Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).

OBJECTIVEGlucose intolerance in pregnancy predicts an increased risk of future type 2 diabetes mellitus (T2DM) that is proportional to the severity of antepartum dysglycemia (i.e., highest in women with gestational diabetes mellitus [GDM], followed by those with milder dysglycemia). However, the pathophysiologic changes driving this risk are not known. Thus, we evaluated the longitudinal changes in b-cell function, insulin sensitivity, and glycemia in the first 3 years postpartum after gestational dysglycemia. RESEARCH DESIGN AND METHODSA total of 337 women underwent glucose challenge test (GCT) and oral glucose tolerance test (OGTT) in pregnancy, followed by repeat OGTT at 3 months, 1 year, and 3 years postpartum. The antepartum GCT/OGTT identified four gestational glucose tolerance groups: GDM (n = 105); gestational impaired glucose tolerance (GIGT; n = 60); abnormal GCT, followed by normal glucose tolerance (NGT) on the OGTT (abnormal GCT NGT; n = 96); and normal GCT with NGT (n = 76). RESULTSAt each of 3 months, 1 year, and 3 years postpartum, the prevalence of glucose intolerance increased from normal GCT NGT to abnormal GCT NGT to GIGT to GDM (all P < 0.001), whereas b-cell function, assessed by the Insulin SecretionSensitivity Index-2 (ISSI-2), and insulin sensitivity (Matsuda index), progressively decreased across the groups (all P < 0.002). Each group predicted distinct trajectories of ISSI-2, Matsuda index, and fasting and 2-h glucose (all P < 0.001). Notably, GDM, GIGT, and abnormal GCT NGT predicted varying rates of declining b-cell function and insulin sensitivity, as well as rising glycemia, compared with normal GCT NGT. CONCLUSIONSEach degree of gestational glucose intolerance predicts distinct trajectories of b-cell function, insulin sensitivity, and glycemia in the first 3 years postpartum that drive their differential risk of future T2DM.

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OBJECTIVEClinical studies evaluating the effects of medications on b-cell function in type 2 diabetes (T2DM) are compromised by an inability to determine the actual baseline degree of b-cell dysfunction independent of the reversible dysfunction induced by hyperglycemia (glucotoxicity). Short-term intensive insulin therapy (IIT) is a strategy for eliminating glucotoxicity before randomization. This study determined whether liraglutide can preserve b-cell function over 48 weeks in early T2DM following initial elimination of glucotoxicity with IIT. RESEARCH DESIGN AND METHODSIn this double-blind, randomized, placebo-controlled trial, 51 patients with T2DM of 2.6 6 1.9 years' duration and an A1C of 6.8 6 0.8% (51 6 8.7 mmol/mol) completed 4 weeks of IIT before randomization to daily subcutaneous liraglutide or placebo injection, with serial assessment of b-cell function by Insulin SecretionSensitivity Index-2 (ISSI-2) on oral glucose tolerance test performed every 12 weeks. RESULTSThe primary outcome of baseline-adjusted ISSI-2 at 48 weeks was higher in the liraglutide group than in the placebo group (339.8 6 27.8 vs. 229.3 6 28.4, P = 0.008). Baseline-adjusted HbA 1c at 48 weeks was lower in the liraglutide group (6.2 6 0.1% vs. 6.6 6 0.1%, P = 0.055) (44 6 1.1 vs. 49 6 1.1 mmol/mol). At each quarterly assessment, >50% of participants on liraglutide had an HbA 1c £6.0% (42 mmol/mol) and glucose tolerance in the nondiabetic range. Despite this level of glycemic control, no difference was found in the incidence of hypoglycemia between the liraglutide and placebo groups (P = 0.61). Two weeks after stopping treatment, however, the beneficial effect on ISSI-2 of liraglutide versus placebo was entirely lost (191.9 6 24.7 vs. 238.1 6 25.2, P = 0.20). CONCLUSIONSLiraglutide provides robust enhancement of b-cell function that is sustained over 48 weeks in early T2DM but lost upon cessation of therapy.The natural history of type 2 diabetes mellitus (T2DM) is characterized by rising glycemia and the need for increased antidiabetic medication over time (1). This clinical course is driven by the progressive deterioration of pancreatic b-cell function, a pathologic process that precedes the diagnosis of T2DM and continues

IMPORTANCE The NAVIGATE ESUS randomized clinical trial found that 15 mg of rivaroxaban per day does not reduce stroke compared with aspirin in patients with embolic stroke of undetermined source (ESUS); however, it substantially reduces stroke risk in patients with atrial fibrillation (AF).OBJECTIVE To analyze whether rivaroxaban is associated with a reduction of recurrent stroke among patients with ESUS who have an increased risk of AF. DESIGN, SETTING, AND PARTICIPANTS Participants were stratified by predictors of AF, including left atrial diameter, frequency of premature atrial contractions, and HAVOC score, a validated scheme using clinical features. Treatment interactions with these predictors were assessed. Participants were enrolled between December 2014 and September 2017, and analysis began March 2018. INTERVENTION Rivaroxaban treatment vs aspirin. MAIN OUTCOMES AND MEASURES Risk of ischemic stroke.RESULTS Among 7112 patients with a mean (SD) age of 67 (9.8) years, the mean (SD) HAVOC score was 2.6 (1.8), the mean (SD) left atrial diameter was 3.8 (1.4) cm (n = 4022), and the median (interquartile range) daily frequency of premature atrial contractions was 48 (13-222). Detection of AF during follow-up increased for each tertile of HAVOC score: 2.3% (score, 0-2), 3.0% (score, 3), and 5.8% (score, >3); however, neither tertiles of the HAVOC score nor premature atrial contractions frequency impacted the association of rivaroxaban with recurrent ischemic stroke (P for interaction = .67 and .96, respectively). Atrial fibrillation annual incidence increased for each tertile of left atrial diameter (2.0%, 3.6%, and 5.2%) and for each tertile of premature atrial contractions frequency (1.3%, 2.9%, and 7.0%). Among the predefined subgroup of patients with a left atrial diameter of more than 4.6 cm (9% of overall population), the risk of ischemic stroke was lower among the rivaroxaban group (1.7% per year) compared with the aspirin group (6.5% per year) (hazard ratio, 0.26; 95% CI, 0.07-0.94; P for interaction = .02). CONCLUSIONS AND RELEVANCEThe HAVOC score, left atrial diameter, and premature atrial contraction frequency predicted subsequent clinical AF. Rivaroxaban was associated with a reduced risk of recurrent stroke among patients with ESUS and moderate or severe left atrial enlargement; however, this needs to be independently confirmed before influencing clinical practice.

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Previous studies have yielded conflicting findings on the relationship between low vitamin D (25-OH-D) and impaired glucose homeostasis. In this context, we hypothesized that combined assessment of 25-OH-D with its regulator parathyroid hormone (PTH) may be required for optimal evaluation of the impact of vitamin D status on glucose metabolism. Thus, we evaluated the prospective associations of 25-OH-D and PTH at 3 months postpartum with b-cell function (Insulin SecretionSensitivity Index-2 [ISSI-2]), insulin sensitivity (Matsuda index), and glycemia at 12 months postpartum in 494 women undergoing serial metabolic characterization. Notably, 32% of those with prediabetes/diabetes mellitus at 12 months postpartum had both vitamin D deficiency and PTH in the highest tertile at 3 months postpartum. On multiple-adjusted linear regression analyses, vitamin D deficiency/insufficiency with PTH in the highest tertile at 3 months independently predicted poorer b-cell function (P = 0.03) and insulin sensitivity (P = 0.01) and increased fasting (P = 0.03) and 2-h glucose (P = 0.002) at 12 months postpartum. In contrast, vitamin D deficiency/insufficiency with lower PTH did not predict these outcomes. In conclusion, only vitamin D deficiency/insufficiency with increased PTH is an independent predictor of b-cell dysfunction, insulin resistance, and glycemia, highlighting the need for consideration of the PTH/25-OH-D axis when studying the impact of vitamin D status on glucose homeostasis.

Background and Purpose— The sources of emboli in patients with embolic stroke of undetermined source (ESUS) are multiple and may not respond uniformly to anticoagulation. In this exploratory subgroup analysis of patients with carotid atherosclerosis in the NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism)-ESUS trial, we assessed whether the treatment effect in this subgroup is consistent with the overall trial population and investigated the association of carotid atherosclerosis with recurrent ischemic stroke. Methods— Carotid atherosclerosis was analyzed either as the presence of mild (ie, 20%–49%) atherosclerotic stenosis or, separately, as the presence of carotid plaque. Primary efficacy outcome was ischemic stroke recurrence. Safety outcomes were major bleeding and symptomatic intracerebral bleeding. Results— Carotid plaque was present in 40% of participants and mild carotid stenosis in 11%. There was no significant difference in ischemic stroke recurrence between rivaroxaban- and aspirin-treated patients among 490 patients with carotid stenosis (5.0 versus 5.9/100 patient-years, respectively, hazard ratio [HR], 0.85; 95% CI, 0.39–1.87; P for interaction of treatment effect with patients without carotid stenosis 0.78) and among 2905 patients with carotid plaques (5.9 versus 4.9/100 patient-years, respectively, HR, 1.20; 95% CI, 0.86–1.68; P for interaction of treatment effect with patients without carotid stenosis 0.2). Among patients with carotid plaque, major bleeding was more frequent in rivaroxaban-treated patients compared with aspirin-treated (2.0 versus 0.5/100 patient-years, HR, 3.75; 95% CI, 1.63–8.65). Patients with carotid stenosis had similar rate of ischemic stroke recurrence compared with those without (5.4 versus 4.9/100 patient-years, respectively, HR, 1.11; 95% CI, 0.73–1.69), but there was a strong trend of higher rate of ischemic stroke recurrence in patients with carotid plaque compared with those without (5.4 versus 4.3/100 patient-years, respectively, HR, 1.23; 95% CI, 0.99–1.54). Conclusions— In ESUS patients with carotid atherosclerosis, we found no difference in efficacy between rivaroxaban and aspirin for prevention of recurrent stroke, but aspirin was safer, consistent with the overall trial results. Carotid plaque was much more often present ipsilateral to the qualifying ischemic stroke than contralateral, supporting an important etiological role of nonstenotic carotid disease in ESUS. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT02313909.