Efficacy and safety of bexagliflozin compared with dapagliflozin as an adjunct to metformin in Chinese patients with type 2 diabetes mellitus: A 24-week, randomized, double-blind, active-controlled, phase 3 trial.

BACKGROUND: Bexagliflozin and dapagliflozin are sodium-glucose cotransporter-2 (SGLT2) inhibitors. No direct comparison of SGLT2 inhibitors in a randomized controlled trial has been reported to date. METHODS: This was a multicenter, randomized, double-blind, active-controlled trial comparing bexagliflozin to dapagliflozin for the treatment of type 2 diabetes mellitus in adults with disease inadequately controlled by metformin. Subjects (n = 406) were randomized to receive bexagliflozin (20 mg) or dapagliflozin (10 mg) plus metformin. The primary endpoint was noninferiority of bexagliflozin to dapagliflozin for the change in glycated hemoglobin (HbA1c) from baseline to week 24. Secondary endpoints included intergroup differences in fasting plasma glucose (FPG), 2-h-postprandial glucose (PPG), body weight, and systolic blood pressure (SBP) from baseline to week 24. The trial also evaluated the safety profiles. RESULTS: The model-adjusted mean change from baseline to week 24 HbA1c was -1.08% for bexagliflozin and -1.10% for dapagliflozin. The intergroup difference of 0.03% (95% confidence interval [CI] -0.14% to 0.19%) was below the prespecified margin of 0.4%, confirming the noninferiority of bexagliflozin. The changes from baseline in FPG, PPG, body weight, and SBP were -1.95 mmol/L, -3.24 mmol/L, -2.52 kg, and -6.4 mm Hg in the bexagliflozin arm and -1.87 mmol/L, -3.07 mmol/L, -2.22 kg, and -6.3 mm Hg in the dapagliflozin arm. Adverse events were experienced in 62.6% and 65.0% and serious adverse events affected 4.4% and 3.5% of subjects in the bexagliflozin and dapagliflozin arm, respectively. CONCLUSIONS: Bexagliflozin showed nearly identical effects and a similar safety profile to dapagliflozin when used in Chinese patients on metformin.

Meta-analysis of risk of major adverse cardiovascular events in adults with type 2 diabetes treated with bexagliflozin.

AIM: To explore the risk of major adverse cardiovascular events (MACE) associated with exposure to bexagliflozin. METHODS: The analysis included 4090 participants with type 2 diabetes (T2D) enrolled in nine phase 2 and 3 double-blind randomized controlled trials. All potential MACE were adjudicated by a blinded committee. The primary endpoint for the meta-analysis was the hazard ratio (HR) for the time to first occurrence of non-fatal stroke, non-fatal myocardial infarction (MI), cardiovascular (CV) death or hospitalization for unstable angina (MACE+), tested for non-inferiority to a ratio of 1.8. The secondary endpoints were time to first occurrence of (i) non-fatal stroke, non-fatal MI or CV death (MACE), tested for non-inferiority to a ratio of 1.3; and (ii) CV death or hospitalization for heart failure, tested for superiority. RESULTS: The HR for the primary endpoint of MACE+ was 0.80 (95% confidence interval [CI] 0.58, 1.09), which fulfilled the non-inferiority objective with a P value of less than 0.0001. Non-inferiority for the first key secondary endpoint of MACE was also shown (HR = 0.82; 95% CI 0.59, 1.13; P = 0.0023). Superiority for time to CV death or first hospitalization for heart failure was not shown. CONCLUSIONS: Bexagliflozin did not increase the risk of MACE in participants with T2D when compared with placebo or active control. Both the preapproval and postapproval thresholds for CV safety were met and bexagliflozin has been approved by the US Food and Drug Administration.

Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial.

BACKGROUND: The safety and effectiveness of a continuous, day-and-night automated glycaemic control system using insulin and glucagon has not been shown in a free-living, home-use setting. We aimed to assess whether bihormonal bionic pancreas initialised only with body mass can safely reduce mean glycaemia and hypoglycaemia in adults with type 1 diabetes who were living at home and participating in their normal daily routines without restrictions on diet or physical activity. METHODS: We did a random-order crossover study in volunteers at least 18 years old who had type 1 diabetes and lived within a 30 min drive of four sites in the USA. Participants were randomly assigned (1:1) in blocks of two using sequentially numbered sealed envelopes to glycaemic regulation with a bihormonal bionic pancreas or usual care (conventional or sensor-augmented insulin pump therapy) first, followed by the opposite intervention. Both study periods were 11 days in length, during which time participants continued all normal activities, including athletics and driving. The bionic pancreas was initialised with only the participant's body mass. Autonomously adaptive dosing algorithms used data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. The coprimary outcomes were the mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration less than 3·3 mmol/L, analysed over days 2-11 in participants who completed both periods of the study. This trial is registered with ClinicalTrials.gov, number NCT02092220. FINDINGS: We randomly assigned 43 participants between May 6, 2014, and July 3, 2015, 39 of whom completed the study: 20 who were assigned to bionic pancreas first and 19 who were assigned to the comparator first. The mean CGM glucose concentration was 7·8 mmol/L (SD 0·6) in the bionic pancreas period versus 9·0 mmol/L (1·6) in the comparator period (difference 1·1 mmol/L, 95% CI 0·7-1·6; p<0·0001), and the mean time with CGM glucose concentration less than 3·3 mmol/L was 0·6% (0·6) in the bionic pancreas period versus 1·9% (1·7) in the comparator period (difference 1·3%, 95% CI 0·8-1·8; p<0·0001). The mean nausea score on the Visual Analogue Scale (score 0-10) was greater during the bionic pancreas period (0·52 [SD 0·83]) than in the comparator period (0·05 [0·17]; difference 0·47, 95% CI 0·21-0·73; p=0·0024). Body mass and laboratory parameters did not differ between periods. There were no serious or unexpected adverse events in the bionic pancreas period of the study. INTERPRETATION: Relative to conventional and sensor-augmented insulin pump therapy, the bihormonal bionic pancreas, initialised only with participant weight, was able to achieve superior glycaemic regulation without the need for carbohydrate counting. Larger and longer studies are needed to establish the long-term benefits and risks of automated glycaemic management with a bihormonal bionic pancreas. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and National Center for Advancing Translational Sciences.

Blood glucose concentrations of arm and finger during dynamic glucose conditions.

We set out to determine the physiological difference between the capillary blood of the arm and finger with the greatest possible accuracy using the HemoCue B-glucose analyzer on subjects undergoing a meal tolerance test (MTT) or oral glucose tolerance test (OGTT). MTT study was performed on 50 subjects who drank a liquid meal (Ensure, 40 g of carbohydrates) and who were tested on the arm and finger every 30 min for up to 4 h. OGTT study was performed on 12 subjects who drank a 100-g glucose solution (Glucola) and were tested on the arm and finger every 15 min during the first hour and thereafter every 30 min for up to 3 h. Average percent glucose difference between arm and finger reached a maximal value about 1 h following glucose load, with arm glucose being about 5% lower than that of finger. At other times, average differences were less than this. At the greatest rate of glucose change (>2 mg/dL-min), mean percent bias was found to be about 6%. Despite these measurable differences, when arm results were plotted on the Clarke error grid against finger values, >97% of the data were within zone A (rest in zone B). Thus, physiological differences between arm and finger were clinically insignificant. Our studies with HemoCue confirmed the existence of measurable physiological glucose differences between arm and finger following a glucose challenge, but these differences were found to be clinically insignificant even in those subjects in whom they were measurable.

Whole-blood glucose testing at alternate sites: glucose values and hematocrit of capillary blood drawn from fingertip and forearm.

OBJECTIVE: To measure hematocrit (Hct) and glucose concentration in capillary blood drawn from the fingertip and forearm of a group of 50 nonfasting subjects with diabetes. RESEARCH DESIGN AND METHODS: Hct was determined indirectly by measuring Hb with the HemoCue B-Hemoglobin Photometer. Glucose was assayed with the HemoCue B-Glucose Analyzer, chosen as the independent control assay, and the Sof-Tact Blood Glucose System. Testing session with each subject lasted approximately 30 min and consisted of a sequence of tests with each device (SofTact, HemoCue Glucose, and HemoCue Hemoglobin), performed on the arm and then on the fingertip. This sequence was performed three times, so all tests were done in triplicate. Additional fingersticks were performed on each subject at the start and end of the session to measure net change of glucose status during the experiment with a YSI Glucose Analyzer. The mean of the triplicate assays was used to calculate each subject's percent of glucose difference between arm and finger [(arm glucose - finger glucose)/finger glucose]. Because of the order in which replicates were performed, time-dependent changes in the glucose status of subjects had little effect on the mean values. Thus, the percent of glucose difference calculated herein reflects the intrinsic difference between forearm and fingertip. RESULTS: Hb concentration and Hct were found to be significantly higher in the arm than in the finger. When intraperson differences were calculated, the difference for Hb and Hct was found to be 1.8 +/- 1.1 g/dl (mean +/- SD) and 5.3 +/- 3.0%, respectively. In contrast to Hb, the percent of glucose difference between arm and finger was statistically insignificant. When measured with HemoCue, the percent of glucose difference was -0.1 +/- 8% for all 50 subjects, -1 +/- 6% for 20 subjects, for whom blood glucose varied <9 mg/dl during the experiment, and 2 +/- 10% for 15 subjects, for whom blood glucose varied >18 mg/dl. Thus, irrespective of how much blood glucose changed among the subjects, the glucose difference between forearm and fingertip was insignificant and less than measurement errors. A major source of error in the calculated differences was variability between replicates. No correlation was observed between an individual's Hct bias and his or her percent of glucose difference, as measured with HemoCue. The results with Sof-Tact were similar, with percent of glucose difference again being statistically insignificant. The measured difference was -4 +/- 13% for all 50 subjects, -1 +/- 15% for 20 subjects, for whom blood glucose varied <9 mg/dl during the experiment, and -1 +/- 12% for 15 subjects, for whom blood glucose varied >18 mg/dl. There was no correlation between a subject's Hct bias and his or her glucose difference, as measured with Sof-Tact. CONCLUSIONS: In this cross-sectional study of 50 nonfasting subjects whose blood glucose concentration changed to various degrees during the experiment, no significant glucose difference was observed between the capillary beds of the forearm and fingertip, regardless of whether glucose was assayed with HemoCue or the Sof-Tact Blood Glucose System. On the other hand, Hb concentration and Hct were found to be significantly higher in the capillary blood of the forearm.