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Comparison of mechanisms and transferability of outcomes of SGLT2 inhibition between type 1 and type 2 diabetes.

ABSTRACT: Diabetes mellitus (DM) is a major chronic disease with ever-increasing prevalence and a variety of serious complications for persons with DM, such as cardiovascular and/or renal complications. New glucose-lowering therapies like DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors have undergone cardiovascular outcome trials (CVOTs) for type 2 diabetes (T2DM), as by the guidance of the FDA. However, CVOTs for type 1 diabetes (T1DM) are generally lacking. Both, persons with T1DM and T2DM, are burdened with a high incidence of cardiovascular and renal disease such as atherosclerotic cardiovascular disease (ASCVD) and diabetic kidney disease (DKD). Although pathologies of the two types of diabetes cannot be compared, similar mechanisms and risk factors like sex, hyperglycaemia, hypertension, endothelial damage and (background) inflammation have been identified in the development of CVD and DKD in T1DM and T2DM. Recent CVOTs in T2DM demonstrated that SGLT-2 inhibitors, besides exerting a glucose-lowering effect, have beneficial effects on cardiovascular and renal mechanisms. These mechanisms are reviewed in detail in this manuscript and evaluated for possible transferability to, and thus efficacy in, T1DM. Our review of current literature suggests that SGLT-2 inhibitors have cardioprotective benefits beyond their glucose-lowering effects. As this mainly has been observed in CVOTs in T2DM, further investigation in the adjunctive therapy for type 1 diabetes is suggested.

SUBMITTER: Schnell O

PROVIDER: S-EPMC7375088 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Comparison of mechanisms and transferability of outcomes of SGLT2 inhibition between type 1 and type 2 diabetes.

Schnell Oliver O Valensi Paul P Standl Eberhard E Ceriello Antonio A

Endocrinology, diabetes & metabolism 20200424 3

Diabetes mellitus (DM) is a major chronic disease with ever-increasing prevalence and a variety of serious complications for persons with DM, such as cardiovascular and/or renal complications. New glucose-lowering therapies like DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors have undergone cardiovascular outcome trials (CVOTs) for type 2 diabetes (T2DM), as by the guidance of the FDA. However, CVOTs for type 1 diabetes (T1DM) are generally lacking. Both, persons with T1DM and T ...[more]

PMID: 32704554

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Project description:Background and objectivesSodium-glucose transporter 2 (SGLT2) inhibitor-induced uric acid lowering may contribute to kidney-protective effects of the drug class in people with type 2 diabetes. This study investigates mechanisms of plasma uric acid lowering by SGLT2 inhibitors in people with type 2 diabetes with a focus on urate transporter 1.Design, setting, participants, & measurementsWe conducted an analysis of two randomized clinical trials. First, in the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes study, 44 people with type 2 diabetes were randomized to dapagliflozin or gliclazide for 12 weeks. Plasma uric acid, fractional uric acid excretion, and hemodynamic kidney function were measured in the fasted state and during clamped euglycemia or hyperglycemia. Second, in the Uric Acid Excretion study, ten people with type 2 diabetes received 1 week of empagliflozin, urate transporter 1 blocker benzbromarone, or their combination in a crossover design, and effects on plasma uric acid, fractional uric acid excretion, and 24-hour uric acid excretion were measured.ResultsIn the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes study, compared with the fasted state (5.3±1.1 mg/dl), acute hyperinsulinemia and hyperglycemia significantly reduced plasma uric acid by 0.2±0.3 and 0.4±0.3 mg/dl (both P<0.001) while increasing fractional uric acid excretion (by 3.2%±3.1% and 8.9%±4.5%, respectively; both P<0.001). Dapagliflozin reduced plasma uric acid by 0.8±0.8 during fasting, 1.0±1.0 in hyperinsulinemic-euglycemic state, and 0.8±0.7 mg/dl during hyperglycemic conditions (P<0.001), respectively, whereas fractional uric acid excretion in 24-hour urine increased by 3.0%±2.1% (P<0.001) and 2.6%±4.5% during hyperinsulinemic-euglycemic conditions (P=0.003). Fractional uric acid excretion strongly correlated to fractional glucose excretion (r=0.35; P=0.02). In the Uric Acid Excretion study, empagliflozin and benzbromarone both significantly reduced plasma uric acid and increased fractional uric acid excretion. Effects of combination therapy did not differ from benzbromarone monotherapy.ConclusionsIn conclusion, SGLT2 inhibitors induce uric acid excretion, which is strongly linked to urinary glucose excretion and is attenuated during concomitant pharmacologic blockade of urate transporter 1.Clinical trial registry name and registration numberRenoprotective Effects of Dapagliflozin in Type 2 Diabetes (RED), NCT02682563; SGLT2 Inhibition: Uric Acid Excretion Study (UREX), NCT05210517.

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Comparison of mechanisms and transferability of outcomes of SGLT2 inhibition between type 1 and type 2 diabetes.

Publications

Comparison of mechanisms and transferability of outcomes of SGLT2 inhibition between type 1 and type 2 diabetes.

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