Abstract
BackgroundSodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce glucose levels, body weight, and blood pressure, possibly resulting in cardiovascular protection. In phase III trials, SGLT2i were shown to increase HDL cholesterol. We aimed to evaluate whether the SGLT2i dapagliflozin affects HDL function in a randomized placebo-controlled trial.MethodsThirty-three type 2 diabetic patients were randomized to receive dapagliflozin 10 mg or placebo for 12 weeks on top of their glucose lowering medications. The primary end-point was the change in cholesterol efflux capacity (CEC) from macrophages at study end versus baseline. Secondary endpoints were changes in: distribution of HDL subfractions, lipid profile, activity of enzymes that mediate HDL antioxidant properties (PON1 and ARE) and cholesterol metabolism (CETP), HbA1c, body weight and composition.ResultsThirty-one patients completed the study, n = 16 in the placebo group and n = 15 in the dapagliflozin group. Patients randomized to dapagliflozin were older and had lower adiposity indexes, although these differences disappeared after correction for multiple testing. Therapy with dapagliflozin reduced HbA1c by 0.9% and body weight by 3.1 kg, mainly attributable to reduction of body water and lean mass. As compared to placebo, dapagliflozin reduced CEC (−6.7 ± 2.4 versus 0.3 ± 1.8%; p = 0.043), but this effect was no longer significant after adjusting for age and BMI. No change was detected in HDL cholesterol, HDL subfractions, activity of PON1, ARE, and CETP.ConclusionsDespite improvements in glucose control and reduction in body weight, therapy with dapagliflozin exerted no significant effect on HDL cholesterol levels and HDL functionality.Trial registration EudraCT 2014-004270-42; NCT02327039
Highlights
Sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce glucose levels, body weight, and blood pressure, possibly resulting in cardiovascular protection
As some glucose-lowering medications have shown to increase the risk for major adverse cardiovascular events (MACE), regulatory agencies require that all new medications demonstrate safety in the pre- and/or post-marketing phase [4], including cardiovascular outcome trials [5]
We aimed to evaluate the effects of dapagliflozin on cholesterol efflux capacity (CEC), high density cholesterol (HDL) sub-fractions, and activity of HDL-associated anti-oxidant enzymes
Summary
Sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce glucose levels, body weight, and blood pressure, possibly resulting in cardiovascular protection. In phase III trials, SGLT2i were shown to increase HDL cholesterol. As some glucose-lowering medications have shown to increase the risk for major adverse cardiovascular events (MACE), regulatory agencies require that all new medications demonstrate safety in the pre- and/or post-marketing phase [4], including cardiovascular outcome trials [5]. As glucose exerts osmotic action, glycosuria is accompanied by an increased urinary output and a reduction in blood pressure [6]. In phase III randomized clinical trials (RCTs) the SGLT2i dapagliflozin was found to reduce HbA1c by about 0.6–0.9%, body weight by about 2–3 kg, and blood pressure by about 3–5 mmHg [7]
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