SOdium-glucose CO-transporter inhibition in patients with newly detected Glucose Abnormalities and a recent Myocardial Infarction (SOCOGAMI).

AIMS/HYPOTHESIS: Established dysglycaemia (impaired glucose tolerance [IGT] or type 2 diabetes [T2DM]) is a risk factor for further cardiovascular events in patients with coronary artery disease. Sodium-glucose cotransporter 2 inhibitors reduce this risk. The aim of the present investigation was to test the hypothesis that empagliflozin exerts beneficial effects on myocardial function in patients with a recent acute coronary syndrome and newly detected dysglycaemia. METHODS: Forty-two patients (mean age 67.5 years, 81 % male) with recent myocardial infarction (n = 36) or unstable angina (n = 6) and newly detected IGT (n = 27) or T2DM (n = 15) were randomised to 25 mg of empagliflozin daily (n = 20) or placebo (n = 22) on top of ongoing therapy. They were investigated with oral glucose tolerance tests, stress-perfusion cardiac magnetic resonance imaging (CMR) and echocardiography at three occasions: before randomisation, after seven months on study drug and three months following cessation of such drug. Primary outcome was a change in left ventricular (LV) end-diastolic volume (LVEDV) and secondary outcomes were a change in a) systolic and diastolic LV function; b) coronary flow reserve; c) myocardial extracellular volume (ECV) in non-infarcted myocardium; d) aortic pulse wave velocity. RESULTS: Empagliflozin induced a significant decrease in fasting and post load glucose (p < 0.05) and body weight (p < 0.01). Empagliflozin did not influence LVEDV, LV systolic or mass indexes, coronary flow reserve, ECV or aortic pulse wave velocity. Echocardiographic indices of LV diastolic function (E/e' and mitral E/A ratio) were not influenced. No safety concerns were identified. CONCLUSIONS/INTERPRETATION: Empagliflozin had predicted effects on the dysglycaemia but did not influence variables expressing LV function, coronary flow reserve and ECV. An explanation may be that the LV function of the patients was within the normal range.

High released lactate by epicardial fat from coronary artery disease patients is reduced by dapagliflozin treatment.

BACKGROUND AND AIMS: Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, improves glucose uptake by epicardial adipose tissue (EAT). However, its metabolism might raise the lactate production and acidosis under hypoxia conditions, i.e. coronary artery disease (CAD), or lipogenesis and, in consequence, expand adipose tissue. Since lactate secreted by adipose tissue is correlated with tissue stress and inflammation, our aim was to study glucose metabolism by epicardial fat in CAD and its regulation by dapagliflozin. METHODS: Paired EAT and subcutaneous adipose tissue (SAT) biopsies from 49 patients who underwent open-heart surgery were cultured and split into three equal pieces, some treated with and others without dapagliflozin at 10 or 100 µM for 6 h. Anaerobic glucose metabolites were measured in supernatants of fat pads, and acidosis on adipogenesis-induced primary culture cells was analysed by colorimetric or fluorescence assays. Gene expression levels were assessed by real-time polymerase chain reaction. RESULTS: Our results showed that dapagliflozin reduced the released lactate and acidosis in epicardial fat (p < 0.05) without changes in lipid storage-involved genes. In addition, this drug induced gene expression levels of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α), a mitochondrial biogenesis-involved gene in both EAT and SAT (p < 0.05). After splitting the population regarding the presence of CAD, we observed higher lactate production in EAT from these patients (2.46 [1.75-3.47] mM), which was reduced after treatment with dapagliflozin 100 µM (1.99 [1.08-2.99] mM, p < 0.01). CONCLUSIONS: Dapagliflozin improved glucose metabolism without lipogenesis-involved gene regulation or lactate production, mainly in patients with CAD. These results suggest an improvement of glucose oxidation metabolism that can contribute to cardiovascular benefits.

Efficacy of dapagliflozin as an adjunct therapy in patients with inadequately controlled type 1 diabetes mellitus.

INTRODUCTION: There is a clear unmet clinical need in people with Type 1 diabetes (T1DM) considering present day insulin therapy. New insulin analogues and novel technologies allowing more tailored insulin administration have improved the quality of life of people with T1DM, but issues like hypoglycemia, weight gain and variability in glucose profiles remain problematic. Areas covered: In this review, the clinical efficacy, safety and tolerability of dapagliflozin, a sodium-glucose cotransporter type 2 inhibitor, in type 1 diabetes (T1DM) is described based on a review of phase 2 and 3 studies to date. Expert opinion: Dapagliflozin has shown promising results as an adjunct therapy in T1DM, resulting in better glucose control, weight loss and lower blood pressure. No increase in hypoglycemia risk, in particular severe hypoglycemia, was observed, but, in comparison with reports in Type 2 diabetes (T2DM), genital infections were more prevalent. Dapagliflozin use was accompanied with decreases in insulin doses, but, to date, only a low risk of diabetic ketoacidosis (DKA) was reported. However, caution is needed when interpreting this data, arising from well controlled clinical trials, with intensive education programs around ketone measurements and DKA prevention. Further studies will need to establish how high the DKA risk is and how to mitigate this in a real-world setting.

Increased sugar intake as a form of compensatory hyperphagia in patients with type 2 diabetes under dapagliflozin treatment.

AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) cause substantially less weight loss than would be expected based on their caloric deficits, probably due to enhanced appetite regulation known as "compensatory hyperphagia," which occurs to offset the negative energy balance caused by increased glycosuria. We examined whether any specific nutrients contributed to the compensatory hyperphagia in diabetic patients taking SGLT2i. METHODS: Sixteen patients with type 2 diabetes were newly administered dapagliflozin 5 mg daily as the experimental SGLT2i group. Sixteen age-, sex- and BMI-matched type 2 diabetes patients not receiving dapagliflozin served as controls. A brief-type self-administered diet history questionnaire (BDHQ) was undertaken just before and 3 months after study initiation to evaluate changes of energy and nutrient intakes in each group. RESULTS: At 3 months, daily intakes of total calories and the proportions of the three major nutrients were not significantly increased in either group. However, daily sucrose intake was significantly increased after treatment versus the baseline value in the SGLT2i group (p = .003), but not in controls. The calculated intakes of all other nutrients were not significantly changed in either group. CONCLUSIONS: Dapagliflozin treatment specifically increased sucrose intake, which might be an ideal target for nutritional approaches to attenuate compensatory hyperphagia.

Dapagliflozin-lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice.

BACKGROUND AND PURPOSE: Hyperglycaemia increases glucose concentrations in airway surface liquid and increases the risk of pulmonary Pseudomonas aeruginosa infection. We determined whether reduction of blood and airway glucose concentrations by the anti-diabetic drug dapagliflozin could reduce P. aeruginosa growth/survival in the lungs of diabetic mice. EXPERIMENTAL APPROACH: The effect of dapagliflozin on blood and airway glucose concentration, the inflammatory response and infection were investigated in C57BL/6J (wild type, WT) or leptin receptor-deficient (db/db) mice, treated orally with dapagliflozin prior to intranasal dosing with LPS or inoculation with P. aeruginosa. Pulmonary glucose transport and fluid absorption were investigated in Wistar rats using the perfused fluid-filled lung technique. KEY RESULTS: Fasting blood, airway glucose and lactate concentrations were elevated in the db/db mouse lung. LPS challenge increased inflammatory cells in bronchoalveolar lavage fluid from WT and db/db mice with and without dapagliflozin treatment. P. aeruginosa colony-forming units (CFU) were increased in db/db lungs. Pretreatment with dapagliflozin reduced blood and bronchoalveolar lavage glucose concentrations and P. aeruginosa CFU in db/db mice towards those seen in WT. Dapagliflozin had no adverse effects on the inflammatory response in the mouse or pulmonary glucose transport or fluid absorption in the rat lung. CONCLUSION AND IMPLICATIONS: Pharmacological lowering of blood glucose with dapagliflozin effectively reduced P. aeruginosa infection in the lungs of diabetic mice and had no adverse pulmonary effects in the rat. Dapagliflozin has potential to reduce the use, or augment the effect, of antimicrobials in the prevention or treatment of pulmonary infection.

Dapagliflozin: a review of its use in type 2 diabetes mellitus.

Dapagliflozin (Forxiga®) is the first in a novel class of glucose-lowering agents known as sodium-glucose co-transporter-2 (SGLT2) inhibitors and is used in the treatment of patients with type 2 diabetes. By inhibiting the transporter protein SGLT2 in the kidneys, dapagliflozin reduces renal glucose reabsorption, leading to urinary glucose excretion and a reduction in blood glucose levels. Unlike oral antidiabetic drugs from several other classes, the efficacy of dapagliflozin is independent of insulin secretion and action. Therefore, when used in combination with other antidiabetic drugs, dapagliflozin provides complementary therapy via its unique mechanism of action. A consistent finding across phase III, randomized, double-blind trials in patients with inadequately controlled type 2 diabetes was that dapagliflozin 5 or 10 mg/day for 24 weeks as monotherapy in previously untreated patients, or as add-on combination therapy with metformin, glimepiride, pioglitazone or insulin-based therapy, significantly reduced both glycosylated haemoglobin values (primary endpoint) and fasting plasma glucose levels compared with placebo. Various randomized trials have also shown improvements in postprandial blood glucose with dapagliflozin monotherapy and combination therapy compared with placebo. In addition, dapagliflozin was noninferior to glipizide, in terms of glycaemic control after 52 weeks, when used as add-on therapy in patients with type 2 diabetes that was inadequately controlled with metformin. In most clinical trials, dapagliflozin was associated with reductions in body weight that were statistically superior to placebo or active comparators. Longer-term extension studies indicate that the efficacy of dapagliflozin is maintained for up to ≈2 years. Dapagliflozin was generally well tolerated in clinical trials of 24 or 52 weeks duration and in extension studies of up to ≈2 years. Events suggestive of genital infections and urinary tract infections occurred more frequently among dapagliflozin than placebo recipients. These adverse events are of special interest because they appear to be related to the mechanism of action of dapagliflozin. Dapagliflozin has a low propensity to cause hypoglycaemia, especially when used alone or in combination with metformin, although the incidence of hypoglycaemic events reported with dapagliflozin in clinical trials varied depending on the background therapy. Longer-term tolerability/safety data with dapagliflozin are awaited with interest. In conclusion, dapagliflozin, with its unique and complementary mechanism of action, appears to be an important addition to the therapeutic options for the management of type 2 diabetes, particularly when used as add-on therapy.