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Glucagon-Like Peptide 1 Receptor Agonists, Carotid Atherosclerosis

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Glucagon-Like Peptide 1 Receptor Agonists, Carotid Atherosclerosis 1 Diabetes Care Volume 44, June 2021 ] Glucagon-Like Peptide 1 Guillaume Marquis-Gravel and Jean-Claude Tardif Receptor Agonists, Carotid Atherosclerosis, and Cardiovascular Outcomes Diabetes Care 2021;44:1–2 | https://doi.org/10.2337/DCi20-0076 Glucagon-like peptide 1 receptor ago- and they are preferred to insulin if in- there was no significant difference in nists (GLP-1 RA) represent an integral jectable therapy is needed (8). the change over time in plaque volume part of the arsenal used in clinical Although the impact of GLP-1RA between study groups. Plaque composi- practice to improve cardiovascular out- on cardiovascular outcomes has been tion was also not modified by once- comes in patients with diabetes. showntobedirectlycorrelatedwith weekly exenatide, without significant Large-scale randomized controlled tri- the reduction in glycated hemoglobin differences detected in changes over als have shown that liraglutide, dula- (9), pleiotropic effects of agents from time in the dimensions of calcified pla- glutide, albiglutide, and semaglutide this class have been documented, in- ques, lipid-rich necrotic core plaques, all reduce the risk of cardiovascular cluding reduction of systolic and diastol- and fibrouscapsbetweenthetwo events in patients with diabetes and ic blood pressure (10), body weight treatment arms. Results were consis- fl fi either established atherosclerotic (11), and vascular in ammation (12), in tent among key prespeci ed subgroups cardiovascular disease (ASCVD) or addition to improvement of endothelial and after excluding participants not high-risk characteristics (1–4). In con- function (13). However, the impact of completely adhering to the protocol. fi trast, exenatide and lixisenatide im- GLP-1 RA on atherosclerotic plaque vol- The lack of bene tofonce-weekly proved glycemic control but did not ume and composition had not yet been exenatide on carotid plaque volume investigated. and composition observed in this study have a sizable impact on cardiovascu- As reported in this issue of Diabetes is consistent with its modest effect on lar events in clinical trials (5,6), sug- Care, Koska et al. (14) examined wheth- the primary composite end point of gesting that glycemic control and er the GLP-1 RA exenatide modifies ca- death from cardiovascular causes, non- cardiovascular outcomes are at least rotid plaque volume and composition in fatal myocardial infarction, or nonfatal partly uncoupled. A meta-analysis in- patients with type 2 diabetes. They con- stroke in the Exenatide Study of Cardio- cluding 42,920 participants from five ducted a placebo-controlled, double- vascular Event Lowering (EXSCEL) trial randomized trials demonstrated that blind, pragmatic randomized trial in of 14,752 patients followed for a medi- GLP-1 RA as a drug class are associat- which 163 participants were randomly an of 3.2 years (hazard ratio 0.91, 95% fi ed with a signi cant 13% reduction in allocated to receive either exenatide 2 CI 0.83–1.00, P 5 0.06). Whether other the risk of the composite of myocardi- mg (n 5 109) or placebo (n 5 54) sub- GLP-1 RA associated with more marked al infarction, stroke, or cardiovascular fi COMMENTARY cutaneously once weekly. Patients with cardiovascular bene ts (liraglutide, du- death in patients with diabetes and a high carotid atherosclerosis burden at laglutide, albiglutide, and semaglutide) established ASCVD (7). GLP-1 RA are baseline were enrolled, with the majori- would yield different results on carotid recommended in patients with diabe- ty presenting calcified plaques and lip- MRI is not known. Nevertheless, a pre- tes and established ASCVD or at high id-rich necrotic cores. Plaque volume vious study without a placebo group risk of ASCVD (8). They are also indi- and composition were measured using found that liraglutide, a GLP-1 RA that cated as second-line therapy in pa- serial carotid MRI at baseline, 9 demonstrated cardiovascular benefits tients without ASCVD (or without months, and 18 months of follow-up. (1), significantly reduced carotid intima- indicators of high risk) who do not Despite a mean reduction in glycated media thickness (15). In the Harmony meet treatment goals with lifestyle hemoglobin of 0.55% with once-weekly Outcomes trial, the reduction of cardio- modifications and metformin alone, exenatide compared with placebo, vascular risk with albiglutide was Montreal Heart Institute, Universite de Montreal, Montreal, Quebec, Canada Corresponding author: Jean-Claude Tardif, [email protected] © 2021 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/content/license. See accompanying article, p. XXX. Diabetes Care Publish Ahead of Print, published online May 20, 2021 care.diabetesjournals.org Marquis-Gravel and Tardif 2 greater than would have been expected observed in this study does not exclude exenatide on cardiovascular outcomes in type 2 – given the degree of glycated hemoglo- a potential effect on coronary athero- diabetes. N Engl J Med 2017;377:1228 1239 6. Pfeffer MA, Claggett B, Diaz R, et al.; ELIXA bin reduction, suggesting that the cardi- sclerosis. Notwithstanding these limita- Investigators. Lixisenatide in patients with type 2 oprotective effects are not exclusively tions, the study by Koska et al. suggests diabetes and acute coronary syndrome. N Engl J linked to glycemic control (3,9). In the that the cardiovascular benefits of GLP- Med 2015;373:2247–2257 current study, a correlation was ob- 1 RA might not be entirely due to struc- 7. Zelniker TA, Wiviott SD, Raz I, et al. Comparison of the effects of glucagon-like served between reductions of glycated tural changes in atherosclerotic plaques. hemoglobin and plaque volume in the peptide receptor agonists and sodium-glucose In order to definitely answer that ques- cotransporter 2 inhibitors for prevention of fi exenatide group, but the signi cance of tion, additional placebo-controlled ran- major adverse cardiovascular and renal out- this observation is uncertain given the domized trials involving imaging of comes in type 2 diabetes mellitus. Circulation 2019;139:2022–2031 lack of overall effect on changes in ca- carotid and coronary arteries should be rotid MRI end points compared with 8. American Diabetes Association. 9. Pharma- conducted with those GLP-1 RA that placebo. cologic approaches to glycemic treatment: have shown more pronounced benefits Standards of Medical Care in Diabetes—2021. The increase in heart rate of 9 bpm at on cardiovascular outcomes. Diabetes Care 2021;44(Suppl. 1):S111–S124 3 months of treatment with once-weekly 9. Zweck E, Roden M. GLP-1 receptor agonists exenatide compared with placebo was and cardiovascular disease: drug-specificor more marked than that reported in clini- class effects? Lancet Diabetes Endocrinol 2019; Duality of Interest. J.-C.T. reports grants – cal trials of GLP-1 RA associated with 7:89 90 from Amarin, AstraZeneca, Ceapro, DalCor, Es- 10. Wang B, Zhong J, Lin H, et al. Blood greater reductions in cardiovascular perion, Ionis, Pfizer, and RegenXBio; honoraria pressure-lowering effects of GLP-1 receptor event rates (1,4,11). In light of the prog- from AstraZeneca, DalCor, HLS Therapeutics, agonists exenatide and liraglutide: a meta- nostic value of resting heart rate on car- Pharmascience, and Servier; and minor equity analysis of clinical trials. Diabetes Obes Metab diovascular outcomes and its link with interest in DalCor. G.M.G. reports grants from 2013;15:737–749 Bayer. No other potential conflicts of interest 11. Robinson LE, Holt TA, Rees K, Randeva HS, experimental atherosclerosis (16), the ’ – relevant to this article were reported. O Hare JP. Effects of exenatide and liraglutide on heart rate elevating effect of once- heart rate, blood pressure and body weight: weekly exenatide might explain in part References systematic review and meta-analysis. BMJ Open the disappointing carotid imaging results 1. Marso SP, Daniels GH, Brown-Frandsen K, 2013;3:e001986 12. Drucker DJ. The cardiovascular biology of in the current study. et al.; LEADER Steering Committee; LEADER Trial glucagon-like peptide-1. Cell Metab 2016;24: The study by Koska et al. (14) needs Investigators. Liraglutide and cardiovascular 15–30 outcomes in type 2 diabetes. N Engl J Med 2016; to be carefully interpreted in light of 13. Koska J, Sands M, Burciu C, et al. Exenatide 375:311–322 the relatively small sample size and the protects against glucose- and lipid-induced 2. Gerstein HC, Colhoun HM, Dagenais GR, high rate (25%) of incomplete imaging endothelial dysfunction: evidence for direct et al.; REWIND Investigators. Dulaglutide procedures at 18 months of follow-up. vasodilation effect of GLP-1 receptor agonists and cardiovascular outcomes in type 2 – The latter may be of importance given in humans. Diabetes 2015;64:2624 2635 diabetes (REWIND): a double-blind, 14. Koska J, Migrino RQ, Chan KC, Cooper-Cox K, that patients who withdrew early had randomised placebo-controlled trial. Lancet Reaven PD. The effect of exenatide once weekly – lower BMI and triglyceride values than 2019;394:121 130 on carotid atherosclerosis in individuals with those who completed the study. Given 3. Hernandez AF, Green JB, Janmohamed S, type 2 diabetes: an 18-month randomized that some clinical trials of GLP-1 RA etal.;HarmonyOutcomescommitteesand placebo-controlled study. Diabetes Care 2021; investigators. Albiglutide and cardiovascular 44:XXX–XXX have shown limited differences in out- outcomes in patients with type 2 diabetes fi 15. Rizzo M, Rizvi AA, Patti AM, et al. Liraglutide comes within the rst 2 years but and cardiovascular disease (Harmony Out- improves metabolic parameters and carotid greater separation of cumulative car- comes): a double-blind, randomised placebo- intima-media thickness in diabetic patients diovascular event curves thereafter, controlled trial. Lancet 2018;392:1519–1529 with the metabolic syndrome: an 18-month the 18-month follow-up duration in the 4.
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