Long-term changes in cardiovascular risk markers during administration of exenatide twice daily or glimepiride: results from the European exenatide study

Abstract

ObjectiveThe risk of cardiovascular morbidity and mortality is significantly increased in patients with diabetes; thus, it is important to determine whether glucose-lowering therapy affects this risk over time. Changes in cardiovascular risk markers were examined in patients with type 2 diabetes treated with exenatide twice daily (a glucagon-like peptide-1 receptor agonist) or glimepiride (a sulfonylurea) added to metformin in the EURopean EXenAtide (EUREXA) study.Research design and methodsPatients with type 2 diabetes failing metformin were randomized to add-on exenatide twice daily (n = 515) or glimepiride (n = 514) until treatment failure defined by hemoglobin A1C. Anthropomorphic measures, blood pressure (BP), heart rate, lipids, and high-sensitivity C-reactive protein (hsCRP) over time were evaluated.ResultsOver 36 months, twice-daily exenatide was associated with improved body weight (−3.9 kg), waist circumference (−3.6 cm), systolic/diastolic BP (−2.5/−2.6 mmHg), high-density lipoprotein (HDL)-cholesterol (0.05 mmol/L), triglycerides (−0.2 mmol/L), and hsCRP (−1.7 mg/L). Heart rate did not increase (−0.3 beats/minute), and low-density lipoprotein-cholesterol (0.2 mmol/L) and total cholesterol (0.1 mmol/L) increased slightly. Between-group differences were significantly in favor of exenatide for body weight (P < 0.0001), waist circumference (P < 0.001), systolic BP (P < 0.001), diastolic BP (P = 0.023), HDL-cholesterol (P = 0.001), and hsCRP (P = 0.004). Fewer patients randomized to exenatide twice daily versus glimepiride required the addition of at least one antihypertensive (20.4 vs 26.4 %; P = 0.026) or lipid-lowering medication (8.4 vs 12.8 %; P = 0.025).ConclusionsAdd-on exenatide twice daily was associated with significant, sustained improvement in several cardiovascular risk markers in patients with type 2 diabetes versus glimepiride.Clinical trial registration: NCT00359762, http://www.ClinicalTrials.gov

The Cardiovascular Biology of Glucagon-like Peptide-1

“…More sustained GLP-1R agonism is associated with a persistent increase in HR but a drop in systolic BP in hypertensive individuals (Ferdinand et al, 2014;Meier et al, 2015;. Patients treated with twice-daily exenatide for 36 months achieved better BP control and required less frequent addition of anti-hypertensive agents to control BP compared to subjects treated with glimepiride (Simó et al, 2015). The increase in HR persists with sustained GLP-1R agonism in subjects with T1D, T2D, or obesity Dungan et al, 2014;Meier et al, 2015;Pi-Sunyer et al, 2015).…”

“…GLP-1R agonists reduce BP in clinical trials of subjects with T2D and hypertension, and the changes in BP are not strictly dependent on weight loss (Jimenez-Solem et al, 2010;Meier et al, 2015;Simó et al, 2015;. Treatment of diabetic hypertensive subjects (mean age 64, BMI 31.9, HbA1c 7.7%) for 7 weeks with 1.8 mg liragutide daily reduced both systolic BP (by 7 mm Hg) and extracellular volume (by 2.0 L) (von Scholten et al, 2015).…”

The Use of Exenatide in Managing Markers of Cardiovascular Risk in Patients with Type 2 Diabetes: A Systematic Review

“…All the eleven studies [19,20,21,22,23,24,25,26,27,28,29] (Table 1) for this review were multicentre and randomised controlled studies involving patients with type 2 diabetes. While seven of the studies [19,21,22,23,25,27,28] were conducted in at least 2 countries, the remaining 4 [20,24,26,29] were conducted in Italy, Japan, the US and Germany respectively.…”

“…While seven of the studies [19,21,22,23,25,27,28] were conducted in at least 2 countries, the remaining 4 [20,24,26,29] were conducted in Italy, Japan, the US and Germany respectively. However, all eleven studies had background treatment in addition to the intervention treatments except the study by Gastaldelli et al [19].…”

“…While one of the remaining 4 studies had placebo + lifestyle modification as control [26], the other 3 studies were not placebo controlled [27,28,29]. The interventions included; exenatide + lifestyle modification versus placebo + lifestyle modification with metformin and/or sulfonylurea as background treatment [25]; exenatide versus Glimepiride with metformin as background treatment [27,28]; exenatide versus premixd insulin aspart with metformin as background treatment [29].…”