Background: Glycated hemoglobin (HbA1c) and measures of short-term glycemia do not fully capture daily patterns in plasma glucose dynamics. This study evaluated 24-h glycemic profiles in patients with type 2 diabetes (T2D) initiated on dapagliflozin treatment using continuous glucose monitoring (CGM).Methods: This randomized double-blind placebo-controlled multicenter parallel-design 4-week study compared dapagliflozin (10 mg/d; n = 50) with placebo (n = 50) in adult patients with T2D uncontrolled (HbA1c 7.5%–10.5%) on either stable doses of metformin monotherapy (≥1500 mg/d) or insulin (≥30 U/d with or without up to two oral antidiabetes drugs). CGM was used to measure 24-h glycemic profiles for 7 days pretreatment and during week 4 of treatment. The primary outcome was change from baseline in 24-h mean glucose (MG) at week 4.Results: The 24-h MG decreased 18.2 mg/dL with dapagliflozin and increased 5.8 mg/dL with placebo (P < 0.001). The proportion of time spent in the target glucose range (70–180 mg/dL) increased significantly with dapagliflozin versus placebo (69.6% vs. 52.9%; P < 0.001), with a small (0.3%) increase in time spent in the hypoglycemic range (<70 mg/dL), driven by those on background insulin therapy. Dapagliflozin reduced postprandial glucose and significantly decreased overall glucose variability. Few events of symptomatic hypoglycemia occurred. The most common adverse event was urinary tract infection (6% in each treatment arm).Conclusions: Compared with placebo, dapagliflozin improved measures of glycemic control and variability as assessed by CGM. Glycemic improvements were more pronounced in the group on background metformin than those receiving basal insulin.

These results suggest that the local delivery of antiproliferative agents using a thermosensitive, injectable biodegradable copolymer (ReGel) for sustained delivery is a promising strategy to inhibit neointimal hyperplasia of arteriovenous hemodialysis grafts.

Perivascular delivery of antiproliferative drugs has been proposed as an approach to prevent neointimal hyperplasia associated with hemodialysis polytetrafluoroethylene (PTFE) grafts. We examined this approach to deliver dipyridamole in a porcine graft model. PTFE grafts were implanted between the carotid artery and external jugular vein bilaterally in pigs. During the surgery or 1 week post-graft placement, dipyridamole (0.26-52 mg) alone or incorporated in microspheres was mixed with an injectable polymeric gel and applied to the graft-arterial and graft-venous anastomoses on one side, whereas the contralateral control graft received no treatment. Three or four weeks after operation, the grafts and adjacent vessels were explanted en bloc and cross-sections of the anastomoses were examined histologically. The degree of neointimal hyperplasia was quantified by planimetry. In separate experiments, dipyridamole was extracted from the explanted tissues and assayed by spectrofluorometry. The normalized median hyperplasia areas of the treated and control graft-venous anastomoses were 0.45 (25th-75th percentile, 0.30-0.86) and 0.24 (0.21-0.30), respectively (N=7; P=0.08). The median hyperplasia areas of the treated and control graft-arterial anastomoses were 0.12 (0.07-0.39) and 0.11 (0.09-0.13), respectively (N=7; P=0.31). The dipyridamole levels in the vascular walls around the anastomoses were at or above the in vitro inhibitory concentrations for approximately 3 weeks. These results suggest that the local perivascular sustained delivery of dipyridamole, even at high dosages, was ineffective in inhibiting neointimal hyperplasia associated with PTFE grafts in a porcine model.

AimTo assess the effects of once‐weekly exenatide on 24‐hour glucose control and variability.Materials and methodsThis double‐blind, placebo‐controlled trial randomized metformin‐treated adults with type 2 diabetes to once‐weekly exenatide 2.0 mg or placebo. Continuous glucose monitoring (CGM) was performed at baseline and weeks 4 and 10. The primary outcome was change in CGM‐measured 24‐hour mean glucose level.ResultsIn the once‐weekly exenatide (n = 60) and placebo (n = 56) groups (modified intention‐to‐treat population), the baseline glycated haemoglobin (HbA1c) concentrations were 8.2% and 8.0%, respectively, and the fasting plasma glucose (FPG) concentration was 9.86 and 9.32 mmol/L, respectively. Once‐weekly exenatide significantly (p < 0.001) reduced 24‐hour mean glucose level versus placebo (week 4, −1.44 vs −0.29 mmol/L; week 10, −1.71 vs −0.17 mmol/L), with consistent control throughout the week. Once‐weekly exenatide significantly reduced FPG and 2‐hour postprandial glucose (PPG) levels versus placebo at week 4 (FPG, −1.65 vs −0.11 mmol/L; PPG, −1.79 vs −0.11 mmol/L) and week 10 (FPG, −2.32 vs −0.28 mmol/L; PPG, −2.46 vs −0.33 mmol/L). At week 10, once‐weekly exenatide reduced the mean amplitude of glucose excursions (MAGE; −0.84 vs 0.16 mmol/L) and standard deviation (s.d.) of mean glucose (−0.35 vs 0.04 mmol/L). By week 10, once‐weekly exenatide‐treated participants spent more time in euglycaemia (once‐weekly exenatide, 77% vs placebo, 58%), less time in hyperglycaemia (22% vs 42%), and a similar time in hypoglycaemia (0.7% vs 0.3%). Common adverse events were injection‐site nodule (once‐weekly exenatide, 10.0% vs placebo, 0.0%), urinary tract infection (6.7% vs 8.9%) and nausea (6.7% vs 0.0%).ConclusionsIn metformin‐treated participants with type 2 diabetes, once‐weekly exenatide significantly improved daily glucose control and reduced glycaemic variability at weeks 4 and 10, as shown by reductions in 24‐hour glucose, FPG and PPG levels, MAGE and s.d., and increased time spent in euglycaemia.

Dipyridamole is a potential pharmacological agent to prevent vascular stenosis because of its antiproliferative properties. The mechanisms by which dipyridamole inhibits the growth of vascular smooth muscle cells, especially venous smooth muscle cells, are unclear. In the present study, dipyridamole transiently but significantly increased cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels in human venous and arterial smooth muscle cells in a time-and dose-dependent manner. Peak concentrations of both cyclic nucleotides were achieved at 15-30 min. and correlated with inhibition of proliferation in both cell types. The antiproliferative effects of dipyridamole observed at 48 hr were similar whether drug exposure was only 15 min. or sustained for 48 hr. Specific competitive inhibitors of protein kinases A and G attenuated the antiproliferative effects of subsaturating concentrations of dipyridamole, with the effects of protein kinase inhibition being particularly pronounced in venous smooth muscle cells. Flow cytometry analysis showed that dipyridamole caused an enrichment of cells in G 0 /G 1 and a corresponding reduction of cells in S phase. These data indicate that a transient increase in cGMP and cAMP is sufficient to induce downstream kinase activation and subsequent cell cycle arrest, and that protein kinase G may be more important than protein kinase A in mediating the growth inhibitory effect of dipyridamole in venous protein kinase.