Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial.

BACKGROUND: Oral semaglutide is the first oral glucagon-like peptide-1 (GLP-1) receptor agonist for glycaemic control in patients with type 2 diabetes. Type 2 diabetes is commonly associated with renal impairment, restricting treatment options. We aimed to investigate the efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment. METHODS: This randomised, double-blind, phase 3a trial was undertaken at 88 sites in eight countries. Patients aged 18 years and older, with type 2 diabetes, an estimated glomerular filtration rate of 30-59 mL/min per 1·73 m2, and who had been receiving a stable dose of metformin or sulfonylurea, or both, or basal insulin with or without metformin for the past 90 days were eligible. Participants were randomly assigned (1:1) by use of an interactive web-response system, with stratification by glucose-lowering medication and renal function, to receive oral semaglutide (dose escalated to 14 mg once daily) or matching placebo for 26 weeks, in addition to background medication. Participants and site staff were masked to assignment. Two efficacy-related estimands were defined: treatment policy (regardless of treatment discontinuation or rescue medication) and trial product (on treatment without rescue medication) in all participants randomly assigned. Endpoints were change from baseline to week 26 in HbA1c (primary endpoint) and bodyweight (confirmatory secondary endpoint), assessed in all participants with sufficient data. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on ClinicalTrials.gov, number NCT02827708, and the European Clinical Trials Registry, number EudraCT 2015-005326-19, and is now complete. FINDINGS: Between Sept 20, 2016, and Sept 29, 2017, of 721 patients screened, 324 were eligible and randomly assigned to oral semaglutide (n=163) or placebo (n=161). Mean age at baseline was 70 years (SD 8), and 168 (52%) of participants were female. 133 (82%) participants in the oral semaglutide group and 141 (88%) in the placebo group completed 26 weeks on treatment. At 26 weeks, oral semaglutide was superior to placebo in decreasing HbA1c (estimated mean change of -1·0 percentage point (SE 0·1; -11 mmol/mol [SE 0·8]) vs -0·2 percentage points (SE 0·1; -2 mmol/mol [SE 0·8]); estimated treatment difference [ETD]: -0·8 percentage points, 95% CI -1·0 to -0·6; p<0·0001) and bodyweight (estimated mean change of -3·4 kg [SE 0·3] vs -0·9 kg [SE 0·3]; ETD, -2·5, 95% CI -3·2 to -1·8; p<0·0001) by the treatment policy estimand. Significant differences were seen for the trial product estimand: mean change in HbA1c -1·1 percentage points (SE 0·1; -12 mmol/mol [SE 0·8] versus -0·1 percentage points (SE 0·1; -1 mmol/mol [SE 0·8]; ETD -1·0 percentage points, 95% CI -1·2 to -0·8; p<0·0001); mean change in bodyweight -3·7 kg (SE 0·3) versus -1·1 kg (SE 0·3; ETD -2·7 kg, 95% CI -3·5 to -1·9; p<0·0001). More patients taking oral semaglutide than placebo had adverse events (120 [74%] of 163 vs 105 [65%] of 161), and discontinued treatment as a result (24 [15%] vs eight [5%]). Gastrointestinal events, mainly mild-to-moderate nausea, were more common with oral semaglutide than with placebo. Three deaths occurred during the treatment period that were not condsidered to be treatment related, one in the semaglutide group and two in the placebo group. INTERPRETATION: Oral semaglutide was effective in patients with type 2 diabetes and moderate renal impairment, potentially providing a new treatment option for this population. Safety, including renal safety, was consistent with the GLP-1 receptor agonist class. FUNDING: Novo Nordisk A/S.

Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial.

Importance: Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy. Objective: To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to metformin with or without sulfonylurea, in patients with type 2 diabetes. Design, Setting, and Participants: Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized. Interventions: Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved. Main Outcomes and Measures: The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with respect to HbA1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA1c and body weight. Results: Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c (differences, -0.3% [95% CI, -0.4% to -0.1%] and -0.5% [95% CI, -0.6% to -0.4%], respectively; P < .001 for both) and body weight (differences, -1.6 kg [95% CI, -2.0 to -1.1 kg] and -2.5 kg [95% CI, -3.0 to -2.0 kg], respectively; P < .001 for both) from baseline to week 26. Noninferiority of semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated. Week 78 reductions in both end points were statistically significantly greater with semaglutide, 14 mg/d, vs sitagliptin. Conclusions and Relevance: Among adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks, but there was no significant benefit with the 3-mg/d dosage. Further research is needed to assess effectiveness in a clinical setting. Trial Registration: ClinicalTrials.gov Identifier: NCT02607865.

Benefit of clopidogrel therapy in patients with myocardial infarction and chronic kidney disease-a Danish nation-wide cohort study.

BACKGROUND: The aim of the present study was to evaluate clopidogrel treatment after incident myocardial infarction (MI) in patients with and without chronic kidney disease (CKD). METHODS AND RESULTS: By linking nation-wide registries, information about patients admitted with incident MI was found. Primary endpoints were all-cause and cardiovascular (CV) mortality, a composite of all-cause mortality and recurrent MI, and a composite of fatal and nonfatal bleedings. Effect of clopidogrel use versus clopidogrel nonuse was estimated using an adjusted Cox's regression model stratified according to percutaneous coronary intervention (PCI) treatment.A total of 69 082 incident MI patients in the period 2002-2011 were included. Clopidogrel treatment was associated with hazard ratios (HRs) for the combined endpoint of all-cause mortality and recurrent MI in PCI-treated patients of 0.90 (95% confidence interval [CI], 0.47 to 1.72) in renal replacement therapy (RRT) patients, 0.59 (95% CI: 0.40 to 0.88) in non-end-stage CKD patients and 0.69 (95% CI, 0.61 to 0.77) in patients without kidney disease (P for interaction=0.60). In patients not treated with PCI, HRs were 0.90 (95% CI, 0.68 to 1.21) in RRT patients, 0.86 (95% CI, 0.75 to 0.99) in non-end-stage CKD patients, and 0.91 (95% CI, 0.87 to 0.95) in patients without kidney disease (P for interaction=0.74). An increase in bleeding events (not significant) was noted for clopidogrel-treated patients not undergoing PCI and for non-end-stage CKD patients undergoing PCI, whereas clopidogrel was associated with less bleedings in PCI-treated RRT patients and patients without kidney disease. CONCLUSIONS: During a 1-year follow-up, after MI, clopidogrel was associated with improved outcomes in patients with non-end-stage CKD. Even though no effect difference, compared to patients without CKD, was observed, the benefit associated with the use of clopidogrel after MI in patients requiring RRT is less clear.

Less use of standard guideline-based treatment of myocardial infarction in patients with chronic kidney disease: a Danish nation-wide cohort study.

AIMS: The aim of this Danish nationwide study was to evaluate the treatment of myocardial infarction (MI) in patients with non-end-stage chronic kidney disease (CKD) and in patients requiring renal replacement therapy (RRT). Upgraded guidelines for the management of MI were implemented around 2004; hence, the treatment of MI in the time periods before and after 2004 was compared in order to evaluate the impact for patients with CKD. METHODS AND RESULTS: By linking nationwide registries by the personal registration number, we identified patients admitted to Danish hospitals with first time MI in the period 2000-09 (79 585 with no renal disease, 3144 with non-end-stage CKD, and 725 requiring RRT). Cox proportional hazards model was used to estimate the chance of invasive treatment within 60 days after MI and the chance of filling prescriptions on recommended post-MI drugs within 90 days before and after 2004. Significantly less use of relevant MI treatment in patients with non-end-stage CKD and patients requiring RRT compared with patients with no renal disease were seen; however, the absolute frequencies of invasive procedures and filled prescriptions on post-MI drugs increased after 2004 in all patients. CONCLUSIONS: After 2004, invasive and pharmacological treatment of first-time MI improved in patients with non-end-stage CKD and patients requiring RRT; however, all CKD patients were less treated with standard MI care compared with patients with no renal disease.

[The clinical course of a three year-old girl after overdose of valproic acid]. / Det kliniske forløb ved valproatforgiftning hos en treårig.

Valproic acid (VA) is an antiepileptic drug, and frequently prescribed in pediatrics. VA overdose results in central nervous system depression, insufficient respiration, tachycardia, hypotension, hepatotoxicity, and electrolyte derangement. We describe the clinical course of a three year-old girl after accidental intake of 6,000 mg VA. Treatment included activated charcoal. Clinical observation included measurements of blood pressure, cardiac telemetry, and measurements of serum VA and metabolic parameters every 4-6 hrs. The girl was discharged successfully after 72 hrs with her usual dose of VA.