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Macrovascular Residual Risk Studies

2 November 2021
New meta-analysis reaffirms the favourable benefit versus risk of GLP-1 receptor agonists in patients with type 2 diabetes mellitus
This latest report including data from over 60,000 patients with type 2 diabetes mellitus (T2DM) showed that Glucagon-Like Peptide-1 (GLP-1) receptor agonists reduce the risk of cardiovascular events, all-cause mortality, hospital admission for heart failure, and worsening kidney function.
Sattar N, Lee MMY, Kristensen SL, 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 randomised trials. Lancet Diabetes Endocrinol 2021; doi: 10.1016/S2213-8587(21)00203-5. Online ahead of print.


Objective: To investigate the cardiovascular benefits and risks of GLP-1 receptor agonists using the most up-to-date evidence from outcome trials in patients with T2DM.
Study design: Meta-analysis of published randomised placebo-controlled trials (>500 patients) testing GLP-1 receptor agonists in patients with T2DM.
Study population: Eight trials comprising 60,080 patients. All trials had a primary outcome that included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.
Study outcomes: • Primary efficacy endpoint: major adverse cardiovascular events (MACE), i.e, cardiovascular death, myocardial infarction, or stroke.
• Other outcomes: all-cause mortality; hospital admission for heart failure; composite kidney outcome, defined as development of macroalbuminuria, doubling of serum creatinine, or at least 40% decline in estimated glomerular filtration rate (eGFR), kidney replacement therapy, or death due to kidney disease; worsening of kidney function, based on eGFR change
• Key safety outcomes: severe hypoglycaemia, retinopathy, pancreatitis, and pancreatic cancer
Methods: Meta-analysis using a random effects model to estimate overall hazard ratio for each of the outcomes defined above.
Main results:

GLP-1 receptor agonists significantly reduced MACE by 14%, all-cause mortality by 12%, and hospital admission for heart failure by 11%, and improved kidney outcomes by 21% (Table 1). There was also no increase in the risk of severe hypoglycaemia, retinopathy, or pancreatic adverse effects associated with GLP-receptor agonists therapy. There was no significant heterogeneity across GLP-1 receptor agonist structural homology.  

Table 1. Hazard ratio (95% confidence interval) for cardiovascular and renal outcomes and all-cause mortality


HR (95% CI)



0.86 (95% CI 0.80-0.93)


Hospital admission for heart failure

0.89 (95% CI 0.82-0.98)


All-cause mortality

0.88 (95% CI 0.82-0.94)


Composite kidney outcome

0.79 (95% CI 0.73-0.87)


Authors’ conclusion: GLP-1 receptor agonists, regardless of structural homology, reduced the risk of individual MACE components, all-cause mortality, hospital admission for heart failure, and worsening kidney function in patients with T2DM.


Extensive evidence shows that treatment with a GLP-1 receptor agonist reduces cardiovascular outcomes, independent of glucose control considerations (1-4). As a result, these agents are among the newer diabetes medications preferentially endorsed in international endocrinology and cardiology society guidelines for patients with T2DM with or at increased risk for atherosclerotic cardiovascular disease (5,6). However, uncertainty regarding their impact on kidney outcomes persists (7-9).

The current meta-analysis aimed to address these uncertainties. The findings clearly show clinical benefit for both cardiovascular and kidney outcomes with GLP-1 receptor agonists in patients with T2DM. Furthermore, there was no evidence to suggest any difference in these benefits with exendin-4-based GLP-1 receptor agonists. The findings of this report strengthen guideline recommendations for the use of GLP-1 receptor agonists to prevent cardiovascular disease in T2DM. Evidence of favourable impact on kidney outcomes is highly relevant given that diabetic nephropathy is a major cause of morbidity and mortality in diabetes.

References 1. McGuire DK, Pagidipati NJ. GLP1 receptor agonists: from antihyperglycaemic to cardiovascular drugs. Lancet Diabetes Endocrinology 2021;
2. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–22.
3. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomized placebo-controlled trial. Lancet 2018;392:1519–29.
4. 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;394:121–30
5. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88.
6. Cosentino F, Grant PJ, Ab V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: The Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). Eur Heart J 2020;41255–323.
7. Yamada T, Wakabayashi M, Bhalla A, et al. Cardiovascular and renal outcomes with SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and network meta-analysis. Cardiovasc Diabetol 2021;20(1):14.
8. Bellary S, Tahrani AA, Barnett AH. Improving management of diabetic kidney disease: will GLP-1 receptor agonists have a role? Lancet Diabetes Endocrinol 2020 Nov;8(11):870-871.
9. Sarafidis P, Ferro CJ, Morales E, et al. SGLT-2 inhibitors and GLP-1 receptor agonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease. A consensus statement by the EURECA-m and the DIABESITY working groups of the ERA-EDTA. Nephrol Dial Transplant. 2020 Oct 1;35(10):1825
Key words : Glucagon-Like Peptide-1 (GLP-1) receptor agonists; residual cardiovascular risk; MACE; kidney outcomes