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Renal effects of dapagliflozin in patients with type 2 diabetes.

ABSTRACT: Diabetes mellitus was originally conceived as a renal disorder. In the last decade, however, there has been renewed interest in role of the kidney in the development and maintenance of high glucose levels. This has led to the development of novel agents to inhibit sodium glucose transporter-2 (SGLT2) as a means to better control glucose levels and at the same time augment calorie wasting and lower insulin, blood pressure and uric acid levels. Such actions, indirectly, may also have benefits for the prevention of diabetic complications including renal disease. However, there are also data to support the potential for direct renoprotective actions arising from inhibition of SGLT2, including actions to attenuate diabetes-associated hyperfiltration and tubular hypertrophy, as well as reduce the tubular toxicity of glucose. Some studies have demonstrated significant reductions in albumin excretion in various experimental models, independent of its effects on blood pressure or glucose control. Although promising, such actions remain to be established by comprehensive clinical trials with a renal focus, many of which are currently in progress. This article reviews the clinical and experimental data pertaining to the renal effects of SGLT2 inhibition with a particular focus on dapaglifozin.

SUBMITTER: Thomas MC

PROVIDER: S-EPMC4132377 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Renal effects of dapagliflozin in patients with type 2 diabetes.

Thomas Merlin C MC

Therapeutic advances in endocrinology and metabolism 20140601 3

Diabetes mellitus was originally conceived as a renal disorder. In the last decade, however, there has been renewed interest in role of the kidney in the development and maintenance of high glucose levels. This has led to the development of novel agents to inhibit sodium glucose transporter-2 (SGLT2) as a means to better control glucose levels and at the same time augment calorie wasting and lower insulin, blood pressure and uric acid levels. Such actions, indirectly, may also have benefits for ...[more]

PMID: 25126408

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Project description:Dapagliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor approved as a treatment for type 2 diabetes mellitus (T2DM) in the United States, the European Union and other countries. Dapagliflozin increases renal glucose excretion in an insulin-independent manner, and its mechanism of action is complementary to those of other antidiabetes medications. When used as monotherapy or in combination with other oral antidiabetes medications or insulin, dapagliflozin improves glycemic measures in patients with T2DM. Dapagliflozin treatment is also associated with weight reduction and a decrease in blood pressure, both of which may be beneficial in patients with T2DM. Because of its mechanism of action, dapagliflozin has a low intrinsic propensity to cause hypoglycemia. Overall, dapagliflozin is well tolerated, with the frequency of most adverse events similar to that seen with placebo. Cases of genital infections and, in some studies, urinary tract infections have been more frequent in dapagliflozin-treated groups compared with placebo groups. In the clinical development program, more cases of newly diagnosed bladder cancer were reported for patients treated with dapagliflozin (0.17%) compared with placebo or comparator (0.03%). Although there were not enough cases to determine causality, dapagliflozin should not be used in patients with bladder cancer and should be used with caution in patients with a history of bladder cancer. Dapagliflozin may decrease glomerular filtration rate (GFR), especially in elderly patients and patients with impaired renal function. Renal function should be monitored before initiation of dapagliflozin. Dapagliflozin should not be used in patients with an estimated GFR <60 ml/min/1.73 m(2). No cardiovascular safety signals have been detected for dapagliflozin, and a long-term cardiovascular outcomes study is ongoing. Evidence from clinical trials suggests that dapagliflozin is a promising new treatment option for T2DM.

Project description:A pre-specified meta-analysis of cardiovascular (CV) events from 21 phase 2b/3 dapagliflozin clinical trials was undertaken to characterise the CV profile of dapagliflozin. This showed no increase in CV risk with dapagliflozin compared with control (placebo or comparator treatment) with or without background glucose-lowering therapies. The analysis reported here aimed to characterise the CV profile of dapagliflozin in subgroups of patients in these 21 studies grouped by degree of CV risk, based on both baseline and in-study risk factors (including hypoglycaemic events), with a focus on major adverse CV events (MACE).Patients with type 2 diabetes, both overall and with different levels of CV risk, including CV disease (CVD) history, age and other CV risk factors, were analysed. A further analysis compared CV risk in patients who experienced a hypoglycaemic event prior to MACE and those who did not. Analyses were based on time to first event using a Cox proportional hazards model stratified by study comparing dapagliflozin versus control.In total, 9339 patients were included in this meta-analysis; 5936 patients received dapagliflozin 2.5-10 mg (6668 patient-years) and 3403 received control (3882 patient-years). Dapagliflozin is not associated with increased CV risk and results further suggest the potential for a beneficial effect both in the overall population [Hazard Ratio (HR) 0.77; 95 % CI (0.54, 1.10) for MACE] and in those with a history of CVD [HR 0.80 (0.53, 1.22)]. These findings were consistent in patients with varying degrees of CV risk, including age, number and type of CVD events in medical history and number of CV risk factors present. Furthermore, there was no increased risk of MACE in patients who experienced a hypoglycaemic event compared with those who did not.There was no suggestion of increased risk for MACE with dapagliflozin compared with control in any of the populations investigated. In addition, the results suggest the potential for a beneficial CV effect which is consistent with the multifactorial benefits on CV risk factors associated with sodium-glucose cotransporter-2 (SGLT2) inhibitors.

Project description:ObjectiveSGLT2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes; the underlying mechanism may be metabolic adaptations due to urinary glucose loss. Here, we investigated the cellular and molecular effects of 5 weeks of dapagliflozin treatment on skeletal muscle metabolism in type 2 diabetes patients.MethodsTwenty-six type 2 diabetes mellitus patients were randomized to a 5-week double-blind, cross-over study with 6-8-week wash-out. Skeletal muscle acetylcarnitine levels, intramyocellular lipid (IMCL) content and phosphocreatine (PCr) recovery rate were measured by magnetic resonance spectroscopy (MRS). Ex vivo mitochondrial respiration was measured in skeletal muscle fibers using high resolution respirometry. Intramyocellular lipid droplet and mitochondrial network dynamics were investigated using confocal microscopy. Skeletal muscle levels of acylcarnitines, amino acids and TCA cycle intermediates were measured. Expression of genes involved in fatty acid metabolism were investigated.ResultsMitochondrial function, mitochondrial network integrity and citrate synthase and carnitine acetyltransferase activities in skeletal muscle were unaltered after dapagliflozin treatment. Dapagliflozin treatment increased intramyocellular lipid content (0.060 (0.011, 0.110) %, p = 0.019). Myocellular lipid droplets increased in size (0.03 μm2 (0.01-0.06), p < 0.05) and number (0.003 μm-2 (-0.001-0.007), p = 0.09) upon dapagliflozin treatment. CPT1A, CPT1B and malonyl CoA-decarboxylase mRNA expression was increased by dapagliflozin. Fasting acylcarnitine species and C4-OH carnitine levels (0.4704 (0.1246, 0.8162) pmoles∗mg tissue-1, p < 0.001) in skeletal muscle were higher after dapagliflozin treatment, while acetylcarnitine levels were lower (-40.0774 (-64.4766, -15.6782) pmoles∗mg tissue-1, p < 0.001). Fasting levels of several amino acids, succinate, alpha-ketoglutarate and lactate in skeletal muscle were significantly lower after dapagliflozin treatment.ConclusionDapagliflozin treatment for 5 weeks leads to adaptive changes in skeletal muscle substrate metabolism favoring metabolism of fatty acid and ketone bodies and reduced glycolytic flux. The trial is registered with ClinicalTrials.gov, number NCT03338855.

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Renal effects of dapagliflozin in patients with type 2 diabetes.

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Renal effects of dapagliflozin in patients with type 2 diabetes.

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