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      Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: evidence to date

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          Abstract

          Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the latest therapeutic strategy in the treatment of type 2 diabetes mellitus (T2DM). Using an insulin-independent mechanism (glycosuria), they reduce glucose toxicity and improve insulin sensitivity and β-cell function. The promising results obtained in clinical trials show that SGLT2 significantly improves glycemic control and provides greater cardiovascular protection, combined with a reduction in body weight and blood pressure (BP). This review focuses on ertugliflozin, a new, highly selective, and reversible SGLT2 inhibitor. Clinical trials published to date show that ertugliflozin, both as a monotherapy and as an add-on to oral antidiabetic agents, is safe and effective in reducing glycosylated hemoglobin (HbA1c), body weight, and BP in T2DM patients.

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          Most cited references 54

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          The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease.

          In recent years, the focus of interest on the role of the renin-angiotensin system (RAS) in the pathophysiology of hypertension and organ injury has changed to a major emphasis on the role of the local RAS in specific tissues. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by independent multiple mechanisms. Proximal tubular angiotensinogen, collecting duct renin, and tubular angiotensin II type 1 (AT1) receptors are positively augmented by intrarenal Ang II. In addition to the classic RAS pathways, prorenin receptors and chymase are also involved in local Ang II formation in the kidney. Moreover, circulating Ang II is actively internalized into proximal tubular cells by AT1 receptor-dependent mechanisms. Consequently, Ang II is compartmentalized in the renal interstitial fluid and the proximal tubular compartments with much higher concentrations than those existing in the circulation. Recent evidence has also revealed that inappropriate activation of the intrarenal RAS is an important contributor to the pathogenesis of hypertension and renal injury. Thus, it is necessary to understand the mechanisms responsible for independent regulation of the intrarenal RAS. In this review, we will briefly summarize our current understanding of independent regulation of the intrarenal RAS and discuss how inappropriate activation of this system contributes to the development and maintenance of hypertension and renal injury. We will also discuss the impact of antihypertensive agents in preventing the progressive increases in the intrarenal RAS during the development of hypertension and renal injury.
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            Sodium-Glucose Cotransport Inhibition With Dapagliflozin in Type 2 Diabetes

            OBJECTIVE Dapagliflozin, a novel inhibitor of renal sodium-glucose cotransporter 2, allows an insulin-independent approach to improve type 2 diabetes hyperglycemia. In this multiple-dose study we evaluated the safety and efficacy of dapagliflozin in type 2 diabetic patients. RESEARCH DESIGN AND METHODS Type 2 diabetic patients were randomly assigned to one of five dapagliflozin doses, metformin XR, or placebo for 12 weeks. The primary objective was to compare mean change from baseline in A1C. Other objectives included comparison of changes in fasting plasma glucose (FPG), weight, adverse events, and laboratory measurements. RESULTS After 12 weeks, dapagliflozin induced moderate glucosuria (52–85 g urinary glucose/day) and demonstrated significant glycemic improvements versus placebo (ΔA1C −0.55 to −0.90% and ΔFPG −16 to −31 mg/dl). Weight loss change versus placebo was −1.3 to −2.0 kg. There was no change in renal function. Serum uric acid decreased, serum magnesium increased, serum phosphate increased at higher doses, and dose-related 24-h urine volume and hematocrit increased, all of small magnitude. Treatment-emergent adverse events were similar across all groups. CONCLUSIONS Dapagliflozin improved hyperglycemia and facilitates weight loss in type 2 diabetic patients by inducing controlled glucosuria with urinary loss of ∼200–300 kcal/day. Dapagliflozin treatment demonstrated no persistent, clinically significant osmolarity, volume, or renal status changes.
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              Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin.

              Dapagliflozin, a highly selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycaemia and weight in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. Long-term glycaemic control, body composition and bone safety were evaluated in patients with T2DM after 102 weeks of dapagliflozin treatment.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2017
                03 October 2017
                : 11
                : 2905-2919
                Affiliations
                Center for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario A Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
                Author notes
                Correspondence: Andrea Giaccari, Center for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario A Gemelli, Università Cattolica del Sacro Cuore, Largo A Gemelli 8, 00168 Rome, Italy, Tel +39 06 3015 7094, Email andrea.giaccari@ 123456unicatt.it
                [*]

                These authors contributed equally to this work

                Article
                dddt-11-2905
                10.2147/DDDT.S114932
                5633300
                © 2017 Cinti et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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