Sodium-glucose Cotransporter 2 Inhibitor Treatment Research Articles

PS-BPB06-1: GLOMERULAR HEMODYNAMIC CHANGES WITH SGLT2 INHIBITION IN TYPE 2 DIABETIC RATS USING IN VIVO IMAGING

Background and aim: Clinical trials have shown that sodium-glucose co-transporter 2 inhibitor (SGLT2i) not only reduce the risk of heart failure and cardiovascular events in people with type 2 diabetes, but also inhibit DKD progression. Improvement of glomerular hyperfiltration via tubuloglomerular feedback (TGF) is considered to be one of the possible pathways for renal protection with SGLT2i in DKD. However, the mechanisms responsible for kidney protection, especially in the setting of T2D, remain incompletely understood. In previous work, we established a method for measuring single nephron GFR (SNGFR) in mice using in vivo imaging and found that the adenosine/adenosine A1 receptor (A1aR) pathway is central for tubuloglomerular feedback (TGF) signaling and the pathogenesis of glomerular hyperfiltration in animal models of type 1 diabetes (Kidokoro K. et al. Circulation 2019). The mechanism of development of glomerular hyperfiltration, and improvement of glomerular hyperfiltration by SGLT2i may, however, be different in type 1 vs type 2 diabetes and related DKD. However, the detailed regulatory mechanism of GFR have not yet been elucidated in DKD related to T2D. Methods: Zucker lean (ZL) rats and Zucker diabetic fatty (ZDF) rats were used. In the first experiment, SNGFR and diameters of glomerular afferent/efferent arterioles were measured in both groups. Next, we examined the change of SNGFR and diameters of glomerular afferent/efferent arterioles, as well as urinary excretions of glucose and sodium in ZDF after a single-dose administration of SGLT2i (luseogliflozin; 10 mg/kg, gavage) for 120 minutes, which generated the following three groups: SGLT2i group, SGLT2i + adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine, 1 mg/kg) group, and insulin group. Results: SNGFR, afferent and efferent arteriole diameter were significantly increased in ZDF compared to ZL, with greater afferent vs. efferent dilatation. SGLT2i treatment resulted in correction of afferent arteriole vasodilation, with post-SGLT2i diameter that was comparable to baseline levels (p > 0.05). Post-SGLT2i SNGFR was also similar compared to baseline levels. Changes in efferent arteriole diameter were not significant. The inhibitory effect on hyperfiltration by SGLT2i was abolished by the concomitant use of an A1aR antagonist. In contrast, urinary sodium and urinary glucose in SGLT2 inhibitor group increased significantly regardless of adenosine A1 receptor antagonist use. In response to SGLT2i, urinary adenosine and PGE2 increased significantly (p > 0.05), while urine NOx did not change. Conclusion: Regulation of afferent arteriolar tone with SGLT2i is dependent on adenosine/ A1aR signaling an experimental model of T2D related hyperfiltration, regardless of ARB use.

Use of sodium-glucose cotransporter 2 inhibitors in Alberta adults with chronic kidney disease: a cross-sectional study identifying care gaps to inform knowledge translation.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have important kidney and cardiovascular benefits in adults with chronic kidney disease. Among adults with diabetes, we characterized the prevalence of chronic kidney disease eligible for SGLT2 inhibitor treatment, based on definitions of eligibility from trials and diabetes guidelines, and assessed the predictors of SGLT2 inhibitor use. We conducted a cross-sectional study using linked administrative data from Alberta Health in adults with diabetes (2002-2019). Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR) less than 90 mL/min/1.73 m2 with severe or greater proteinuria (trial-based definition); or eGFR less than 60 mL/min/1.73 m2 or moderate or greater proteinuria regardless of eGFR (diabetes guideline-based definition). Predictors (sociodemographic characteristics, comorbidities and health care utilization) of SGLT2 inhibitor use were identified using logistic regression. Of 446 315 adults with diabetes, 76 630 (17.2%, guideline-based definition; 12 867 [2.9%], trial-based definition) had chronic kidney disease eligible for SGLT2 inhibitor treatment. A total of 7.1% used SGLT2 inhibitors. Older age, lower hemoglobin A1c (HbA1c) levels, female sex, lower neighbourhood income, rural residence and hospital admission were among variables associated with nonuse of SGLT2 inhibitors (adjusted odds ratios [ORs] from 0.13 [age ≥ 85 yr] to 0.92 [rural residence], p < 0.05). Family physician visits were associated with higher SGLT2 inhibitor use (adjusted OR 4.01, p < 0.001 for > 4 visits/yr). Considering all adults, both with and without diabetes, 162 012 individuals with chronic kidney disease (5% of all Alberta adults) may benefit from treatment with SGLT2 inhibitors. Many adults with chronic kidney disease would derive heart and kidney benefits from treatment with SGLT2 inhibitors but had low SGLT2 inhibitor use as of 2019. Efforts will be needed to address lower use of SGLT2 inhibitors among female, older and lower-income adults, and to enhance primary care and promote awareness of the benefits of SGLT2 inhibitors independent of glycemic control.

Effects of second-line antihyperglycemic drugs on the risk of chronic kidney disease: applying a target trial approach to a hospital-based cohort of Thai patients with type 2 diabetes

BackgroundThe reno-protective effect of second-line treatments in type 2 diabetes has been assessed by clinical trials but generalizability to routine clinical practice is still uncertain. We aimed to assess the effectiveness of these treatments, when added to metformin, on the risk of chronic kidney disease (CKD).MethodsA real-world, hospital-based, type 2 diabetes cohort was retrospectively assembled at Ramathibodi Hospital from 2010 to 2019. Patients who received sulfonylureas (SU), thiazolidinediones (TZD), dipeptidyl peptidase-4 inhibitors (DPP4i), or sodium-glucose cotransporter-2 inhibitors (SGLT2i), as second-line antihyperglycemic treatment were included. Treatment effect models with inverse probability weighting and regression adjustment were used to estimate CKD risk according to treatment.ResultsCKD was identified in 4,132 of the 24,777 patients with type 2 diabetes (16.7%). The CKD incidence (95% CI) was 4.1% (2.2%, 6.9%), 13.5% (12.5%, 14.6%), 14.8% (13.5%, 16.1%), and 18.0% (17.4%, 18.5%) for patients receiving SGLT2i, DPP4i, TZD, and SU treatment, respectively. The average treatment effects (i.e., the difference in CKD risk) for SGLT2i, DPP4i, and TZD compared to SU were − 0.142 (− 0.167, − 0.116), − 0.046 (− 0.059, − 0.034), and − 0.004 (− 0.023, 0.014), respectively, indicating a significant reduction in CKD risk of 14.2% and 4.6% in the SGLT2i and DPP4i groups, respectively, compared to the SU group. Furthermore, SGLT2i significantly reduced CKD risk by 13.7% (10.6%, 16.8%) and 9.5% (6.8%, 12.2%) when compared to TZD and DPP4i, respectively.ConclusionsOur study identified 14.2%, 13.7%, and 9.5% reduced CKD risk in Thai patients with type 2 diabetes who were treated with SGLT2i compared to those treated with SU, TZD, and DPP4i, respectively, in real-world clinical data. Previous evidence of a reno-protective effect of SGLT2i reported in other populations is consistent with our observations in this Southeast Asian cohort.

The effect of sodium-glucose cotransporter 2 inhibitors on biomarkers of inflammation: A systematic review and meta-analysis of randomized controlled trials.

Aims: Inflammatory biomarkers may play vital roles in the pathophysiology of diabetes and diabetic cardiorenal complications. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have a potential cardiovascular and renal protective effect in type 2 diabetes. The aim of this meta-analysis was to quantify the effects of SGLT2 inhibitors on biomarkers of inflammation in randomized controlled trials (RCTs). Methods: PubMed, Cochrane Library, EMBASE, and Web of Science were searched for eligible RCTs of adults with type 2 diabetes (T2D) with no time limit (updated to 12 October 2022). The biomarkers selected included C-reactive protein (CRP), interleukin-6, tumor necrosis factor-alpha, leptin, adiponectin, ferritin, plasminogen activator inhibitor (PAI)-1, and vascular cell adhesion molecule-1. Data were analyzed using a random-effect model in Review Manager 5.4. Results: Thirty-four studies with 6,261 patients (68.6% male) were eligible for this meta-analysis. The mean age of the participants was 62.57(±11.13) years old, and the median treatment duration length with follow-up was 24weeks. Generally, the included trials were of good methodological quality. The meta-analysis revealed that ferritin levels were significantly reduced in SGLT2 inhibitor treatment groups versus placebo or standard diabetes therapies (SMD: -1.21; 95% CI: -1.91, -0.52, p < 0.001). The effects of CRP (SMD: 0.25; 95% CI: -0.47, -0.03, p = 0.02) and leptin (SMD: -0.22; 95% CI: -0.43, -0.01, p = 0.04) were reduced, and the effects of adiponectin were improved (SMD: 0.28; 95% CI: 0.15, 0.41, p < 0.001) in placebo-controlled studies. PAI-1 levels were significantly reduced in studies controlled for diabetes therapies (SMD: -0.38; 95% CI: -0.61, -0.15, p = 0.001). Conclusion: This analysis provides strong evidence supporting anti-inflammatory effects of SGLT2 inhibitors in T2D subjects. The mechanisms and possible targets for the inflammation reducing and cardiorenal protective properties of SGLT2 inhibitors remain to be explored.

Therapeutic effect of sodium‑glucose cotransporter 2 inhibitor and benazepril on diabetic nephropathic rats.

The present study aimed to compare the therapeutic effect of sodium/glucose cotransporter 2 (SGLT2) inhibitor and benazepril on diabetic nephropathy (DN) rats and provide a potential novel agent for the clinical treatment of DN. The DN model was established on rats. Animals were dosed orally with SGLT2 and benazepril daily for 4 weeks. The pathological state of renal tissues were evaluated using hematoxylin and eosin, Masson and periodic acid-Schiff staining. The change in the morphology of renal tissues was observed through transmission electron microscopy. Western blotting was utilized to determine the expression level of TGF-β, N-terminal fragment of the B-type natriuretic peptide precursor (NT-proBNP) and matrix metalloproteinase-9 (MMP-9). The expression level of endothelin 1 (ET-1), von Willebrand factor (vWF), collagen (col)-I and α smooth muscle actin (α-SMA) in renal tissues was visualized using immunohistochemical assay. Significant pathological changes in the glomerular basement membrane, mesangial membrane, renal tubules, lumen, renal interstitial region and renal tubular epithelial cells were observed in DN rats, accompanied by increased collagen fibers. SGLT2 inhibitor treatment demonstrated more alleviatory effects on the pathological changes of renal tissues compared with benazepril. Compared with control, TGF-β and NT-proBNP were upregulated in DN rats, accompanied by the downregulation of MMP-9, ET-1, vWF, col-I and α-SMA, which were markedly reversed by treatment with SGLT2 inhibitor and benazepril. Compared with benazepril, the effects of SGLT2 inhibitor on the expression level of TGF-β, NT-proBNP, MMP-9, ET-1, vWF, col-I and α-SMA were more significant. Overall, SGLT2 inhibitor demonstrated an increased therapeutic effect against DN rats compared with benazepril by regulating cytokines, renal fibrosis and extracellular matrix degradation.

Effects of sodium-glucose cotransporter-2 inhibitors on nutritional status in heart failure with reduced ejection fraction.

This study aimed to evaluate the effects of sodium-glucose cotransporter-2 inhibitors on nutritional status in patients with heart failure with reduced ejection fraction. The sodium-glucose cotransporter-2 inhibitor treatment was initiated in 153 patients with heart failure with reduced ejection fraction who were symptomatic despite optimal medical treatment and were followed up for 6 months. The Minnesota Living With Heart Failure Questionnaire scores, New York Heart Association functional class, NT-pro-BNP levels, and nutritional index scores of the patients were evaluated before sodium-glucose cotransporter-2 inhibitor treatment and at the 6-month follow-up. The nutritional status of the patients was evaluated with the COntrolling NUTritional Status score, Geriatric Nutritional Risk Index, and Prognostic Nutritional Index. After sodium-glucose cotransporter-2 inhibitor treatment, significant changes were observed in the mean scores of the three different nutritional indexes: COntrolling NUTritional Status (before: 2.76±2.43 vs. after: 1.12±1.23, p<0.001), Geriatric Nutritional Risk Index (before: 98.2±9.63 vs. after: 104.4±5.83, p<0.001), and Prognostic Nutritional Index (before: 37.9±4.63 vs. after: 42.9±3.83, p<0.001) scores. A significant decrease in the number of patients with malnutrition was observed according to the COntrolling NUTritional Status (before: 46.4% vs. after: 9.7%, p<0.001), Geriatric Nutritional Risk Index (before: 41.8% vs. after: 18.9%, p=0.006), and Prognostic Nutritional Index (before: 36.6% vs. after: 13.7%, p=0.007) scores. A significant functional improvement was observed in patients after sodium-glucose cotransporter-2 treatment: Minnesota Living With Heart Failure Questionnaire scores (before: 39.2±7.2 vs. after: 20.4±7.4, p<0.001), NT-pro-BNP levels (before: 2989±681 vs. after: 1236±760, p<0.001), and New York Heart Association class (before: class II-III: 95.5%; class IV: 4.5% vs. after: class II-III: 78%; class IV: 0%, p<0.001). In patients with heart failure with reduced ejection fraction who are symptomatic despite optimal medical treatment, the addition of an sodium-glucose cotransporter-2 inhibitor to treatment can significantly improve both the nutritional and functional statuses.

RF16 | PSUN335 Clinical Effects of Sodium Glucose Transporter Type 2 Inhibitors in Patients with Severe Insulin Resistance

Abstract Background Severe insulin resistance syndromes including lipodystrophy and pathogenic variants in the insulin receptor (INSR) lead to diabetes that is challenging to control. Oral antidiabetic agents have been used to control hyperglycemia, however the efficacy of these treatments has not been studied systematically. This study explores safety and efficacy of sodium glucose cotransporter 2 inhibitors (SGLT2i) in these patients. Methods This was a retrospective chart-review assessing safety (N=31) and efficacy (N=18) of SGLT2i use in patients with clinically or genetically confirmed diagnosis of lipodystrophy or INSR pathogenic variants at our institute. Efficacy outcomes included HbA1c, insulin dose, C-peptide, fasting insulin and 24-hour urine glucose at 12 months and throughout follow-up from 2 to 24 months. Glycemic parameters were analyzed as change from baseline (prior to SGLT2i) adjusted for baseline values after 12 months of SGLT2i and across all timepoints using linear mixed models with post-hoc Dunnett-adjusted comparison of each time point compared to baseline. For HbA1c, additional models were conducted including change in insulin dose as a covariate. Results HbA1c did not significantly change after 1 year of SGLT2i (baseline 9.5±2.5 [80.3±27.7]; 12 months 8.8±2.3% [72.6±25.3 mmol/mol]; p=0.093), or across all time points (p=0.11). However, most patients (83%) were taking insulin, and SGLT2i treatment led to 35% reduction in total daily dose of insulin after 12 months (baseline 186 [100,1010]; 12 months 120 [75,260] units/day; p=0.07) and across all visits (p=0.035), which may have mitigated the reduction in HbA1c. Reduction in HbA1c was significant after adjustment for changes in insulin dose over time (p=0.0498). No significant change was noted in C-peptide, however fasting insulin decreased after 12 months (p=0.021) and across all visits (p=0.005). Urinary glucose excretion increased greater than 5-fold after 12 months of SGLT2i, to over 80 grams per day after 1 year (p=0.04). Adverse effects occurring in &amp;gt;1 subject included hypoglycemia, fungal infections, and extremity pain. Conclusions SGLT2i reduced insulin dose, insulinemia, and insulin dose-adjusted HbA1c in patients with severe insulin resistance, with a similar safety profile compared to type 2 diabetes. SGLT2i use may lead to overall better glycemic control and should be considered as part of the treatment armamentarium for these rare forms of diabetes, but larger trials are needed to confirm these findings. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:36 p.m. - 12:41 p.m.

Effect of sacubitril/valsartan and empagliflozin on systemic inflammation and scar remodeling in a swine model of myocardial infarction

Abstract Background Angiotensin receptor neprilysin inhibitor (ARNI) and sodium glucose cotransporter 2 inhibitors (SGLT2i) lead to reduced cardiovascular death and hospitalization rates for heart failure, but mechanisms of action remain unclear. Purpose To evaluate the effect of ARNI and SLGT2i on cardiac function, systemic inflammation and scar remodeling in a porcine model of acute myocardial infarction (MI). Methods Thirty-three pigs (18 female, 15 male) with non-revascularized MI were randomized to receive treatment with beta-blocker (BB) only (BB group, n=8), empagliflozin + BB (SGLT2i group, n=8), sacubitril/valsartan + BB (ARNI group, n=9) or empagliflozin + sacubitril/valsartan + BB (SGLT2i + ARNI group, n=8) for 30 days post-MI. Cardiac function parameters were studied at 2- and 30-days post-MI by cardiac magnetic resonance imaging. The systemic immune response was analysed at baseline, 2-, 15- and 30-days post-MI to estimate 1) the absolute number of neutrophils and lymphocytes by FSC-A/SSC-A, 2) the circulating monocytes (CD172a+) and their phenotype according to CD73+, and CCR2+ expression. Animals were euthanized at 30 days, interstitial collagen and vascular density of the scar were quantified. Results Left ventricular ejection fraction (LVEF) and stoke volume (LVSV) improved in SGLT2i + ARNI group (P=0.02, P=0.002, respectively, 2 vs 30 days post-MI). Right ventricular ejection fraction (RVEF) and stroke volume (RVSV) improved in ARNI treatment arm (P=0.03; P=0.02, respectively, 2 vs 30 days post-MI). Significant increase in LV mass was only observed in BB group (P=0.02; 2 vs 30 days post-MI). SGLT2i and ARNI treatment prevented the acute increase in circulating leukocytes 2 days post-MI (P=0.0095; P=0.0091, respectively). Moreover, SGLT2i reduced the CCR2+ activated monocytes count at 15 days post-infarction (P=0.01). In contrast, the combined treatment increased the number of circulating monocytes (CD172a+) at 30 days (P=0.008). Reduced collagen I (P=0.04), and Col I/Col III ratio (P=0.02) was observed in ARNI group, and higher collagen III content (P=0.02) in SGLT2i group. Vascular density was significantly increased in SGLT2i + ARNI group (P=0.03). Conclusions SGLT2i modulates systemic inflammatory state. ARNI reduces myocardial fibrosis and improves right ventricular function. Combined treatment improves vascular density and left cardiac function in a post-MI porcine model. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Boehringer Ingelheim Spain, S.A, and Instituto de Salud Carlos III, CIBER Cardiovascular

Comparison of the blood pressure management between sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists

The cardiovascular and renal protective effects of sodium-glucose cotransporter 2 inhibitors (SGLT-2is) and glucagon-like peptide 1 receptor agonists (GLP-1Ras) are enhanced by low/controlled blood pressure (BP). However, the BP-lowering efficacy of SGLT-2is and GLP-1Ras have not been compared directly. We compared the rates of achieving target BP with SGLT-2i and GLP-1Ra treatments in Japanese patients with type 2 diabetes mellitus (T2DM). This retrospective study included 384 SGLT-2i- and 160 GLP-1Ra-treated patients with BP > 130/80 mmHg before treatment. Inverse probability weighting methods using propensity scores were used in this study. The integrated odds ratios (OR) for BP control rates were calculated and clinical changes were analyzed using a generalized linear model. SGLT-2i treatment resulted in significantly higher BP control rates than that in the GLP-1Ra treatment (integrated OR = 2.09 [1.80, 2.43]). Compared with GLP-1Ra, SGLT-2i treatment demonstrated significantly larger decreases in diastolic BP, mean arterial pressure, and body weight (− 3.8 mmHg, P = 0.006; − 4.1 mmHg, P = 0.01; and − 1.5 kg, P = 0.008, respectively) and increased annual estimated glomerular filtration rate (eGFR; 1.5 mL/min/1.73 m2/year, P = 0.04). In T2DM patients with poorly controlled BP, compared with GLP-1Ra, SGLT-2i treatment significantly improved BP management and increased eGFR.

Prevention is still the key to success.

In this issue of the journal, we publish a survey of cardiovascular disease (CVD) risk factors in patients with rheumatoid arthritis (RA) in 14 503 patients from 19 countries during 2014–2019. Dr Semb and co-workers report considerable geographical differences in estimated CVD risk and preventive treatment. Low goal attainment for lipid lowering treatment was observed, and only half of the patients obtained blood pressure goal. The authors conclude that despite a high focus on the increased CVD risk in RA patients over the last decade,1 there is still substantial potential for improvement in CVD preventive measures. In recent years, numerous cardiovascular (CV) outcomes trials have demonstrated not only CV safety but reductions in CV outcomes with two new classes of glucose lowering drugs, namely glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT-2i) in patients with type II DM.2–6 In a Danish study, Dr Nørgaard and co-workers examined CV outcomes associated with the initiation of GLP-1RA vs. SGLT-2i treatment in a real-world setting among patients with type 2 diabetes. They used a Danish nationwide registry-based cohort study included patients with type 2 diabetes with a first-ever prescription of either GLP-1RA or SGLT-2i from 2013 through 2015, with follow-up until the end of 2018. The authors concluded that in this nationwide study of patients with type 2 diabetes, initiating GLP-1RA vs. SGLT-2i was not found to be associated with significant differences in CV risk.

Impact of SGLT2 inhibitors treatment on the chronic kidney disease in people with type 2 diabetes

Diabetes is the most common cause of CKD (chronic kidney disease). CKD is also one of the most important diabetic complication. SGLT2 (sodium glucose co‐transporter‐2) inhibitors are new class of medication used to lower high blood glucose level in people with type 2 diabetes. In new researches SGLT2 inhibitors demonstrated a significant and clinically relevant reduction in the risks of albuminuria and progression of nephropathy, doubling of serum creatinine levels, and initiation of renal replacement therapy. This review focuses on the therapeutic effectiveness of using SGLT2 inhibitors for the treatment of CKD in type 2 diabetes.

Key updates to the management of type 2 diabetes in adults: how to embrace and embed the new NICE guidance

Key updates to the management of type 2 diabetes in adults: how to embrace and embed the new <scp>NICE</scp> guidance

Effect of Empagliflozin and Dapagliflozin on Ambulatory Arterial Stiffness in Patients with Type 2 Diabetes Mellitus and Cardiovascular Co-Morbidities: A Prospective, Observational Study

Background and Objectives: Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular disease. Arterial stiffness is an independent prognostic marker for cardiovascular disease development. We aimed at determining the effect of two different sodium-glucose co-transporter-2 (SGLT-2) inhibitors on ambulatory arterial stiffness in individuals with T2DM. Materials and Methods: In this single-center, single-arm, prospective study performed from January 2020 to August 2021, we planned to enroll adult subjects with T2DM and stable antidiabetic and antihypertensive treatment, assigned either to empagliflozin or dapagliflozin for 6 months. All eligible subjects underwent ambulatory blood pressure monitoring. We set as the primary efficacy outcome the change in ambulatory pulse wave velocity (PWV) from baseline to week 24. Results: We finally enrolled 46 diabetic subjects, with a mean age of 62.89 (8.53) years and mean T2DM duration of 9.72 (6.37) years. Thirty patients received dapagliflozin, while sixteen patients received empagliflozin. Due to COVID-19 pandemic restrictive measures during the study, the mean follow-up period extended from 6 months to 9.98 (3.27) months. Regarding the prespecified primary efficacy outcome, we found that the SGLT-2 inhibitor treatment did not have a significant effect on PWV (p = 0.65). Prior history of cardiovascular disease did not significantly affect the observed effects. Other indices of arterial stiffness, such as augmentation index and central pulse pressure, were not significantly affected, neither by empagliflozin nor by dapagliflozin. Conclusions: SGLT-2 inhibitor treatment with empagliflozin or dapagliflozin in subjects with T2DM failed to improve ambulatory PWV over a mean follow-up of 10 months. Registration number: ISRCTN88851713.

Liver tests and outcomes in heart failure with reduced ejection fraction: findings from DAPA-HF.

Reflecting both increased venous pressure and reduced cardiac output, abnormal liver tests are common in patients with severe heart failure and are associated with adverse clinical outcomes. We aimed to investigate the prognostic significance of abnormal liver tests in ambulatory patients with heart failure with reduced ejection fraction (HFrEF), explore any treatment interaction between bilirubin and sodium-glucose cotransporter 2 (SGLT2) inhibitors and examine change in liver tests with SGLT2 inhibitor treatment. We explored these objectives in the Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA-HF) trial, with focus on bilirubin. We calculated the incidence of cardiovascular death or worsening heart failure by bilirubin tertile. Secondary cardiovascular outcomes were examined, along with the change in liver tests at the end-of-study visit. Baseline bilirubin was available in 4720 patients (99.5%). Participants in the highest bilirubin tertile (T3) have more severe HFrEF (lower left ventricular ejection fraction, higher N-terminal pro-B-type natriuretic peptide [NT-proBNP] and worse New York Heart Association class), had a greater burden of atrial fibrillation but less diabetes. Higher bilirubin (T3 vs. T1) was associated with worse outcomes even after adjustment for other predictive variables, including NT-proBNP and troponin T (adjusted hazard ratio for the primary outcome 1.73 [95% confidence interval 1.37-2.17], p < 0.001; and 1.52 [1.12-2.07], p=0.01 for cardiovascular death). Baseline bilirubin did not modify the benefits of dapagliflozin. During follow-up, dapagliflozin had no effect on liver tests. Bilirubin concentration was an independent predictor of worse outcomes but did not modify the benefits of dapagliflozin in HFrEF. Dapagliflozin was not associated with change in liver tests. ClinicalTrials.gov NCT03036124.

Effect of SGLT-2 inhibitors on cardiac autonomic function in type 2 diabetes mellitus: a meta-analysis of randomized controlled trials.

Cardiac autonomic neuropathy (CAN) is a common complication of type 2 diabetes mellitus (T2DM). We sought to determine whether sodium-glucose co-transporter-2 (SGLT-2) inhibitors affect indices of CAN in patients with T2DM. We searched for parallel group or cross-over randomized controlled trials (RCTs) enrolling adult subjects with T2DM, assigned to a SGLT-2 inhibitor versus placebo or active comparator and addressing their effect on CAN. PubMed, Cochrane Library and gray literature sources were searched. We set as primary efficacy outcome the change in the low-frequency-to-high-frequency (LF/HF) ratio. We set as secondary efficacy outcomes: first, the change in the standard deviation of all 5min mean normal RR intervals and second, the change in the square root of the mean of the sum of the squares of differences between adjacent RR intervals (r-MSSD). Protocol has not been registered at a publicly available repository. We pooled data from four RCTs in a total of 247 subjects with T2DM. SGLT-2 inhibitor treatment did not have a significant effect on LF/HF ratio (MD = - 0.11, 95% CI - 0.35 to 0.12, I2 = 0%, p = 0.36). SGLT-2 inhibitor treatment did not have a significant impact either on SDNN (MD = - 2.83, 95% CI - 7.41 to 1.75, I2 = 31%, p = 0.23), or on r-MSSD (MD = - 0.14, 95% CI - 3.52 to 3.25, I2 = 46%, p = 0.94). Overall risk of bias was graded as low across the selected RCTs. SGLT-2 inhibitor treatment in patients with T2DM does not seem to provide any significant beneficial effect on CAN indices.

Effects of Sodium-Glucose Co-Transporter-2 Inhibition on Pulmonary Arterial Stiffness and Right Ventricular Function in Heart Failure with Reduced Ejection Fraction.

Background and Objectives: In addition to left ventricular (LV) functions, right ventricular (RV) functions and pulmonary arterial stiffness (PAS) may be adversely affected in patients with heart failure with reduced ejection fraction (HFrEF). Sodium-glucose co-transporter-2 (SGLT2) inhibitor therapy positively affects LV functions as well as having functional and symptomatic benefits in HFrEF patients. In this study, we aimed to evaluate the effects of SGLT2 inhibitor treatment on RV function and PAS in HFrEF patients. Materials and Methods: 168 HFrEF patients with New York Heart Association (NYHA) class ≥2 symptoms despite optimal medical treatment and who were started on SGLT2 inhibitor therapy were included in this retrospective study. NYHA classification, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, Minnesota Living with Heart Failure Questionnaire (MLWHFQ) scores, laboratory tests, and transthoracic echocardiography (TTE) measurements were recorded before treatment and at the end of the 6-month follow-up. Results: The mean age of the patients was 62.7 ± 11.4 years, and 38 (22.6%) were women. RV function (RV fractional area change (FAC) (33.8 ± 6.4% vs. 39.2 ± 7.3%, p < 0.001); tricuspid annular plane systolic excursion (TAPSE) (18.4 ± 3.8 mm vs. 19.6 ± 3.6 mm, p < 0.001); RV S’ (10 (8 − 13) cm/s vs. 13 (10 − 16) cm/s, p < 0.001); RV myocardial performance index (RV MPI) (0.68 ± 0.12 vs. 0.59 ± 0.11, p < 0.001); mean pulmonary artery pressure (mPAP) (39.6 ± 7.8 mmHg vs. 32 ± 6.8 mmHg, p = 0.003)) and PAS (24.2 ± 4.6 kHz/ms vs. 18.6 ± 3.1 kHz/ms, p < 0.001) values at the 6-month follow-up after SGLT2 inhibitor therapy significantly improved. It was found that SGLT2 inhibitor treatment provided significant improvement in NYHA classification, MLWHFQ scores, and NT-proBNP levels (2876 ± 401 vs. 1034 ± 361, p < 0.001), and these functional and symptomatic positive changes in HFrEF patients were significantly correlated with positive changes in LVEF, PAS, and RV functional status. Conclusions: SGLT2 inhibitor treatment results in symptomatic and functional well-being in HFrEF patients, as well as positive changes in RV function and PAS.

SGLT2 inhibitor treatment is not associated with an increased risk of osteoporotic fractures when compared to GLP-1 receptor agonists: A nationwide cohort study.

BackgroundType 2 diabetes mellitus (T2D) is associated with an increased fracture risk. It is debated whether sodium-glucose cotransporter 2 (SGLT2) inhibitors influence fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) with SGLT2 inhibitors compared to glucagon-like peptide 1 (GLP-1) receptor agonists when used as add-on therapies to metformin.MethodsWe conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either SGLT2 inhibitors or GLP-1 receptor agonists were identified and enrolled from 2012 to 2018. Subjects were then propensity-score matched 1:1 based on age, sex, and index date. Major osteoporotic fractures (MOF) were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator.ResultsIn total, 27,543 individuals treated with either combination were identified and included. After matching, 18,390 individuals were included in the main analysis (9,190 in each group). Median follow-up times were 355 [interquartile range (IQR) 126-780] and 372 [IQR 136-766] days in the SGLT2 inhibitor and GLP-1 receptor agonist group, respectively. We found a crude HR of 0.77 [95% CI 0.56-1.04] for MOF with SGLT2 inhibitors compared to GLP-1 receptor agonists. In the fully adjusted model, we obtained an unaltered HR of 0.77 [95% CI 0.56-1.05]. Results were similar across subgroup- and sensitivity analyses.ConclusionThese results suggest that SGLT2 inhibitors have no effect on fracture risk when compared to GLP-1 receptor agonists. This is in line with results from previous studies.

Mitochondrial function and oxidative stress in white adipose tissue in a rat model of PCOS: effect of SGLT2 inhibition

BackgroundPolycystic ovary syndrome (PCOS), characterized by androgen excess and ovulatory dysfunction, is associated with a high prevalence of obesity and insulin resistance (IR) in women. We demonstrated that sodium–glucose cotransporter-2 inhibitor (SGLT2i) administration decreases fat mass without affecting IR in the PCOS model. In male models of IR, administration of SGLT2i decreases oxidative stress and improves mitochondrial function in white adipose tissue (WAT). Therefore, we hypothesized that SGLT2i reduces adiposity via improvement in mitochondrial function and oxidative stress in WAT in PCOS model.MethodsFour-week-old female rats were treated with dihydrotestosterone for 90 days (PCOS model), and SGLT2i (empagliflozin) was co-administered during the last 3 weeks. Body composition was measured before and after SGLT2i treatment by EchoMRI. Subcutaneous (SAT) and visceral (VAT) WAT were collected for histological and molecular studies at the end of the study.ResultsPCOS model had an increase in food intake, body weight, body mass index, and fat mass/lean mass ratio compared to the control group. SGLT2i lowered fat mass/lean ratio in PCOS. Glucosuria was observed in both groups, but had a larger magnitude in controls. The net glucose balance was similar in both SGLT2i-treated groups. The PCOS SAT had a higher frequency of small adipocytes and a lower frequency of large adipocytes. In SAT of controls, SGLT2i increased frequencies of small and medium adipocytes while decreasing the frequency of large adipocytes, and this effect was blunted in PCOS. In VAT, PCOS had a lower frequency of small adipocytes while SGLT2i increased the frequency of small adipocytes in PCOS. PCOS model had decreased mitochondrial content in SAT and VAT without impacting oxidative stress in WAT or the circulation. SGLT2i did not modify mitochondrial function or oxidative stress in WAT in both treated groups.ConclusionsHyperandrogenemia in PCOS causes expansion of WAT, which is associated with decreases in mitochondrial content and function in SAT and VAT. SGLT2i increases the frequency of small adipocytes in VAT only without affecting mitochondrial dysfunction, oxidative stress, or IR in the PCOS model. SGLT2i decreases adiposity independently of adipose mitochondrial and oxidative stress mechanisms in the PCOS model.

SGLT2 Inhibitors: New Hope for the Treatment of Acute Myocardial Infarction?

Among all of the new antidiabetic drugs, an increasing number of studies have evaluated the relationship between the sodium-glucose cotransporter 2 inhibitors (SGLT2i) and acute myocardial infarction (AMI). Since SGLT2i like empagliflozin, canagliflozin, and recently, dapagliflozin have shown impressive positive effects in patients with chronic heart failure with reduced ejection fraction (HFrEF), it has increased research interest to explore the cardiac molecular mechanisms underlying the clinical benefits and attracted more attention to the effects of SGLT2i on a series of cardiovascular events. Experimental and clinical data on SGLT2i treatment after AMI is limited. This is a review of the clinical and preclinical effects of SGLT2i, focusing on available data on the effects of SGLT2i in AMI patients with a brief overview of ongoing trials.

Association of acute increases in serum creatinine with subsequent outcomes in patients with type 2 diabetes mellitus treated with sodium-glucose cotransporter 2 inhibitor or dipeptidyl peptidase-4 inhibitor.

The frequency of an acute increase in serum creatinine (sCr) of >30%, following treatment of sodium-glucose cotransporter-2 inhibitors (SGLT2is) and its clinical implications in patients with type 2 diabetes remains unclear. We used medical data from a multicentre health care provider in Taiwan and recruited 11 657 and 8117 diabetic patients with baseline/follow-up sCr data available within 12 weeks of SGLT2i and dipeptidyl peptidase-4 inhibitor (DPP4i) treatment from 1 June 2016 to 31 December 2018. Participants receiving SGLT2i or DPP4i were categorized by initial sCr change into three groups: >30% sCr increase, 0-30% increase, or no-sCr increase. Participants receiving SGLT2i were associated with a higher proportion of sCr increase of 0-30% (52.7 vs. 42.6%) but a lower proportion of sCr increase of >30% (5.9 vs. 9.6%) when compared with DPP4i. In contrast to DPP4i, the mean estimated glomerular filtration rate over time became stable after 24 weeks in three categories of sCr increase following SGLT2i initiation. Compared with no sCr increase, an initial sCr increase of >30% was associated with a higher risk of major adverse cardiovascular events {adjusted hazard ratio (aHR): 2.91, [95% confidence interval (95% CI):1.37-6.17]}, heart failure hospitalization (HHF) [aHR:1.91, (95% CI:1.08-3.40)], and composite renal outcome [aHR:1.53, (95% CI:1.05-2.25)] in the SGLT2i group; an initial sCr increase of >30% associated with a higher risk of HHF and composite renal outcome in the DPP4i group after multivariate adjustment. Overall, participants receiving SGLT2i were associated with a lower risk of HHF [aHR:0.64, (95% CI:0.48-0.85)] and composite renal outcomes [aHR:0.40, (95% CI:0.34-0.48)] compared with DPP4i after multivariate adjustment, and the treatment benefit was persistent across three categories of sCr increase (P interaction>0.05). A modest increase in serum creatinine (<30%) was common following SGLT2i initiation, and was not associated with worse clinical outcomes, therefore should not stop therapy prematurely, but a larger increase in creatinine following drug therapy was not typical and should raise concern and review of the patient.