Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Abstract BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)

Prevention of serious vascular events by aspirin amongst patients with peripheral arterial disease: randomized, double-blind trial

Objective. To assess the prophylactic efficacy of aspirin and a high-dose antioxidant vitamin combination in patients with peripheral arterial disease (PAD) in terms of reduction of the risk of a first vascular event (myocardial infarction, stroke, vascular death) and critical limb ischaemia

Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial

Background: We aimed to assess efficacy and safety, with a special focus on cardiovascular safety, of the novel dual GIP and GLP-1 receptor agonist tirzepatide versus insulin glargine in adults with type 2 diabetes and high cardiovascular risk inadequately controlled on oral glucose-lowering medications. Methods: This open-label, parallel-group, phase 3 study was done in 187 sites in 14 countries on five continents. Eligible participants, aged 18 years or older, had type 2 diabetes treated with any combination of metformin, sulfonylurea, or sodium-glucose co-transporter-2 inhibitor, a baseline glycated haemoglobin (HbA1c) of 7·5–10·5% (58–91 mmol/mol), body-mass index of 25 kg/m2 or greater, and established cardiovascular disease or a high risk of cardiovascular events. Participants were randomly assigned (1:1:1:3) via an interactive web-response system to subcutaneous injection of either once-per-week tirzepatide (5 mg, 10 mg, or 15 mg) or glargine (100 U/mL), titrated to reach fasting blood glucose of less than 100 mg/dL. The primary endpoint was non-inferiority (0·3% non-inferiority boundary) of tirzepatide 10 mg or 15 mg, or both, versus glargine in HbA1c change from baseline to 52 weeks. All participants were treated for at least 52 weeks, with treatment continued for a maximum of 104 weeks or until study completion to collect and adjudicate major adverse cardiovascular events (MACE). Safety measures were assessed over the full study period. This study was registered with ClinicalTrials.gov, NCT03730662. Findings: Patients were recruited between Nov 20, 2018, and Dec 30, 2019. 3045 participants were screened, with 2002 participants randomly assigned to tirzepatide or glargine. 1995 received at least one dose of tirzepatide 5 mg (n=329, 17%), 10 mg (n=328, 16%), or 15 mg (n=338, 17%), or glargine (n=1000, 50%), and were included in the modified intention-to-treat population. At 52 weeks, mean HbA1c changes with tirzepatide were −2·43% (SD 0·05) with 10 mg and −2·58% (0·05) with 15 mg, versus −1·44% (0·03) with glargine. The estimated treatment difference versus glargine was −0·99% (multiplicity adjusted 97·5% CI −1·13 to −0·86) for tirzepatide 10 mg and −1·14% (−1·28 to −1·00) for 15 mg, and the non-inferiority margin of 0·3% was met for both doses. Nausea (12–23%), diarrhoea (13–22%), decreased appetite (9–11%), and vomiting (5–9%) were more frequent with tirzepatide than glargine (nausea 2%, diarrhoea 4%, decreased appetite &lt;1%, and vomiting 2%, respectively); most cases were mild to moderate and occurred during the dose-escalation phase. The percentage of participants with hypoglycaemia (glucose &lt;54 mg/dL or severe) was lower with tirzepatide (6–9%) versus glargine (19%), particularly in participants not on sulfonylureas (tirzepatide 1–3% vs glargine 16%). Adjudicated MACE-4 events (cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina) occurred in 109 participants and were not increased on tirzepatide compared with glargine (hazard ratio 0·74, 95% CI 0·51–1·08). 60 deaths (n=25 [3%] tirzepatide; n=35 [4%] glargine) occurred during the study. Interpretation: In people with type 2 diabetes and elevated cardiovascular risk, tirzepatide, compared with glargine, demonstrated greater and clinically meaningful HbA1c reduction with a lower incidence of hypoglycaemia at week 52. Tirzepatide treatment was not associated with excess cardiovascular risk. Funding: Eli Lilly and Company

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

BACKGROUN

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin- kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months. RESULTS At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of -56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P = 0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P = 0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P = 0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001). CONCLUSIONS In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower-risk patients but did have a significant benefit in the trial involving higher-risk patients