Treatment with exenatide once weekly or twice daily for 30 weeks is associated with changes in several cardiovascular risk markers

Abstract

Background: Cyslipidemia and type 2 diabetes are two of the most significant risk factors for the development of cardiovascular disease. Measurement of lipoprotein subclasses provides important information about derangements in lipid metabolism and helps refine cardiovascular risk assessment. Exenatide, a glucagon-like peptide 1 receptor agonist, improved glycemic control, obesity, hypertension, and dyslipidemia in patients with type 2 diabetes in clinical trials.

Methods: In the DURATION-1 trial, patients with type 2 diabetes were treated with exenatide once weekly or twice daily for 30 weeks. This post hoc analysis evaluated the impact of exenatide on lipoprotein subclasses in 211 DURATION-1 patients using vertical auto profile methodology and the Statistical Package for the Social Sciences general linear model adjusted for glycosylated hemoglobin (HbA(1c)) and weight.

Results: Baseline lipids and high sensitivity C-reactive protein were normal overall based on the standard lipid panel. Once-weekly exenatide reduced apolipoprotein B and the apolipoprotein B to apolipoprotein A1 ratio (P < 0.05), independent of glycemic improvement and weight loss. A significant shift in lipoprotein pattern away from small, dense low-density lipoprotein-4 cholesterol was also observed (P < 0.05). Exenatide once weekly increased high-density lipoprotein-2 cholesterol, even after adjustment for changes in HbA(1c) and weight (P < 0.05). Triglycerides, very low-density lipoprotein cholesterol, and high sensitivity C-reactive protein were reduced with both the once-weekly and twice-daily exenatide regimens (P < 0.05).

Conclusion: In this post hoc analysis, exenatide significantly improved a number of cardiovascular risk markers. Continuous exenatide exposure with exenatide once weekly elicited a greater response than did immediate-release exenatide twice daily, generally independent of glycemic improvement and weight loss. Thus, in addition to improving glycemic control, exenatide induced favorable changes in lipid and lipoprotein metabolism and decreased systemic inflammation.

Trial registration: ClinicalTrials.gov NCT00308139.

Keywords: dyslipidemia; glucagon-like protein-1 receptor agonist; incretin mimetic; type 2 diabetes mellitus.

Figures

Figure 1

Effects of exenatide on glycosylated hemoglobin, body weight, apolipoproteins, and lipoproteins in the total analysis cohort with an overall normal lipid profile at baseline. Week 30 change data are independent of glycemic improvement and weight loss. (A) Glycosylated hemoglobin. (B) Body weight. (C) Apolipoprotein B. (D) Percentage of apolipoprotein B/apolipoprotein A1. (E) Low-density lipoprotein cholesterol and its subclasses. (F) Triglycerides, very low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol. (G) High-density lipoprotein cholesterol and its subclasses. (H) Percentage changes in high-density lipoprotein cholesterol and its subclasses. (Panels A and B) Least squares mean + 95% confidence intervals. *Change from baseline P < 0.0001. (PanelsC–G) Adjusted mean + standard error of the mean. Notes: *Week 30 change from baseline P< 0.05. Once weekly, n = 106, twice daily, n = 105. Abbreviations: A1c, glycosylated hemoglobin; ApoB, apolipoprotein B; ApoA1, apolipoprotein A1; BID, twice daily; LDL-C, low-density lipoprotein cholesterol; VLDL-C, very low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; QW, once weekly.

Figure 2

Effects of exenatide on apolipoproteins, lipoproteins, and high sensitivity C-reactive protein in the subgroup of patients with abnormal lipid values– at baseline. (A) Apolipoprotein A1, apolipoprotein B, and the ratio of these apolipoproteins; once weekly, n = 85, n = 9, and n = 22, respectively; twice daily, n = 78, 18, and 29, respectively. (B) Low-density lipoprotein cholesterol and subclass ratios; once weekly, n = 28, 28, and 28, respectively; twice daily, n = 36, 36, and 36, respectively. (C) Triglycerides, very low-density lipoprotein (VLDL) cholesterol, VLDL3 cholesterol, ratio of VLDL cholesterol/VLDL3 cholesterol, and intermediate-density lipoprotein cholesterol; once weekly, n = 55, 18, 77, 106, and 7, respectively; twice daily, n = 52, 20, 75, 104, and 6, respectively. (D) Non-high-density lipoprotein cholesterol and remnant lipoproteins; once weekly, n = 26 and n = 13, respectively; and twice daily, n = 34 and n = 21, respectively. (E) Total high-density lipoprotein cholesterol and its subclasses stratified by gender and overall subclass ratio; once weekly, n = 51, 39, 57, 22, 47, and 95, respectively; twice daily, n = 46, 39, 55, 17, 44, and 96, respectively. (F) High sensitivity C-reactive protein in the total cohort; once weekly, n = 104; twice daily, n = 103. Notes: High sensitivity C-reactive protein in the subgroup with baseline > 3 mg/L and <10 mg/L; once weekly, n = 41; twice daily, n = 32. Adjusted mean + standard error of the mean. *Week 30 change from baseline P < 0.05. Abbreviations: BL, baseline; ApoB, apolipoprotein B; ApoA1, apolipoprotein A1; LDL-C, low-density lipoprotein cholesterol; BID, twice daily; HDL-C, high-density lipoprotein cholesterol; VLDL-C, very low-density lipoprotein cholesterol; IDL-C, intermediate-density lipoprotein cholesterol; RLPs, remnant lipoproteins; hsCRP, high sensitivity C-reactive protein; QW, once weekly.