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      Efficacy and Safety of Empagliflozin in Renal Transplant Recipients With Posttransplant Diabetes Mellitus

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          Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications.

          Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ≈5 mL·min(-1)·1.73 m(-2) and ≈30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate 30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus.
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            Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin.

            Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion, and weight loss is a consistent associated finding. Our objectives were to confirm weight loss with dapagliflozin and establish through body composition measurements whether weight loss is accounted for by changes in fat or fluid components. This was a 24-wk, international, multicenter, randomized, parallel-group, double-blind, placebo-controlled study with ongoing 78-wk site- and patient-blinded extension period at 40 sites in five countries. Included were 182 patients with T2DM (mean values: women 63.3 and men 58.6 yr of age; hemoglobin A1c 7.17%, body mass index 31.9 kg/m2, and body weight 91.5 kg) inadequately controlled on metformin. Dapagliflozin 10 mg/d or placebo was added to open-label metformin for 24 wk. Primary endpoint was total body weight (TBW) change from baseline at wk 24. Key secondary endpoints were waist circumference and dual-energy x-ray absorptiometry total-body fat mass (FM) changes from baseline at wk 24, and patient proportion achieving body weight reduction of at least 5% at wk 24. In a subset of patients, magnetic resonance assessment of visceral adipose tissue (VAT) and sc adipose tissue (SAT) volume and hepatic lipid content were also evaluated. At wk 24, placebo-corrected changes with dapagliflozin were as follows: TBW, -2.08 kg [95% confidence interval (CI)=-2.84 to -1.31; P<0.0001]; waist circumference, -1.52 cm (95% CI=-2.74 to -0.31; P=0.0143); FM, -1.48 kg (95% CI=-2.22 to -0.74; P=0.0001); proportion of patients achieving weight reduction of at least 5%, +26.2% (95% CI=15.5 to 36.7; P<0.0001); VAT, -258.4 cm3 (95% CI=-448.1 to -68.6; nominal P=0.0084); SAT, -184.9 cm3 (95% CI=-359.7 to -10.1; nominal P=0.0385). In the dapagliflozin vs. placebo groups, respectively, serious adverse events were reported in 6.6 vs. 1.1%; events suggestive of vulvovaginitis, balanitis, and related genital infection in 3.3 vs. 0%; and lower urinary tract infections in 6.6 vs. 2.2%. Dapagliflozin reduces TBW, predominantly by reducing FM, VAT and SAT in T2DM inadequately controlled with metformin.
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              Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity.

              The oral glucose tolerance test (OGTT) has often been used to evaluate apparent insulin release and insulin resistance in various clinical settings. However, because insulin sensitivity and insulin release are interdependent, to what extent they can be predicted from an OGTT is unclear. We studied insulin sensitivity using the euglycemic-hyperinsulinemic clamp and insulin release using the hyperglycemic clamp in 104 nondiabetic volunteers who had also undergone an OGTT. Demographic parameters (BMI, waist-to-hip ratio, age) and plasma glucose and insulin values from the OGTT were subjected to multiple linear regression to predict the metabolic clearance rate (MCR) of glucose, the insulin sensitivity index (ISI), and first-phase (1st PH) and second-phase (2nd PH) insulin release as measured with the respective clamps. The equations predicting MCR and ISI contained BMI, insulin (120 min), and glucose (90 min) and were highly correlated with the measured MCR (r = 0.80, P < 0.00005) and ISI (r = 0.79, P < 0.00005). The equations predicting 1st PH and 2nd PH contained insulin (0 and 30 min) and glucose (30 min) and were also highly correlated with the measured 1st PH (r = 0.78, P < 0.00005) and 2nd PH (r = 0.79, P < 0.00005). The parameters predicted by our equations correlated better with the measured parameters than homeostasis model assessment for secretion and resistance, the delta30-min insulin/delta30-min glucose ratio for secretion and insulin (120 min) for insulin resistance taken from the OGTT. We thus conclude that predicting insulin sensitivity and insulin release with reasonable accuracy from simple demographic parameters and values obtained during an OGTT is possible. The derived equations should be used in various clinical settings in which the use of clamps or the minimal model would be impractical.
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                Author and article information

                Journal
                Diabetes Care
                Dia Care
                American Diabetes Association
                0149-5992
                1935-5548
                May 20 2019
                June 2019
                June 2019
                March 12 2019
                : 42
                : 6
                : 1067-1074
                Article
                10.2337/dc19-0093
                30862658
                5f3df3d1-0251-4fad-a51c-c673552f4646
                © 2019

                Free to read

                http://www.diabetesjournals.org/site/license

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