Effect of Dapagliflozin on Cardiac Function and Metabolic and Hormonal Responses to Exercise.

OBJECTIVE: This work aimed to investigate the effect of the SGLT2 inhibitor, dapagliflozin (DAPA), on cardiac function and the metabolic and hormonal response to moderate exercise in people with type 2 diabetes. METHODS: This was a double-blind, placebo-controlled crossover study with a 4-week washout period. Nine participants were randomly assigned to receive either 4 weeks of DAPA or 4 weeks of placebo. After each treatment, they underwent an exercise protocol with 2 consecutive 10-minute stages at a constant load corresponding to 40% and 70% maximal oxygen consumption (VO2max), coupled with hormonal and metabolic analysis. A blinded transthoracic echocardiogram was performed 3 days later. RESULTS: During the exercise protocol, glucose and lactate were lower (P < .0001 and P < .05, respectively) and ß-hydroxybutyrate (BOBH) and growth hormone (GH) were higher (P < .0005 and P = .01) following DAPA treatment compared to placebo. There was a trend for lower insulin with DAPA. Adrenalin, noradrenalin, and glucagon were not different. Following DAPA participants demonstrated an increased mean peak diastolic mitral annular velocity (e') in comparison to placebo (P = .03). The indexed left atrial volume and right ventricular e" were reduced following DAPA compared with placebo (P = .045 and P = .042, respectively). Arterial stiffness was not different between treatments (DAPA 9.35 ± 0.60 m/s; placebo 9.07 ± 0.72 m/s). CONCLUSION: During exercise, GH may be more important than catecholamines in driving the shift from glucose to fatty acid metabolism by SGLT2 inhibitors. The 4-week crossover design showed changes in cardiac function were rapid in onset and reversible.

The SGLT2 Inhibitor Dapagliflozin Increases the Oxidation of Ingested Fatty Acids to Ketones in Type 2 Diabetes.

OBJECTIVE: To investigate the mechanism for increased ketogenesis following treatment with the SGLT2 inhibitor dapagliflozin in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: The design was a double-blind, placebo-controlled, crossover study with a 4-week washout period. Participants received dapagliflozin or placebo in random order for 4 weeks. After each treatment, they ingested 30 mL of olive oil containing [U-13C]palmitate to measure ketogenesis, with blood sampling for 480 min. Stable isotopes of glucose and glycerol were infused to measure glucose flux and lipolysis, respectively, at 450-480 min. RESULTS: Glucose excretion rate was higher and peripheral glucose uptake lower with dapagliflozin than placebo. Plasma ß-hydroxybutyrate (BOHB) concentrations and [13C2]BOHB concentrations were higher and glucose concentrations lower with dapagliflozin than placebo. Nonesterified fatty acids (NEFAs) were higher with dapagliflozin at 300 and 420 min, but lipolysis at 450-480 min was not different. Triacylglycerol at all time points and endogenous glucose production rate at 450-480 min were not different between treatments. CONCLUSIONS: The increase in ketone enrichment from the ingested palmitic acid tracer suggests that meal-derived fatty acids contribute to the increase in ketones during treatment with dapagliflozin. The increase in BOHB concentration with dapagliflozin occurred with only minimal changes in plasma NEFA concentration and no change in lipolysis. This finding suggests a metabolic switch to increase ketogenesis within the liver.

Metabolic Effects of an SGLT2 Inhibitor (Dapagliflozin) During a Period of Acute Insulin Withdrawal and Development of Ketoacidosis in People With Type 1 Diabetes.

OBJECTIVE: To determine the effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on glucose flux, lipolysis, and ketone body concentrations during insulin withdrawal in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: A double-blind, placebo-controlled crossover study with a 4-week washout period was performed in 12 people with type 1 diabetes using insulin pump therapy. Participants received dapagliflozin or placebo in random order for 7 days. Stable isotopes were infused to measure the glucose Ra, Rd, and lipolysis. At isotopic steady state, insulin was withdrawn, and the study was terminated after 600 min or earlier if blood glucose reached 18 mmol/L, bicarbonate <15 mmol/L, venous pH <7.35, or capillary ketones >5.0 mmol/L. RESULTS: At baseline, glucose Ra was significantly higher for the dapagliflozin group than the placebo group. Following insulin withdrawal, plasma glucose concentrations at the end point were significantly lower with dapagliflozin than placebo and glucose Rd area under the curve (AUC)0-180 min and ß-hydroxybutyrate (BOHB) AUC0-180 min were significantly higher. There was a small but significantly higher glycerol Ra (measure of lipolysis) AUC0-180 min with dapagliflozin. Nonesterified fatty acid concentrations were not different between treatments. When divided by BMI >27 and <27 kg/m2, basal glucose Ra, BOHB, and glycerol Ra AUC0-180 min were significantly higher in the low-BMI group with dapagliflozin treatment versus the low-BMI group with placebo. CONCLUSIONS: During insulin withdrawal, the increase in BOHB with dapagliflozin may be partially due to increased lipolysis. However, reduced renal excretion, reduced BOHB uptake by peripheral tissues, or a metabolic switch to increased ketogenesis within the liver may also play a role.

HDL-apoA-I kinetics in response to 16 wk of exercise training in men with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is characterized by low-circulating concentration of high-density lipoprotein cholesterol (HDL-C) and raised triacylglycerol (TAG). Exercise reduces hepatic fat content, improves insulin resistance and increases clearance of very-low-density lipoprotein-1 (VLDL1). However, the effect of exercise on TAG and HDL-C metabolism is unknown. We randomized male participants to 16 wk of supervised, moderate-intensity aerobic exercise (n = 15), or conventional lifestyle advice (n = 12). Apolipoprotein A-I (apoA-I) and VLDL-TAG and apolipoprotein B (apoB) kinetics were investigated using stable isotopes (1-[13C]-leucine and 1,1,2,3,3-2H5 glycerol) pre- and postintervention. Participants underwent MRI/spectroscopy to assess changes in visceral fat. Results are means ± SD. At baseline, there were no differences between exercise and control groups for age (52.4 ± 7.5 vs. 52.8 ± 10.3 yr), body mass index (BMI: 31.6 ± 3.2 vs. 31.7 ± 3.6 kg/m2), and waist circumference (109.3 ± 7.5 vs. 110.0 ± 13.6 cm). Percentage of liver fat was 23.8 (interquartile range 9.8-32.5%). Exercise reduced body weight (101.3 ± 10.2 to 97.9 ± 12.2 kg; P < 0.001) and hepatic fat content [from 19.6%, interquartile range (IQR) 14.6-36.1% to 8.9% (4.4-17.8%); P = 0.001] and increased the fraction HDL-C concentration (measured following ultracentrifugation) and apoA-I pool size with no change in the control group. However, plasma and VLDL1-TAG concentrations and HDL-apoA-I fractional catabolic rate (FCR) and production rate (PR) did not change significantly with exercise. Both at baseline (all participants) and after exercise there was an inverse correlation between apoA-I pool size and VLDL-TAG and -apoB pool size. The modest effect of exercise on HDL metabolism may be explained by the lack of effect on plasma and VLDL1-TAG.