Saxagliptin clinical trials: evaluation of CV risk

Diabetes is Australia's fastest growing chronic disease with approximately 890,000 patients currently diagnosed with diabetes. 1 By 2031 it is predicted that 3.3 million Australians will have type 2 diabetes mellitus, 2 thus increasing the demand for treatment. However, several diabetes, obesity, and lipid drug trials have had unexpected and unfavourable cardiovascular (CV) results. The saxagliptin (SAXA) phase 2b/3 program enrolled a range of patients with diabetes and included a controlled, long-term safety extension phase. SAXA is a potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor. In the SAXA clinical data, the primary endpoint, major adverse cardiovascular events (MACE; stroke, myocardial infarction or CV death, analysed post hoc) and acute cardiovascular events (ACE; acute, clinically significant events, including cardiac revascularisation procedures) were identified using selected MedDRA Preferred Terms. CV events were analysed in a comprehensive dataset: 8 randomised, double-blind, phase 2b/3 trials, which included 4607 patients (3206 randomised to SAXA 2.5, 5, or 10 mg; 150 randomised to SAXA 20, 40, or 100 mg; and 1251 randomised to placebo, metformin, or up-titrated glyburide). Overall exposure was 3758 patient-years on SAXA and 1293 patient-years on comparators. Within the SAXA population, 81% had at least 1 CV risk factor in addition to diabetes, with hypertension (52%), dyslipidaemia (44%), or history of smoking (39%) the most common; 12% had known prior CV disease. Comparator group had similar proportions. Numbers of patients with events are shown in Table. The Cox proportional hazard ratio for MACE was 0.44 (95% CI: 0.24–0.82) and for ACE was 0.59 (95% CI: 0.35–1.00). A series of sensitivity analyses using related endpoints and alternative analytic methods produced consistent results. Based on a >5000 patient-year clinical trial experience, there was no evidence of increased CV risk with SAXA treatment ― as monotherapy or in combination with other oral antidiabetic agents. These data raise the hypothesis of a cardioprotective effect of SAXA, which will be studied in the SAVOR trial

β-cell stimulation by saxagliptin in patients with type 2 diabetes

Diabetes is Australia’s fastest growing chronic disease with approximately 890,000 patients currently diagnosed with diabetes.1By 2031 it is predicted that 3.3 million Australians will have type 2 diabetes2thus increasing the demand for prevention strategies and an emphasis on early diagnosis and treatment. Saxagliptin (SAXA) is a potent, selective DPP-4 inhibitor, specifically designed for extended inhibition of the DPP-4 enzyme. DPP-4 inactivates incretins that stimulate glucose-dependent insulin secretion and inhibit glucagon secretion. A proposed MOA of SAXA involves protecting incretins from DPP-4 degradation, thus improving β-cell response. This randomised, parallel-group, double-blind, PBO-controlled study (CV181-041) assessed SAXA’s effect on β-cell function by intravenous hyperglycaemic clamp (IV HC) in T2DM patients. Patients were assessed at baseline (BL) and wk 12 in the fasting state (0-180min, IV HC) and after stimulating incretin secretion by orally ingesting 75g glucose (180-480min, IV-oral HC). HC infusions were adjusted to maintain plasma glucose at 280mg/dL. Insulin secretion was calculated by C-peptide deconvolution. Primary endpoint was %Δfrom BL in total insulin secretion (%Δinsulin) during IV-oral HC (180-480min). Secondary endpoint was %Δinsulin during IV HC (120-180min). Patients were drug-naïve with T2DM aged 43-69yrs with BL A1C range 5.9%-8.1%. Twenty patients received SAXA 5mg od; 16 received PBO. After 12 wks, SAXA significantly increased %Δinsulin from BL during IV-oral HC (adj% difference of 18.5% vs PBO, p=.035). In the fasting state during IV HC SAXA significantly increased %Δinsulin from BL (adj% difference of 27.9% vs PBO, p=.020). At wk 12 insulin secretion increased from BL with SAXA but not with PBO (Fig). Glucagon AUC during IV-oral HC also improved from BL with SAXA, (adj% difference of –21.8% vs PBO, p=.031). SAXA was generally safe and well-tolerated. In conclusion, SAXA improved pancreatic β-cell function in the postprandial and fasting states and decreased postprandial glucagon concentration

Treatment With a Ghrelin Agonist in Outpatient Women With Anorexia Nervosa: A Randomized Clinical Trial.

OBJECTIVE: To assess the effects of relamorelin-an agonist of the appetite-stimulating hormone ghrelin, which has effects on gastric emptying-on (1) weight gain and (2) gastric emptying in women with anorexia nervosa. METHODS: In a randomized, double-blind, placebo-controlled design, the effects of the ghrelin agonist relamorelin were studied in 22 outpatient women with anorexia nervosa, diagnosed using DSM-5 criteria. The study was conducted at the Massachusetts General Hospital Clinical Research Center between March 11, 2013, and February 26, 2015. Ten participants were randomly assigned to relamorelin 100 μg subcutaneously daily (mean ± SEM age: 28.9 ± 2.4 y), and 12 were randomly assigned to placebo (28.9 ± 1.9 y). We measured changes in weight and gastric emptying time using a gastric emptying breath test (GEBT) for relamorelin versus placebo after 4 weeks of treatment. RESULTS: At baseline, subjects did not differ in weight, plasma ghrelin levels, or gastric emptying time. Three subjects randomized to relamorelin stopped use of the study medication due to reported feelings of increased hunger. After 4 weeks, there was a trend toward an increase in weight in participants randomized to relamorelin (mean ± SEM change: 0.86 ± 0.40 kg) compared to placebo (0.04 ± 0.28 kg; P = .07), and gastric emptying time was significantly shorter in patients taking relamorelin (median [interquartile range]: 58.0 [51.0, 78.0] minutes) compared to placebo (85.0 [75.8,100.5] minutes; P = .03). CONCLUSIONS: Treatment with a ghrelin agonist in women with anorexia nervosa significantly decreases gastric emptying time, leads to a trend in weight gain after only 4 weeks, and is well-tolerated. Further study is necessary to determine the long-term safety and efficacy of a ghrelin agonist in the treatment of anorexia nervosa. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01642550

Apixaban versus warfarin in patients with atrial fibrillation

BACKGROUND: Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. METHODS: In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. RESULTS: The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P = 0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P = 0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P = 0.42). CONCLUSIONS: In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. Copyright © 2011 Massachusetts Medical Society. All rights reserved