, eight; dapagliflozin, 18), consisting of 34,987 patients with type 2 diabetes mellitus were included. Pooled results show that SGLT2 inhibitors, when compared to placebo, significantly reduce all-cause mortality (OR 0.79, 95% CI 0.70-0.89; P < 0.001), major adverse cardiac events (OR 0.8, 95% CI 0.76-0.92; P < 0.001), non-fatal myocardial infarction (OR 0.85, 95% CI 0.73-0.98; P = 0.03) and heart failure/hospitalisation for heart failure (OR 0.67, 95% CI 0.59-0.76; P < 0.001) in patients with type 2 diabetes mellitus. No significant difference was noted in the occurrence of stroke (OR 1.02, 95% CI 0.85-1.21; P = 0.87), atrial fibrillation (OR 0.61, 95% CI 0.31-1.19; P = 0.15) or unstable angina (OR 0.95, 95% CI 0.73-1.25; P = 0.73). In addition, there was no heterogeneity between different drugs in the SGLT2 inhibitor class for all of the clinical outcomes studied ( I2 = 0). Conclusions SGLT2 inhibitors significantly reduce the incidence of mortality, major adverse cardiac events, non-fatal myocardial infarction and heart failure in patients with type 2 diabetes mellitus. Subtypes of SGLT2 inhibitors appear to have similar cardiovascular effects.