Effects of semaglutide on stroke subtypes in type 2 diabetes: post hoc analysis of the randomised SUSTAIN 6 & PIONEER 6

This is the final version. Available on open access from Lippincott, Williams & Wilkins via the DOI in this record Background: Glucagon-like peptide-1 receptor agonists, including semaglutide, may reduce stroke risk in people with type 2 diabetes (T2D). This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with T2D at high cardiovascular (CV) risk. Methods: SUSTAIN 6 and PIONEER 6 were randomised CV outcome trials of subcutaneous and oral semaglutide in people with T2D at high CV risk, respectively. Time to first stroke and stroke subtypes were analysed using a Cox proportional hazards model stratified by trial with pooled treatment as a factor. The impact of prior stroke, prior myocardial infarction or stroke, age, sex, systolic blood pressure, estimated glomerular filtration rate, and prior atrial fibrillation on treatment effects was assessed using interaction p-values. Risk of major adverse CV event (MACE) was analysed according to prior stroke. Results: 106/6480 participants had a stroke (1.0 event/100 patient-years of observation [PYO]). Semaglutide reduced incidence of any stroke versus placebo (0.8 vs 1.1 events/100 PYO; HR 0.68, 95%CI 0.46–1.00;p=0.048), driven by significant reductions in risk of small-vessel occlusion (0.3 vs 0.7 events/100 PYO; HR 0.51, 95%CI 0.29–0.89;p=0.017). HRs for risk of any stroke with semaglutide versus placebo were 0.60 (95%CI 0.37–0.99; 0.5 vs 0.9 events/100 PYO) and 0.89 (95%CI 0.47–1.69; 2.7 vs 3.0 events/100 PYO) in those without and with prior stroke, respectively. Except for prior atrial fibrillation (pinteraction=0.025), no significant interactions were observed between treatment effects on risk of any stroke and subgroups investigated, or between treatment effects on risk of MACE and prior stroke (pinteraction>0.05 for all). Conclusions: Semaglutide reduced incidence of any first stroke during the trials versus placebo in people with T2D at high CV risk, primarily driven by small-vessel occlusion prevention. Semaglutide treatment, versus placebo, lowered the risk of stroke irrespective of prior stroke at baseline. Clinical Trial Registration Information: SUSTAIN 6: NCT01720446 (https://clinicaltrials.gov/ct2/show/NCT01720446); PIONEER 6: NCT02692716 (https://clinicaltrials.gov/ct2/show/NCT02692716).Novo Nordisk A/S (Søborg, Denmark

Impact of microvascular disease on cardiovascular outcomes in type 2 diabetes: Results from the LEADER and SUSTAIN 6 clinical trials

The randomized, double-blind, cardiovascular outcomes trials LEADER (NCT01179048) and SUSTAIN 6 (NCT01720446) showed cardiovascular risk reduction in patients with type 2 diabetes treated with liraglutide and semaglutide, respectively, compared with placebo. This post hoc analysis examined the impact of microvascular disease at baseline on cardiovascular outcomes in these trials, and the efficacy of liraglutide (1.8 mg) and once-weekly semaglutide (0.5-1.0 mg) in patients with and without microvascular disease. In total, 9340 patients from LEADER and 3297 patients from SUSTAIN 6 were included in this analysis; of these, 5761 and 2356 had a history of microvascular disease at baseline and 3835 and 1640 had a history of both microvascular and macrovascular disease, respectively. Patients with microvascular disease were shown to have an increased risk of major adverse cardiovascular events compared with patients without microvascular disease (hazard ratio [95% confidence interval] in LEADER: 1.15 [1.03; 1.29], P =.0136; SUSTAIN 6: 1.56 [1.14; 2.17], P =.0064). Liraglutide and semaglutide consistently reduced cardiovascular risk in patients with and without microvascular disease

Influences of electrocardiographic ischaemia grades and symptom duration on outcomes in patients with acute myocardial infarction treated with thrombolysis versus primary percutaneous coronary intervention: results from the DANAMI‐2 trial

OBJECTIVE: To determine whether ischaemia grade (GI) on the presenting ECG and duration of symptoms can identify subgroups of patients who would derive more benefit than the general population of patients with ST segment elevation acute myocardium infarction (STEMI) from primary percutaneous coronary intervention (pPCI) over thrombolytic treatment (TT) in reducing mortality or reinfarction. METHODS: 1319 DANAMI‐2 (Danish trial in Acute Myocardial Infarction‐2) patients were classified as having grade 2 ischaemia (GI2; ST segment elevation without terminal QRS distortion) or grade 3 ischaemia (GI3; ST segment elevation with terminal QRS distortion in ⩾ 2 adjacent leads), and were divided into early and late groups split by the median time (3 h) from symptom onset to treatment. Outcomes were 30‐day mortality and reinfarction. RESULTS: Mortality was significantly higher for GI3 than for GI2 (9.7% v 4.8%, p < 0.001) and doubled for patients presenting late (GI2: 6.0% v 3.3%, p  =  0.01; GI3: 12.5% v 4.7%, p  =  0.05). Overall mortality did not differ significantly between pPCI and TT; however, a 5.5% absolute mortality reduction was seen in GI3 treated early with pPCI (1.4% v 6.9%, p  =  0.10). Reinfarction rate was particularly high among GI3 patients presenting late and treated with TT (12.2%). pPCI in such patients significantly reduced the rate of reinfarction (0%, p < 0.001). Logistic regression analysis showed that age (odds ratio (OR) 1.09, 95% confidence interval (CI) 1.06 to 1.12, p < 0.001), prior angina (OR 2.56, 95% CI 1.44 to 4.54, p  =  0.001), heart rate (OR 1.03, 95% CI 1.01 to 1.04, p  =  0.001) and GI3 (OR 1.91, 95% CI 1.06 to 3.44, p  =  0.031) were independently associated with mortality, whereas the sum of ST segment elevation was not. CONCLUSIONS: GI3 is an independent predictor of mortality among patients with STEMI. Mortality increased significantly with symptom duration in both GI2 and GI3. pPCI may be especially beneficial for patients with GI3 presenting early, whereas patients with GI3 presenting late and treated with TT are at particular risk of reinfarction

Effects of Semaglutide on Stroke Subtypes in Type 2 Diabetes: Post Hoc Analysis of the Randomized SUSTAIN 6 and PIONEER 6

BACKGROUND: GLP-1 RA (glucagon-like peptide-1 receptor agonists), including semaglutide, may reduce stroke risk in people with type 2 diabetes. This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk. METHODS: SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and PIONEER 6 (Peptide Innovation for Early Diabetes Treatment) were randomized cardiovascular outcome trials of subcutaneous and oral semaglutide in people with type 2 diabetes at high cardiovascular risk, respectively. Time to first stroke and stroke subtypes were analyzed using a Cox proportional hazards model stratified by trial with pooled treatment as a factor. The impact of prior stroke, prior myocardial infarction or stroke, age, sex, systolic blood pressure, estimated glomerular filtration rate, and prior atrial fibrillation on treatment effects was assessed using interaction P values. Risk of major adverse cardiovascular event was analyzed according to prior stroke. RESULTS: A total of 106/6480 participants had a stroke (1.0 event/100 patient-years of observation [PYO]). Semaglutide reduced incidence of any stroke versus placebo (0.8 versus 1.1 events/100 PYO; hazard ratio, 0.68 [95% CI, 0.46-1.00]; P=0.048), driven by significant reductions in risk of small-vessel occlusion (0.3 versus 0.7 events/100 PYO; hazard ratio, 0.51 [95% CI, 0.29-0.89]; P=0.017). Hazard ratios for risk of any stroke with semaglutide versus placebo were 0.60 (95% CI, 0.37-0.99; 0.5 versus 0.9 events/100 PYO) and 0.89 (95% CI, 0.47-1.69; 2.7 versus 3.0 events/100 PYO) in those without and with prior stroke, respectively. Except for prior atrial fibrillation (P(interaction)=0.025), no significant interactions were observed between treatment effects on risk of any stroke and subgroups investigated, or between treatment effects on risk of major adverse cardiovascular event and prior stroke (P(interaction) >0.05 for all). CONCLUSIONS: Semaglutide reduced incidence of any first stroke during the trials versus placebo in people with type 2 diabetes at high cardiovascular risk, primarily driven by small-vessel occlusion prevention. Semaglutide treatment, versus placebo, lowered the risk of stroke irrespective of prior stroke at baseline. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01720446 and NCT02692716.RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted.Published version, accepted version, submitted versio

Changes in circulating mesenchymal stem cells, stem cell homing factor, and vascular growth factors in patients with acute ST elevation myocardial infarction treated with primary percutaneous coronary intervention

OBJECTIVE: To investigate the spontaneous occurrence of circulating mesenchymal stem cells (MSC) and angiogenic factors in patients with ST elevation acute myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). DESIGN: In 20 patients with STEMI, blood samples were obtained on days 1, 3, 7, 14, 21, and 28 after the acute PCI. Fifteen patients with a normal coronary angiography formed a control group. MSC (CD45−/CD34−), plasma stromal derived factor 1 (SDF‐1), vascular endothelial growth factor A (VEGF‐A), and fibroblast growth factor 2 (FGF‐2) were measured by multiparametric flow cytometry and enzyme linked immunosorbent assay (ELISA). RESULTS: Circulating CD45−/CD34− cells were significantly decreased on day 7 compared with day 3. Cell counts normalised one month after the acute onset of STEMI. The changes were mainly seen in patients with a large infarction. Plasma SDF‐1 increased significantly from day 3 to day 28, and VEGF‐A and FGF‐2 increased significantly from day 7 to day 28. CONCLUSIONS: Spontaneous sequential fluctuations in MSC and the increase in vascular growth factor concentrations after STEMI suggest that the optimal time for additional stem cell therapy is three weeks after a myocardial infarction to obtain the maximum effects by stimulating endogenous growth factors on the delivered stem cells

Dr. Galen Wagner (1939-2016) as an Academic Writer: An Overview of his Peer-reviewed Scientific Publications

Cardiolog