Umanath K., Lewis J.B. Update on Diabetic Nephropathy: Core Curriculum 2018. 2023 May 31;15(1):113. doi: 10.1186/s13098-023-01085-y. [104] proved that neither empagliflozin, canagliflozin nor dapagliflozin was associated with increased risk of all-cause mortality and cardiovascular outcomes when used to treat patients with T2DM. In addition, its use reduced HFrEF hospitalizations as well as cardiovascular deaths [18,19]. Nassif M.E., Windsor S.L., Borlaug B.A., Kitzman D.W., Shah S.J., Tang F., Khariton Y., Malik A.O., Khumri T., Umpierrez G., et al. After 18 days of therapy with empagliflozin, the benefits reached statistical significance and remained significant thereafter. 1). and E.M.; Software: E.M.; Validation: E.M., B.F. and J.R.; Formal analysis: J.F., J.H., J.K., P.W., M.W. -, Alvarez Guisasola F, Mavros P, Nocea G, Alemao E, Alexander CM, Yin D. Glycaemic control among patients with type 2 diabetes mellitus in seven European countries: findings from the Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) study. [71] The aim of their study was to investigate the effect of empagliflozin on myocardium injury and the potential mechanism in type 2 diabetic KK-Ay mice. This research started rapid growth in exploration for more possible benefits of this drug group and changed the recommendations for treating DM and HF [66]. The analyses were performed for HbA1c, FPG, body weight, waist circumference, SBP, and DBP on the full analysis set (all randomized patients who were treated with at least one dose of study drug and had a baseline HbA1c assessment). 2014 May;2(5):369-84. doi: 10.1016/S2213-8587(13)70208-0. If further control of glycemia is needed in patients with T2DM and coexisting renal impairment, the addition of other anti-hyperglycemic agents should be considered. In this extension trial, the proportion of patients with at least one AE in empagliflozin groups was similar to that with metformin and sitagliptin as add-on to metformin. Epub 2014 Jun 16. SGLT2 is the main transporter responsible for the reabsorption of glucose from the glomerular filtrate and represents a novel target in the treatment of T2DM [5]. Search for other works by this author on: Fate of the beta-cell in the pathophysiology of type 2 diabetes, Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. A post hoc analysis of a long-term randomized trial analyzed the differences that occur in patients receiving dapagliflozin in doses of 5 mg and 10 mg versus those on placebo. Kohan D.E., Fioretto P., Tang W., List J.F. In addition, treatment is often complicated by common comorbidities of type 2 diabetes such as obesity and hypertension, which are not addressed by existing oral antidiabetes agents (57). Potential SGLT2 inhibitor benefits in heart failure [67]. The baseline for these analyses was defined as the last observed measurement before the first administration of the study drug in study 1 or study 2. Diabetic kidney disease: A clinical update from Kidney Disease: Improving Global Outcomes. Tuttle K.R., Levin A., Nangaku M., Kadowaki T., Agarwal R., Hauske S.J., Elser A., Ritter I., Steubl D., Wanner C., et al. [55] in 2022, the use of empagliflozin in patients with T2DM and advanced CKD found no overall differences in rates of serious adverse events, adverse events leading to the discontinuation or events of special interest with empagliflozin treatment versus placebo with an exception of genital infections [55]. However, a meta-analysis by Jiang et al. contributed to the study design and interpretation of data and reviewed and edited the manuscript. In comparison, the DAPA-HF study dapagliflozin reduced the primary outcome (composite of worsening HF (hospitalization or an urgent visit resulting in intravenous therapy for HF) or cardiovascular death) occurrence (HR, 0.74; 95% CI, 0.65 to 0.85; p < 0.001) and significantly decreased cardiovascular mortality (HR, 0.82; 95% CI, 0.690.98) in patients with HFrEF. Patients in the empagliflozin group after receiving SGLT2 inhibitor were 20% to 50% more likely to have better NYHA class than placebo patients. Figtree G.A., Rdholm K., Barrett T.D., Perkovic V., Mahaffey K.W., De Zeeuw D., Fulcher G., Matthews D.R., Shaw W., Neal B. In a subsequent study by Cherney et al. Potential mechanisms of these interactions are presented in Figure 3 [67]. The efficacy and tolerability of empagliflozin added to pioglitazone was assessed in the EMPA-REG PIO studies (88,89). In comparison, the results of the SOLOIST-WHT Trial diarrhea were more common in the sotagliflozin group than in the placebo group (6.1% vs. 3.4%), as was severe hypoglycemia (1.5% vs. 0.3%) [82,90,91]. Kato E., Silverman M.G., Mosenzon O., Zelniker T.A., Cahn A., Furtado R.H.M., Kuder J., Murphy S.A., Bhatt D.L., Leiter L.A., et al. This study showed that the beneficial effects of empagliflozin on HF outcomes in this patient group are independent of the health status impairment at baseline. The efficacy results were similar between patients with pioglitazone alone as background therapy and patients whose background therapy was pioglitazone plus metformin. Women in particular are at risk for both conditions [23,25]. A meta-analysis. Wrbel M., Rokicka D., Strojek K. FlozinsIn the light of the latest recommendations. Similar conclusions can be drawn when analyzing the effect of SGLT2 inhibitors on cardiovascular mortalityempagliflozin has been shown to be more effective than canagliflozin and dapagliflozin [102]. Stanton R.C. In study 2, patients on stable metformin background therapy were randomized to receive 1, 5, 10, 25, or 50 mg empagliflozin qd, placebo (all double blind), or open-label sitagliptin (100 mg qd) for 12 weeks. Hematocrit and hemoglobin levels significantly increased in the empagliflozin group but not in the sitagliptin group. The main hallmarks of CKD are reduced GFR and increased urinary albumin excretion. Reductions in blood pressure were not associated with increases in heart rate (data not shown). The most frequently reported AEs (by preferred term) were hyperglycemia (11.321.7% of patients on empagliflozin, 14.3% on metformin only, and 19.6% on sitagliptin as add-on to metformin), nasopharyngitis (7.29.4% of patients on empagliflozin, 16.1% on metformin only, and 8.9% on sitagliptin as add-on to metformin), and urinary tract infection (2.810.8% of patients on empagliflozin, 1.8% on metformin only, and 8.9% on sitagliptin as add-on to metformin). The site is secure. -, Inzucchi SE, Bergenstal RM, Buse JB, et al. A.B. The conclusion of the EMPEROR-Reduced study is that empagliflozin should be used in HF patients with HFrEF and CKD. A Safety Evaluation of Empagliflozin for the Treatment of Type 2 Diabetes. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Ndefo U.A., Anidiobi N.O., Basheer E., Eaton A.T. Empagliflozin (Jardiance): A Novel SGLT2 Inhibitor for the Treatment of Type-2 Diabetes. They noted that after 24 weeks of empagliflozin administration, UACR values decreased significantly compared to the placebo group. Consequently, the use of empagliflozin in patients resulted in a significant relative risk reduction in developing or worsening nephropathy of 39% compared to the placebo group [45]. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. The comparisons between empagliflozin and sitagliptin were only exploratory in nature and do not allow firm conclusions to be made about the comparative efficacy of these drugs. Jiang Y., Yang P., Fu L., Sun L., Shen W., Wu Q. These factors are probably involved in stiffening and decreasing myocardial performance. Careers. Molitch M.E., Adler A.I., Flyvbjerg A., Nelson R.G., So W.-Y., Wanner C., Kasiske B.L., Wheeler D.C., de Zeeuw D., Mogensen C.E. Moreover, in those studies, sex has no proven influence on EF [74,75,76]. Wanner C., Inzucchi S.E., Lachin J.M., Fitchett D., Von Eynatten M., Mattheus M., Johansen O.E., Woerle H.J., Broedl U.C., Zinman B., et al. When it comes to adverse reaction, canagliflozin has an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; HR, 1.97; 95% CI, 1.41 to 2.75) primarily at the level of the toe or metatarsal [31,82,86,87]. Neither empagliflozi, canagliflozin nor dapagliflozin was associated with increased risk of all-cause mortality and CV outcomes. All patients provided signed and dated informed consent prior to participation in the extension study. In a pooled analysis of placebo-controlled clinical trials made by Tuttle et al. Summarizing the results and data from these two studies, the reduction in both time to first HF hospitalization and total (first and recurrent) HF hospitalization was similar (by 2535%) in the range of <25% to <65% of patients EF. However, this is not the only result that became statistically significant in the first month of the trial. Epub 2014 Jan 30. It is also not recommended to use the drug during the 2nd and 3rd trimesters of pregnancy and in a group of people over 85 years of age [23,25]. Cherney D., Lund S.S., Perkins B.A., Groop P.-H., Cooper M.E., Kaspers S., Pfarr E., Woerle H.J., von Eynatten M. The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes. Comparing the other SGLT2 inhibitors with the mentioned data, dapagliflozin should not be administered in patients whose eGFR is below 60 mL/min/1.73 m2 [56], in the case of canagliflozin at an eGFR below 45 mL/min/1.73 m2. Another known SGLT2 inhibitor is canagliflozin. Fat accumulation also results in impaired glucose tolerance, dyslipidemia and hypertension due to fat accumulation in the liver and skeletal muscles. Long-term empagliflozin treatment provided sustained glycemic and weight control and was well tolerated with a low risk of hypoglycemia in patients with type 2 diabetes. Empagliflozin is more effective than canagliflozin and dapagliflozin in reducing cardiovascular events and all-cause mortality. The number of patients included in the analysis, after PS matching, was 16,443 for each treatment arm . As a library, NLM provides access to scientific literature. Effect of Empagliflozin on the Clinical Stability of Patients with Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial. Afterwards, the sodium is returned to the bloodstream by the adenosine triphoshatase-mediated sodiumpotassium pump and glucose diffuses to the basolateral glucose transporter 2, through which it passes back into the bloodstream [12]. The risk of doubling plasma creatinine levels was 44% reduced in the empagliflozin group, and the relative risk of starting RRT was significantly 55% lower. In the same group, a decrease in glomerular filtration rate (GFR) was observed only at the beginning of the study, after which it remained stable, compared to the placebo group, in which GFR levels successively decreased. The EMPA-REG OUTCOME trial has provided evidence that SGLT2 inhibitors could become one of the most important drugs in the treatment of HF. Throughout the years, other studies have also appeared to evaluate renal parameters in patients receiving empagliflozin. The reduction of BW by 25 mg empagliflozin was reported to be greater than that caused by 10 mg empagliflozin, but unlike the above report, the difference was not significant [25 mg vs. 10 mg: effect size 0.11 kg; 95%CI 0.38 to 0.15)] . Heerspink H.J.L., Stefnsson B.V., Correa-Rotter R., Chertow G.M., Greene T., Hou F.-F., Mann J.F.E., McMurray J.J.V., Lindberg M., Rossing P., et al. Events consistent with urinary tract infection (based on a special search of MedDRA preferred terms) were reported in 3.86.4% of patients on empagliflozin monotherapy, 3.6% on metformin monotherapy, 9.012.7% on empagliflozin as add-on to metformin, and 12.5% on sitagliptin as add-on to metformin. Mean SE change from baseline in efficacy variables over 90 weeks in patients who received 10 mg empagliflozin, 25 mg empagliflozin, or metformin IR in study 1 or 10 mg empagliflozin, 25 mg empagliflozin, or sitagliptin as add-on to metformin in study 2 without rerandomization at the start of the extension trial. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Gonzalez D.E., Foresto R.D., Ribeiro A.B. This is not a complete list of side effects and others may occur. Epub 2017 Jun 27. On the contrary, SGLT1 can be expressed in the intestines, heart, skeletal muscle [4], as well as in the proximal tubule segment responsible for only 10% of glucose reabsorption [2]. Neal B., Perkovic V., Mahaffey K.W., de Zeeuw D., Fulcher G., Erondu N., Shaw W., Law G., Desai M., Matthews D.R., et al. Furthermore, patients with DM had a worse NYHA class but at the same time lower levels of N-terminal pro b-type natriuretic peptide (NT-proBNP) than those without DM, which may be explained by the association of obesity with lower natriuretic peptide levels and by the lower prevalence of atrial fibrillation (AF) in diabetic patients compared with those without DM. Metformin is the recommended first-line antidiabetes agent for patients with type 2 diabetes (2). The empagliflozin group had greater improvement in all key KCCQ domains, including Total Symptom Score (TSS), physical limitations (PLS), quality of life (QoL), clinical summary score (CSS), and overall summary score (OSS) at last assess (placebo-adjusted mean differences [95% CI]: 4.45 [95% CI, 0.328.59], p = 0.03; 4.80 [95% CI, 0.009.61], p = 0.05; 4.66 [95% CI, 0.329.01], p = 0.04; 4.85 [95% CI, 0.778.92], p = 0.02; and 4.40 [95% CI, 0.338.48], p = 0.03, respectively), and this improvement was present from the 15th day until the end of the trial. Metab. Epub 2022 Nov 24. View all 316 reviews. 2). Terauchi Y., Utsunomiya K., Yasui A., Seki T., Cheng G., Shiki K., Lee J. 2023 Apr 10;59(4):742. doi: 10.3390/medicina59040742. In a Phase 3 trial of empagliflozin as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with T2DM by Kovacs et al. Call your doctor for medical advice about side effects. 2013 by the American Diabetes Association. ; Writingreview and editing: E.M.; Visualization: J.F., J.H., J.K., P.W., M.W. Anders H.-J., Huber T.B., Isermann B., Schiffer M. CKD in diabetes: Diabetic kidney disease versus nondiabetic kidney disease. Until now, we have examined five SGLT2 inhibitors in terms of HF: empagliflozin, dapagliflozin, canagliflozin, ertugliflozin and the most recent sotagliflozin. Integr. In a study performed by Rosenstock at al., empagliflozin caused an improvement of glycemic control and weight reduction in obese patients with T2DM with inadequate control on high multiple dose insulin without increasing the risk of hypoglycemia and with lower insulin requirements [93]. Most AEs were mild or moderate in intensity. Reduced sodium concentration reaches the macula densa and, via tubuloglomerular feedback, activation of the reninangiotensinaldosterone system occurs. 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