Sodium-glucose Transporter-2 Inhibitors Research Articles

Effects of SGLT2 inhibitors on cardiovascular death and all-cause death in patients with type 2 diabetes and chronic kidney disease: an updated meta-analysis including the SCORED trial.

Background:The effects of sodium-glucose transporter 2 (SGLT2) inhibitors on cardiovascular death (CV death) and all-cause death (AC death) in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) are currently under intensive investigation. We intended to conduct an updated meta-analysis including the SCORED trial to evaluate the effects of SGLT2 inhibitors on death and cardiorenal events in this vulnerable population.Methods:Cardiorenal outcome trials of SGLT2 inhibitors were included. Primary outcomes were CV death and AC death, while secondary outcomes were hospitalization for heart failure (HHF), myocardial infarction (MI), CKD progression, cardiovascular death or hospitalization for heart failure (CV death or HHF), major adverse cardiovascular events (MACE), and stroke. Meta-analysis was conducted for each outcome.Results:Eight trials were included for meta-analysis. Compared with placebo, SGLT2 inhibitors significantly lowered the risk of CV death (HR = 0.86, 95% CI = 0.75–0.98), AC death (HR = 0.87, 95% CI = 0.79–0.96), HHF (HR = 0.64, 95% CI = 0.56–0.74), MI (HR = 0.76, 95% CI = 0.65–0.89), CKD progression (HR = 0.62, 95% CI = 0.54–0.72), and CV death or HHF (HR = 0.73, 95% CI = 0.67–0.80). No heterogeneity existed in the above meta-analyses (all I2 values = 0%), whereas moderate heterogeneity existed in the meta-analyses for MACE and stroke (I2 = 31.6% and 44.5%, respectively).Conclusions:Our findings suggest that SGLT2 inhibitors versus placebo significantly lower death, heart failure, renal failure, and MI events in patients with T2D and CKD. Head-to-head trials are needed to examine the possible differences in the effects of various gliflozins on MACE and stroke.

Omecamtiv Mecarbil: A Novel Mechanistic and Therapeutic Approach to Chronic Heart Failure Management.

Heart failure (HF) is a major public health problem in the United States as well as worldwide. Chronic heart failure is a syndrome of reduced cardiac output resulting from impaired ventricular function, impaired filling, or a combination of both. Associated symptoms include dyspnea, fatigue, and decreased exercise tolerance. HF has a marked effect on morbidity and mortality, given limited therapeutic choices. The first line of therapeutic agents indicated in heart failure are beta-blockers. Other drugs and therapeutic modalities employed in HF treatment include angiotensin-receptor blockers (ARBs), sacubitril (neprilysin inhibitor) combination with the ARB, valsartan, small doses of aldosterone receptor antagonists (ARAs) in the setting of angiotensin-converting enzyme (ACE) inhibitors, and beta-blockers. Additionally, the sodium-glucose transporter-2 inhibitor, dapagliflozin in the setting of ACE inhibitors, ARBs, or sacubitril-valsartan plus beta-blocker have been employed. Other therapeutic modalities have included loop diuretics, digoxin, the hydralazine-isosorbide dinitrate combination, ivabradine, the inotropes, dobutamine, milrinone, and dopamine. Decreased cardiac contractility is central to the systolic HF. Therapeutic agents employed to increase cardiac contractility in HF are limited because of their mechanistic-related adverse effect profiles. Omecamtiv mecarbil (OM) is a first of its class cardiac myosin activator that increases the cardiac contractility by specifically binding to the catalytic S1 domain of cardiac myosin, to be employed in heart failure treatment. This agent has demonstrated benefit in reducing heart rate, peripheral vascular resistance, mean left arterial pressure, and left ventricular end-diastolic pressure in the animal models. Additionally, OM is known to improve systolic wall thickening, stroke volume (SV), and cardiac output (CO). OM increases systolic ejection time (SET), cardiac myocyte fractional shortening without significant increase of LV dP/dtmax, myocardial oxygen consumption, and myocyte intracellular calcium. The benefits of OM have been demonstrated through key trials, as (i) The Acute Treatment with Omecamtiv mecarbil to Increase Contractility in Acute Heart Failure (ATOMIC-AHF), and (ii) The Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF). The Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial is ongoing and can help provide further clinical data. OM provides a novel mechanism and therapeutic approach to managing patients with HF. Preclinical and clinical data suggest that OM capability can improve cardiac function, decrease ventricular wall stress, reverse ventricular remodeling, and promote sympathetic withdrawal.

The early effect of dapagliflozin on strain and tissue Doppler parameters of diastolic function in diabetic patients with heart failure with reduced ejection fraction.

IntroductionHeart failure (HF) with reduced ejection fraction (HFrEF) remains a challenging problem due to its high mortality rate. The PARADIGM HF trial and a new class of drugs – angiotensin receptor–neprilysin inhibitors (ARNIs) – managed to change the current perception of HF treatment by reducing cardiovascular mortality and morbidity as well as HF hospitalizations compared with enalapril and have emerged as an evidence-based therapy for HFrEF. Another novelty in HF therapy is dapagliflozin, a sodium-glucose transporter-2 inhibitor (SGLT2i) which decreased the rates of cardiac death and worsening of HF in the DAPA-HF trial, when added in other guideline recommended therapy. A recent study evaluated the potency of dapagliflozin in terms of mortality and deterioration of HF, in patients taking sacubitril/valsartan and in patients who were naive.Material and methodsA prospective cohort study of 30 symptomatic HF patients with EF < 35% (aged 65 ±10 years) was conducted. Diabetic (2TDM) patients of NYHA status II–III, previously treated with ARNI, β-blocker, and mineralocorticoid receptor antagonists (MRA) were included. Dapagliflozin was added to their therapy.ResultsEchocardiographic evaluation revealed improvement of both conventional tissue Doppler and diastolic strain parameters by dapagliflozin addition on HF therapy.ConclusionsDapagliflozin impact on diastolic function may explain the symptom amelioration and the improvement of quality of life. And more specifically, the ratio of early diastolic transmitral flow velocity to global strain rate at the early filling phase of diastole (E/SRE)may be considered a reliable index of HF therapy responders.

SGLT2 inhibition requires reconsideration of fundamental paradigms in chronic kidney disease, 'diabetic nephropathy', IgA nephropathy and podocytopathies with FSGS lesions.

In 2020, the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial first demonstrated that inhibition of the sodium-glucose transporter-2 (SGLT2) with dapagliflozin attenuates the progression of chronic kidney disease (CKD) with proteinuria in patients with or without diabetes at an unprecedented effect size. These results have far-reaching implications for a series of traditional concepts in Nephrology. It now became obvious that CKD with and without diabetes involves a predominant SGLT2-driven pathophysiology compared with the other pathogenic pathways currently under consideration. As SGLT2 inhibition is similarly efficacious in diabetic and non-diabetic CKD with proteinuria, treating CKD rather than 'diabetic nephropathy' becomes the central paradigm. Indeed, in older adults with type 2 diabetes, CKD is rather of multifactorial origin. As the DAPA-CKD trial included more patients with immunoglobulin A nephropathy (IgAN) than any of the previous IgAN trials, dual renin-angiotensin/SGLT2 inhibition may become the new standard. The same applies for patients with podocytopathy-related focal segmental glomerulosclerosis lesions. From now on,IgAN and podocytopathy trials without SGLT2 inhibition as background therapy and without glomerular filtration rate decline as primary outcome criterion will be of limited value. These and other potential implications will trigger broad discussions and secondary research activities with conclusions difficult to predict today. However, one is for sure: Nephrology after the DAPA-CKD trial will be not the same as it was before. Finally!

Effects and safety of SGLT2 inhibitors compared to placebo in patients with heart failure: A systematic review and meta-analysis.

BackgroundHeart failure (HF) prognosis without therapy is poor, however introduction of a range of drugs has improved it. We aimed to perform a systematic review on the effects and safety of sodium-glucose transporter 2 inhibitors (SGLT2i) in HF patients.MethodsWe carried out a systematic review of randomized controlled trials (RCTs) on SGLT2i compared to placebo for HF patients. We searched in PubMed, Scopus, Web of Science and EMBASE, with no language restriction, from inception to 31 August 2020. We included nine RCTs comprising three arms (empagliflozin, dapagliflozin and placebo). Effects sizes for continuous variables were expressed as mean differences (MDs) and 95% confidence intervals (CIs). Effects sizes for dichotomous variables were expresses as risk ratio (RR) and 95% CIs. We used random-effect models with the inverse variance method. We performed subgroup meta-analyses by intervention drug and follow-up period.ResultsSGLT2i significantly reduced all-cause mortality (RR: 0.88, 95%CI 0.79–0.98, I2 = 0%), cardiovascular mortality (RR: 0.87, 95%CI 0.77–0.99, I2 = 0%), HF hospitalization (RR: 0.73, 95%CI 0.66–0.81, I2 = 0%) and emergency room visits due to HF (RR: 0.40, 95%CI 0.21–0.76, I2 = 0%), as well as composite outcomes including the previous ones. Besides, it significantly improved the score of the Kansas City Cardiomyopathy Questionnaire (KCCQ, MD: 1.70, 95%CI 1.67–1.73, I2 = 54%). SGLT2i reduced any serious adverse events, blood pressure and weight. However, it increased hematocrit and creatinine. The meta-analysis of RCTs of > 12 weeks of follow-up showed that SGTL2i significantly reduced NT-proBNP.ConclusionsSGLT2i showed to improve critical outcomes in HF patients, and it is apparently safe.

Nephroprotection by SGLT2i in CKD Patients: May It Be Modulated by Low-Protein Plant-Based Diets?

Sodium-glucose-transporter 2 inhibitors (SGLT2i) are a new class of anti-diabetic drugs that in large trials such as CREDENCE have shown also a reduction of glomerular hyperfiltration and albuminuria in type 2 diabetic patients. Hence, the interest toward SGLT2i is focused toward this potential nephroprotective effect, in order to reduce the progression to overt nephropathy, and it seems to be confirmed in the most recent DAPA-CKD trial. This is the reason why the indication for SGLT2i treatment has been extended to chronic kidney disease (CKD) patients with eGFR up to 30 ml/min, namely with CKD stage 1–3. In patients with CKD stage 3 to 5, the most recent KDIGO guidelines recommend low-protein diet and plant-based regimens to delay end-stage kidney disease (ESKD) and improve quality of life. Similarly to SGLT2i, low-protein diets exert renal-protective effects by reducing single nephron hyperfiltration and urinary protein excretion. Beyond the glomerular hemodynamic effects, both protein restriction and SGLT2i are able to restore autophagy and, through these mechanisms, they may exert protective effects on diabetic kidney disease. In this perspective, it is likely that diet may modulate the effect of SGLT2i in CKD patients. Unfortunately, no data are available on the outcomes of the association of SGLT2i and low-protein and/or vegan diets. It is therefore reasonable to investigate whether CKD patients receiving SGLT2i may have further advantages in terms of nephroprotection from the implementation of a low-protein and/or plant-based diet or whether this association does not result in an additive effect, especially in vascular nephropathies.

Glucose-lowering effects of 7-day treatment with SGLT2 inhibitor confirmed by intermittently scanned continuous glucose monitoring in outpatients with type 1 diabetes. A pilot study.

The present study used intermittently scanned continuous glucose monitoring (isCGM) in 10 patients with type 1 diabetes mellitus (T1DM) to evaluate the efficacy and safety of 7-day outpatient treatment with the combination of intensive insulin therapy and sodium-glucose transporter 2 inhibitor (SGLT2-I). All participants wore isCGM and were treated with either 50 mg/day ipragliflozin or 5 mg/day dapagliflozin. The primary outcome, percent time with glucose at 70-180 mg/dL (TIR: time in range), improved significantly following the addition of SGLT2-I (p = 0.005). TIR increased from 36.0% before addition of SGLT2-I to 70.7% on day 7. Although none of the patients achieved TIR of 70% or higher before the addition of SGLT2-I, 6 patients met that criteria TIR on day 7. The secondary outcome measures, standard deviation (SD) of glucose, average plasma glucose, percent time with glucose at >180 mg/dL (TAR: time above range), maximum plasma glucose, high blood glucose index (HBGI) and average nocturnal plasma glucose (midnight to 05:59 AM) detected by isCGM, also improved significantly by SGLT2-I. There were no significant differences in percent time with glucose at <70 mg/dL (TBR: time below range), minimum plasma glucose and low blood glucose index (LBGI). Our results using isCGM in an actual clinical setting showed that 7-day use of SGLT2-I with intensive insulin therapy improved plasma glucose fluctuations and mean plasma glucose levels without inducing hypoglycemia in patients with T1DM.

Prevalence of Incretin-Mimetic and Sodium-Glucose-Transporter-2-Inhibitor Therapy in German Hospitalized Type-2 Diabetics Following Myocardial Revascularization: An Observational Study.

IntroductionReal-world data indicate that sodium glucose transporter-2–inhibitor therapy and/or incretin mimetics are not widely prescribed in type-2 diabetics with atherosclerotic vascular disease. We hypothesized that incretin-mimetic therapy is associated with better overall survival and 1-year mortality in type-2 diabetics following myocardial revascularization.MethodsHospitalized type-2 diabetics of the Departments of Cardiology and Cardiothoracic Surgery (University Hospital Halle) who needed myocardial revascularization (PCI or CABG) in 2016 were included in this observational study: group 1 (incretin-mimetic therapy), group 2 (insulin therapy without incretin mimetics) and group 3 (oral diabetes medication without incretins or insulin). They were asked to mail in a questionnaire on medical therapy and outcomes 1.9 years following discharge. In non-responders, vital status was obtained by local registration offices 2.4 years after discharge.ResultsTwo hundred four patients were recruited in this study. At discharge, only 4.4% of all type-2 diabetics were on incretin mimetic, 39.7% on insulin and 55.9% on oral diabetes medication. At the time of follow-up (response rate: 44.1%), there was no change in terms of prevalence of incretin-mimetic therapy (5.6% of responders). Prevalence of sodium glucose transporter-2–inhibitor therapy increased from 6.9% to 15.6% in responders. In-hospital mortality (group 1: 0%, group 2: 0%, group 3: 5.2%; p = 0.092), survival after discharge (group 1: 88.9%, group 2: 86.4%, group 3: 88.0%; p = 0.942) and number of rehospitalizations within 12 months after discharge (group 1: 1.0 per capita, group 2: 1.0, group 3: 1.1; p = 0.697) were similar among prespecified groups and between group 2 and 3. By 1.9-year follow-up, hypoglycemic events were more frequent in group 2 (1.5 ± 2.9) than in group 3 (0.02 ± 0.1; p = 0.0001).ConclusionThe prevalence of incretin mimetics and sodium-glucose-transporter-2 inhibitors was low both during the index hospitalization and at a 1.9-year follow-up. When comparing group 2 and group 3 patients, survival and rehospitalizations were similar; hypoglycemic events occurred more often in insulin-treated diabetics than in the those without.

A novel SGLT-2 score to identify HFpEF patients who may benefit from SGLT-2 inhibitors

Abstract Background Established heart failure (HF) treatments have shown no effects in HF and preserved ejection fraction (HFpEF). Subgroup analyses of the HFpEF populations suggest that certain patients benefit from HF treatments. This underlines the importance of individualized therapy regimens in HFpEF. Sodium-glucose transporter 2 (SGLT-2) inhibitors are emerging as a promising treatment of HF. The mechanisms leading to improved outcomes include 1) treatment of diabetes, 2) osmodiuresis preventing volume overload, 3) enhancement of the cardio protective Angiotensin (Ang) 1–7 pathway, instead of Ang II. We aimed to characterize patients by factors which are modified by SGLT-2 inhibitors to identify individuals who may benefit from these drugs. Methods HFpEF patients were included in a single center registry. Baseline evaluation included assessment of HbA1c, fluid status measured by body composition monitor and plasma angiotensin concentration. A “SGLT-2 score” with a maximum of 3 points was calculated using the following parameters: 1) HbA1c &amp;gt;6.5%, 2) overhydration, defined as a fluid overload of &amp;gt;1,5L and 3) plasma renin activity (PRA) levels above the median as a parameter of over-all RAS activity. Primary outcome was defined as all-cause death or HF hospitalization. All parameters used in the “SGLT-2 score” were independently predictive for the chosen endpoint. Kaplan Meier analyses was used to show the association between the score and outcomes. Results 90 patients were included in this registry. Median HbA1c was 6.0%, median fluid status was 1.2L and the median Ang II levels in the “high PRA-group” were 5.35.1 pmol/L. After a mean follow up time of 44.0±38.7 months, 60 patients (66.6%) reached the endpoint. Kaplan Meier analysis showed an association between SGLT-2 score and outcome (p=0.003). Conclusion Patients with HbA1c &amp;gt;6.5%, overhydration and high RAS activity have poor outcomes. We propose the future use of this score to identify a subgroup of HFpEF patients who may benefit from SGLT-2 inhibitors. Kaplan Meier analysis Funding Acknowledgement Type of funding source: None

Ingestion of an exogenous ketone monoester improves the glycemic response during oral glucose tolerance test in individuals with impaired glucose tolerance: A cross-over randomized trial.

Aims/IntroductionAs a low‐carbohydrate diet and the use of sodium–glucose transporter‐2 inhibitors are both known to increase D‐beta‐hydroxybutyrate levels, the effect of these levels on glucose metabolism has attracted attention. We investigated the acute effects of ketone monoester (KM) ingestion on blood glucose levels during the 75‐g oral glucose tolerance test (OGTT) in participants with impaired glucose tolerance.Materials and MethodsNine Japanese adults aged 48–62 years (4 men, 5 women) with impaired glucose tolerance participated in this study. After participants fasted overnight, we carried out OGTT for 180 min with and without KM ingestion on two separate days in a randomized cross‐over design. We compared the area under the curve (AUC) of D‐beta‐hydroxybutyrate, glucose, insulin, C‐peptide, glucagon and free fatty acids during OGTT.ResultsThe AUC of D‐beta‐hydroxybutyrate during OGTT was significantly higher with KM than without KM (KM 5995.3 ± 1257.1 mmol/L·h; without KM 116.1 ± 33.9 mmol/L·h, P < 0.0001), and the AUC of glucose with KM was significantly lower than that without KM (KM 406.6 ± 70.6 mg/dL·h; without KM 483.2 ± 74.3 mg/dL·h, P < 0.0001). This improved glucose excursion was associated with enhanced AUC of insulin during the first half (0–90 min) of OGTT, even though the AUC of C‐peptide during this period was unchanged. In contrast, the AUC of insulin, C‐peptide, glucagon and free fatty acids during 180 min of OGTT were similar in both conditions.ConclusionThe ingestion of KM decreased the AUC of glucose during 75‐g OGTT in Japanese individuals with impaired glucose tolerance, and the mechanism might involve elevated levels of circulating early phase insulin.

Efficacy and Cardiovascular Safety of Thiazolidinediones.

Type 2 diabetes mellitus (T2DM) is characterized by a progressive beta cell dysfunction in the setting of peripheral insulin resistance. Insulin resistance in subjects with type 2 diabetes and metabolic syndrome is primarily caused by an ectopic fat accumulation in the liver and skeletal muscle. Insulin sensitizers are particularly important in the management of T2DM. Though thiazolidinediones (TZDs) are principally insulin sensitizers, they possess an ability to preserve pancreatic β-cell function and thereby exhibit durable glycemic control. Cardiovascular outcome trials (CVOTs) have shown that Glucagon-like-peptide 1 receptor agonists (GLP-1 RAs) and sodium glucose transporter-2 inhibitors (SGLT2i) have proven cardiovascular safety. In this era of CVOTs, drugs with proven cardiovascular (CV) safety are often preferred in patients with preexisting cardiovascular disease or at risk of cardiovascular disease. In this review, we will describe the three available drugs belonging to the TZD family, with special emphasis on their efficacy and CV safety.

Molecular Mechanisms of SGLT2 Inhibitor on Cardiorenal Protection.

The development of sodium-glucose transporter 2 inhibitor (SGLT2i) broadens the therapeutic strategies in treating diabetes mellitus. By inhibiting sodium and glucose reabsorption from the proximal tubules, the improvement in insulin resistance and natriuresis improved the cardiovascular mortality in diabetes mellitus (DM) patients. It has been known that SGLT2i also provided renoprotection by lowering the intraglomerular hypertension by modulating the pre- and post- glomerular vascular tone. The application of SGLT2i also provided metabolic and hemodynamic benefits in molecular aspects. The recent DAPA-CKD trial and EMPEROR-Reduced trial provided clinical evidence of renal and cardiac protection, even in non-DM patients. Therefore, the aim of the review is to clarify the hemodynamic and metabolic modulation of SGLT2i from the molecular mechanism.

Sodium-glucose co-transporter-2 (SGLT-2) inhibition reduces glucose uptake to induce breast cancer cell growth arrest through AMPK/mTOR pathway

ObjectiveThe sodium-glucose transporter 2 (SGLT2) inhibitors Canagliflozin and Dapagliflozin are recently approved medications for type 2 diabetes. Recent studies indicate the potential ability of SGLT2 inhibitors to attenuate cancer growth of SGLT2-expressing cancer cells, but there is little known about the effects of SGLT2 inhibitors on breast cancer. The goal in this research was to assess the anticancer activity of SGLT2 inhibitors in breast cancerin vitro and in vivo. MethodsWe test the SGLT2 expression in breast cancer using immunohistochemistry and immunoblot assay. MTT cytotoxicity assay, colony formation assay and human breast cancer cells nude mice xenograft model were performed to detect the effects of SGLT2 inhibitors on cancer cell proliferation and growth. Flow Cytometry assay was performed to determine if the SGLT2 inhibitors induced cell cycle arrest and apoptosis. ResultsWe proved that SGLT2 expresses in breast cancer cell lines and human breast tumor tissue samples. SGLT2 inhibitors Dapagliflozin and Canagliflozin exhibited a potent anti-proliferative effect in breast cancer cells as demonstrated by MTT, clonogenic survival assay in vitro and xenograft growth model in vivo. Furthermore, we found that SGLT2 inhibitors arrested cell cycle in G1/G0 phase and induced cell apoptosis. Western blot analysis demonstrated that treatment with SGLT2 inhibitors increased the phosphorylation of Amp-activated protein kinase (AMPK) and decreased the phosphorylation of 70 kDa ribosomal protein S6 kinase 1 (p70S6K1) in breast cancer cells. ConclusionsThese findings indicate that SGLT2 inhibitor-therapy induced AMPK-mediated cell cycle arrest and apoptosis, which is a potential novel strategy for the treatment of breast cancer.

Annals for Educators - 6 October 2020.

Annals for Educators - 6 October 2020.

Type 2 diabetes mellitus: pathogenesis and genetic diagnosis.

Type 2 diabetes mellitus (T2DM) is a heterogeneous condition that is related to both defective insulin secretion and peripheral insulin resistance. Beta cells are the major organ for secreting insulin hence, it is important to maintain an adequate beta-cell mass in response to various changes. Insulin resistance is a major cause of T2DM leads to elevated free fatty acid (FFA) levels which increases beta-cell mass and insulin secretion to compensate for insulin insensitivity. Chronic increase of plasma FFA levels results in disturbances in lipid metabolism, which contributes to decreased beta-cell function and lipotoxicity thus promoting T2DM. In the present review, we have discussed the process of beta-cell destruction, the role of genes in contributing to the fast increase in the progression of T2DM in detail. More than 130 variants in various T2DM susceptibility and candidate genes have been discovered to be associated with T2DM. Still, these variants elucidate only a small amount of total heritability of T2DM. Further, there is also an inventory of presently used therapeutic tools and a review of novel therapeutic approaches like incretin-based therapies or sodium-glucose transporter-2 inhibitors. Additionally, providing a concise but comprehensive update, this review will be essential to every clinician involved in the treatment of diabetes mellitus.

Annals for Educators - 18 August 2020.

Annals for Educators - 18 August 2020.

Association between combined treatment with SGLT2 inhibitors and metformin for type 2 diabetes mellitus on fracture risk: a meta-analysis of randomized controlled trials

No study is available evaluating the association between sodium-glucose transporter-2 inhibitors (SGLT2is) in combination with metformin use and fracture risk. Our study aimed to investigate the fracture risk of combination therapy with SGLT2is and metformin in patients with type 2 diabetes mellitus (T2DM). PubMed, Embase, ClinicalTrials.gov site, and the Cochrane Library databases were scrutinized for all eligible randomized controlled trials (RCTs). The summarized odds ratios (ORs) and their 95% confidence intervals (CI) were calculated using Review Manager 5.3 software. A total of 25 RCTs involving 19,500 participants with T2DM were included in our studies. There were 88 fracture cases in the SGLT2is in combination with metformin therapy group and 79 in the control group. SGLT2is combined with metformin use did not influence fracture risk compared with metformin monotherapy or other comparators in patients with T2DM (OR = 0.97, 95% CI 0.71-1.32). After stratification by drug type, follow-up time, control regimen, and type of fracture, the upshots were still stable. SGLT2is and metformin combination therapy did not influence fracture risk compared with metformin monotherapy or other comparators in patients with T2DM. CRD42020168435.

LBP26 - Resolution of non-alcoholic steatohepatitis and hepatic fibrosis by sodium glucose transporter-2 inhibitor, ipragliflozin; a multicenter randomized controlled trial

LBP26 - Resolution of non-alcoholic steatohepatitis and hepatic fibrosis by sodium glucose transporter-2 inhibitor, ipragliflozin; a multicenter randomized controlled trial

Effects of different dosages of Sodium-Glucose Transporter 2 Inhibitors on lipid levels in patients with type 2 diabetes mellitus: A protocol for systematic review and meta-analysis.

Background:Type 2 diabetes mellitus is one of the most common chronic diseases, which endangers peoples health and life qualities. Sodium-Glucose Transporter 2 (SGLT2) inhibitors have been widely recognized since their clinical application in blood glucose control. While, dyslipidemia caused by SGLT2 inhibitors has been identified that affected the prognosis of this disease.Methods:We will retrieve 8 databases including English and Chinese. After multiple screening, all randomized controlled trials (RCTs) related to SGLT2 inhibitors will be included by the 2 authors and data will be extracted. After completion of the risk of bias assessment, we will use these effect values including risk ratio (RR), weighted mean difference (WMD) and 95% confidence interval (CI) to conduct data analysis. Chi-Squared test and I2 test will be used to assess heterogeneity between studies. The robustness of meta-analysis results will be determined by sensitivity analysis. It will be assessed that evidence quality of the outcomes on the GRADE.Results:The results of our research will be published in a peer-reviewed journal.Conclusion:The purpose of this systematic review and meta-analysis is to evaluate the association and degree of association between different doses of SGLT2 inhibitors and changes on blood lipid levels in patients with type 2 diabetes mellitus, in order to provide a reliable basis for clinical medication.INPLASY registration number:INPLASY202040201.

1122-P: Sodium–Glucose Transporter 2 Inhibitor Delays Progression of Diabetic Kidney Disease in Japanese Patients with Type 2 Diabetes: Retrospective Slope Analysis of Renal Function

Objective: Prevention of end stage kidney disease is one of the priorities in diabetes management. But very few data are available in using sodium glucose transporter 2 inhibitor (SGLT2i) at advanced chronic kidney disease (CKD). We assessed annual eGFR decline rate (slope) in patients with type 2 diabetes with diabetic kidney disease (DKD) treated by SGLT2i. Methods: A total of 75 patients with DKD, treated by SGLT2i (on empagliflozin 64% and others), were analyzed. Average age was 70.7±12.2 year-old and duration of diabetes was 15.0±9.3 years. Initial eGFR slopes were calculated from 46±21 months period, and slopes after adding SGLT2i were calculated from 21±8 months. Efficacy was compared by each CKD stage: stage 3A; eGFR 45-59 (n=29), stage 3B; eGFR 30-44 (n=28) and stage 4; eGFR&amp;lt;30ml/min/1.73m2 (n=18) at the time of recruitment (middle in 2019). Results: 1) Average of initial (first month) eGFR changes (drops) are as follows; stage 3A; 57.8±10.5 to 54.9±10.3 ml/min/1.73m2 (P&amp;lt;0.05), stage 3B; 43.2±7.1 to 40.9±6.5 ml/min/1.73m2 (P&amp;lt;0.01), stage 4; 30.6±10.2 to 28.7±9.4ml/min/1.73m2 (P&amp;lt;0.01). The start of SGLT2i treatment decreased eGFR 1.9-2.9ml/min/1.73m2 on initial month. However, annual mean eGFR slopes were improved in all stages; stage 3A: -4.2±3.7 to -1.8±4.4ml/min/1.73m2/year (P&amp;lt;0.02), stage 3B; -4.8±3.7 to -1.7±2.7ml/min/1.73m2/year (P&amp;lt;0.001), stage 4; -12.3±16.3 to -1.9±4.6ml/min/1.73m2/year (P=0.01). 2) The proportion of showing reduction of eGFR slopes after the start of SGLT2i (responder) are similar in all stages: stage 3A; 66% (19/29), stage 3B; 75% (21/28), stage 4; 78%; (14/18). Changes of mean eGFR slopes in those responders were as follows, -8.1±10.3 to -0.6±3.3ml/min/1.73m2/year (P&amp;lt;0.0001). Conclusion: SGLT2i treatment could have a favorable benefit on renal function even in advanced stage of DKD. Slope analysis might be useful for safety and individualized therapy. Disclosure K. Kashima: None. H. Shimizu: None. M. Yamada: None.