Cardiorenal benefits of GLP-1 receptor agonists in the treatment of type 2 diabetes mellitus

Czech version

Authors: Rid Dravecká
Authors‘ workplace: I. interná klinika LF UPJŠ a UNLP Košice
Published in: Diab Obez 2022; 22(43): 30-33
Category:

Overview

Chronic complications of diabetes mellitus (DM), including cardiovascular disease (CVD) and chronic kidney disease (CKD), are associated with increased patient mortality. The 2020 American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) recommendations suggest treatment with GLP-1 (glucagon- like peptide-1) receptor agonists (GLP-1 RAs) or sodium-glucose transporter 2 (SGLT2) inhibitors should be preferred in patients at high CV risk. GLP-1 RAs should also be considered in patients without confirmed CVD but with high risk indicators present. A meta-analysis of CV publications and trials with GLP-1 RAs confirmed a 12% reduction in MACE (Major Adverse Cardiovascular Events – hospitalization for heart failure, CV death, CKD progression). The REWIND study including diabetic patients with only 31.5% prevalence of previous CVD confirmed that dulaglutide reduced the risk of CV events compared to placebo in the first year, with a 36% reduction in HbA_1c able to contribute to the reduction in MACE and 64% of the benefit was unrelated to HbA_1c reduction. Diabetic kidney disease is a strong predictor of morbidity and premature mortality in diabetic patients. The chomost reliable evidence of positive renal effects of GLP-1 RAs comes from CV studies. Based on their meta-analysis, GLP-1 RAs treatment reduced the broader composite endpoint (development of macroalbuminuria, worsening renal function, end-stage renal failure, and death from renal causes) by 17%, mainly due to a reduction in albuminuria. Analysis of the REWIND trial under the secondary objective confirmed a 15% reduction in the renal component of the composite microvascular outcome. The most striking effect was on new macroalbuminuria and a sustained decrease in eGF. The protective effect of dulaglutide on renal outcomes is consistent with other studies with GLP-1 RAs, with only dulaglutide demonstrating a beneficial effect on eGF reduction. Early utilization of the benefits of GLP-1 RAs, beyond improving DM compensation, could prevent CV and renal complications and thus reduce morbidity and mortality in patients with T2DM.

Keywords:

Glomerular filtration rate – cardiovascular disease – diabetes mellitus – chronic kidney disease – GLP-1 receptor agonists – macroalbuminuria

Sources

1. Gerstein HC, Colhoun HM, Dagenais GR et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019; 394(10193): 121–130. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(19)31149–3>.

2. Górriz JL, Romera I, Cobo A et al. Glucagon-Like Peptide-1 Receptor Agonist Use in People Living with Type 2 Diabetes Mellitus and Chronic Kidney Disease: A Narrative Review of the Key Evidence with Practical Considerations. Diabetes Ther 2022; 13(3):389–421. Dostupné z DOI: <http://dx.doi.org/10.1007/s13300–021–01198–5>.

3. Buse JB, Wexler DJ, Tsapas A et al. 2019 update to: Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2020; 63(2): 221–228. Dostupné z DOI: <http://dx.doi.org/10.1007/s00125–019–05039-w>.

4. Kristensen SL, Rorth R, Jhund PS et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019; 7(10): 776–785. Dostupné z DOI: <http://dx.doi.org/10.1016/S2213–8587(19)30249–9>.

5. Colhoun HM, Hasenour C, Riddle MC et al. Exploring Potential Mediators of the Cardiovascylar Benefit of dulaglutide in REWIND. ADA 2020. P-924. Dostupné z WWW: <https://www.easd.org/virtualmeeting/home.html#!resources/exploring-potential-mediators-of-the-cardiovascular-benefit-of-dulaglutide-in-rewind>.

6. Greco EV, Russo G, Giandalia A et al. GLP-1 Receptor Agonists and Kidney Protection. Medicina (Kaunas) 2019; 55(6): 233–247. Dostupné z DOI: <http://dx.doi.org/10.3390/medicina55060233>.

7. Tuttle KR, Lakshmanan MC, Rayner B et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol 2018; 6(8): 605–617. Dostupné z DOI: <http://dx.doi.org/10.1016/S2213–8587(18)30104–9>.

8. Gerstein HC, Colhoun HM, Dagenais GR et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWND randomised, placebo-controlled trial. Lancet 2019; 394(10193): 131–138. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(19)31150-X>.

9. KDIGO 2020 Clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int 2020; 98(4S): S1-S115. Dostupné z DOI: <http://dx.doi.org/10.1016/j.kint.2020.06.019>.

10. Lim S, Kim KM, Nauck MA. Glucagon-like peptide-1 receptor agonists and cardiovascular events: class effects versus individual patterns. Trends Endocrinol Metab 2018; 29(4): 238–248. Dostupné z DOI: <http://dx.doi.org/10.1016/j.tem.2018.01.011>.-

11. Zoungas S, de Galan BE, Ninomiya T et al. Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: new results from the ADVANCE trial. Diabetes Care 2019; 32(11): 2068–2074. Dostupné z DOI: <http://dx.doi.org/10.2337/dc09–0959>.

12. Marso SP, Daniels GH, Brown-Frandsen K et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375(4): 311–322. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1603827>.

13. Marso SP, Bain SC, Consoli A et al. Semaglutide and cardiovascualr outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375(19): 1834–1844. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1607141>.

14. Muskiet MHA, Tonneijck L, Huang Y et al. Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2018; 6(1): 859–869. Dostupné z DOI: <http://dx.doi.org/10.1016/S2213–8587(18)30268–7>.

15. Holman RR, Bethel MA, Mentz RJ et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017; 377(13): 1228–1239. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1612917>.