Abstract
Purpose
We did a meta-analysis with meta-regression to evaluate the relationship between hemoglobin A1c (A1C) reduction and the primary CV outcome of cardiovascular outcome trials (CVOTs).
Methods
We used a random effects meta-analysis of the 12 CVOTs to quantify the effect of A1C reduction on major cardiovascular events (MACE) risk by stratifying the difference in achieved A1C (drug vs placebo) in three strata: A1c < 0.3%, A1c ≥ 0.3% and < 0.5%, and A1c ≥ 0.5%.
Results
We found a relation between the reduction in achieved A1C and the hazard ratio reduction for MACE (P = 0.002), explaining almost all (94.1%) the between-study variances: lowering A1C by 0.5% conferred a significant HRR of 20% (95% CI 4–33%) for MACE.
Conclusions
Blood glucose reduction may play a more important role than previously thought in reducing the risk of MACE during treatment with the newer glucose-lowering drugs, including peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium–glucose co-transporter-2 inhibitors.
References
Giugliano D, Maiorino MI, Bellastella G, Esposito K (2018) Glycemic control in type 2 diabetes: from medication nonadherence to residual vascular risk. Endocrine 61:23–27
Giugliano D, Meier JJ, Esposito K (2019) Heart failure and type 2 diabetes: from CVOTs, with hope. Diabetes Obes Metab. https://doi.org/10.1111/dom.13629
Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 151:W65–W94
Higgins JP, Altman DG, Gøtzsche PC et al (2011) Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928
van Houwelingen HC, Arends LR, Stijnen T (2002) Advanced methods in meta-analysis: multivariate approach and meta-regression. Stat Med 21:589–624
Higgins JP, Thompson SG (2004) Controlling the risk of spurious findings from metaregression. Stat Med 23:1663–1682
Scirica BM, Bhatt DL, Braunwald E, SAVOR-TIMI 53 Steering Committee and Investigators et al (2013) Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369:1317–1326
White WB, Cannon CP, Heller SR, EXAMINE Investigators et al (2013) Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 369:1327–1335
Green JB, Bethel MA, Armstrong PW, TECOS Study Group et al (2015) Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 373:232–242
Rosenstock J, Perkovic V, Johansen OE, CARMELINA Investigators et al (2019) Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk. The CARMELINA randomized clinical trial. JAMA 321:69–79
Pfeffer MA, Claggett B, Diaz R, Dickstein K, ELIXA Investigators et al (2015) Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 373:2247–2257
Marso SP, Daniels GH, Brown-Frandsen K, LEADER Steering Committee; LEADER Trial Investigators et al (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375:311–322
Marso SP, Bain SC, Consoli A, SUSTAIN-6 Investigators et al (2016) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 375:1834–1844
Holman RR, Bethel MA, Mentz RJ, EXSCEL Study Group et al (2017) Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 377:1228–1239
Hernandez AF, Green JB, Janmohamed S, Harmony Outcomes Committees and Investigators et al (2018) Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 392:1519–1529
Zinman B, Wanner C, Lachin JM, EMPA-REG OUTCOME Investigators et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373:2117–2128
Neal B, Perkovic V, Mahaffey KW, CANVAS Program Collaborative Group et al (2017) Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377:644–657
Wiviott SD, Raz I, Bonaca MP, DECLARE–TIMI 58 Investigators et al (2019) Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 380:347–357
Davis SN, Duckworth W, Emanuele N, Investigators of the Veterans Affairs Diabetes Trial et al (2019) Effects of severe hypoglycemia on cardiovascular outcomes and death in the Veterans Affairs Diabetes Trial. Diabetes Care. 42:157–163
Serghiou S, Goodman SN (2019) Random-effects meta-analysis. Summarizing evidence with caveats. JAMA 321:301–302
Funding
No funding was specifically allocated for this study.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
D.G. received honoraria for speaking at meetings from Novartis, Sanofi-Aventis, Lilly, AstraZeneca, and NovoNordisk. M.I.M. received honoraria for speaking at meetings from Lilly and NovoNordisk. K.E. received honoraria for speaking at meetings from Novartis, Sanofi-Aventis, Lilly, AstraZeneca, Boehringer Ingelheim, and NovoNordisk. P.C. declares that he has no conflict of interest. G.B. declares that he has no conflict of interest.
Ethical approval
This article does not contain any studies with human participants performed by any of the authors.
Informed consent
For this type of study, informed consent is not required.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Giugliano, D., Chiodini, P., Maiorino, M.I. et al. Cardiovascular outcome trials and major cardiovascular events: does glucose matter? A systematic review with meta-analysis. J Endocrinol Invest 42, 1165–1169 (2019). https://doi.org/10.1007/s40618-019-01047-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40618-019-01047-0