Understanding EMPA-REG OUTCOME
2015; Elsevier BV; Volume: 3; Issue: 12 Linguagem: Inglês
10.1016/s2213-8587(15)00426-x
ISSN2213-8595
AutoresAntonio Ceriello, Stefano Genovese, Edoardo Mannucci, Edoardo Gronda,
Tópico(s)Pancreatic function and diabetes
ResumoAn increased incidence of heart failure has been reported in patients treated with saxagliptin in the SAVOR-TIMI study, and the authors of a recent meta-analysis warned about the possibility that dipeptidyl peptidase-4 (DPP4) inhibitors, as a class, could precipitate heart failure in type 2 diabetes, although this point is controversial considering that in the TECOS Trial1Green JB Bethel MA Armstrong PW et al.TECOS Study GroupEffect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes.N Engl J Med. 2015; 373: 232-242Crossref PubMed Scopus (1907) Google Scholar with sitaglipton this was not observed.2Savarese G Perrone-Filardi P D'Amore C et al.Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in diabetic patients: a meta-analysis.Int J Cardiol. 2015; 181: 239-244Summary Full Text Full Text PDF PubMed Scopus (76) Google Scholar Conversely, a cardiovascular safety trial with the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin unexpectedly showed a reduction in major adverse cardiovascular events and even greater reductions in cardiovascular death and heart failure, which cannot be entirely accounted for by improvements in classic risk factors.3Zinman B Wanner C Lachin JM et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; (published online Sept 17.)https://doi.org/10.1056/NEJMoa1504720Crossref PubMed Scopus (6811) Google Scholar, 4The Lancet Diabetes & EndocrinologyGetting to the heart of the matter in type 2 diabetes.Lancet Diabetes Endocrinol. 2015; 3: 827Summary Full Text Full Text PDF Scopus (6) Google Scholar Both the detrimental effect of saxagliptin and the beneficial action of empagliflozin on heart failure were not expected. Many different mechanisms could be postulated to explain the apparently opposite effects of saxagliptin and empagliflozin on heart failure. One possible unifying hypothesis is the modification of glucagon concentrations, which are reduced by DPP4 inhibitors5Janardhan S Sastry GN Dipeptidyl peptidase IV inhibitors: a new paradigm in type 2 diabetes treatment.Curr Drug Targets. 2014; 15: 600-621Crossref PubMed Scopus (24) Google Scholar and increased by SGLT2 inhibitors.6Ferrannini E Muscelli E Frascerra S et al.Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients.J Clin Invest. 2014; 124: 499-508Crossref PubMed Scopus (759) Google ScholarGlucagon has a key role in the regulation of myocardial glucose uptake and modulates cardiac function.7Jones BJ Tan T Bloom SR Minireview: glucagon in stress and energy homeostasis.Endocrinology. 2012; 153: 1049-1054Crossref PubMed Scopus (85) Google Scholar Glucagon also has a direct inotropic action, mediated by an increase in cyclic adenosine monophosphate and activation of myocardial calcium ion currents.6Ferrannini E Muscelli E Frascerra S et al.Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients.J Clin Invest. 2014; 124: 499-508Crossref PubMed Scopus (759) Google Scholar Additionally, glucagon exerts an antiarrhythmic action.7Jones BJ Tan T Bloom SR Minireview: glucagon in stress and energy homeostasis.Endocrinology. 2012; 153: 1049-1054Crossref PubMed Scopus (85) Google Scholar For all these reasons, glucagon has been proposed, in the past, as a possible treatment for heart failure.7Jones BJ Tan T Bloom SR Minireview: glucagon in stress and energy homeostasis.Endocrinology. 2012; 153: 1049-1054Crossref PubMed Scopus (85) Google ScholarThe reduced risk of admission to hospital for heart failure with empagliflozin3Zinman B Wanner C Lachin JM et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; (published online Sept 17.)https://doi.org/10.1056/NEJMoa1504720Crossref PubMed Scopus (6811) Google Scholar could be partly explained by a direct enhancement of myocardial function, determined by increased concentrations of glucagon. Additionally, the beneficial effect of glucagon on disturbances of cardiac rhythm could partly cause the reduction of cardiovascular mortality with empagliflozin. Conversely, the reduction of glucagon concentrations during treatment with DPP4 inhibitors could precipitate heart failure in individuals with unstable haemodynamic compensation.Our hypothesis provides a reasonable explanation for the results of both saxagliptin and empagliflozin cardiovascular trials, and suggests a new possible target, glucagon, for the prevention of heart failure and cardiovascular death in patients with diabetes. Future studies are needed to confirm this mechanistic hypothesis. However, if the glucagon hypothesis is confirmed, it would be quite paradoxical for a hormone that has always been considered detrimental in diabetes to play a part in the prevention of cardiovascular complications of the disease.AC has received speaking fees, consulting fees, or research grants from AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Danone, DOC Generici, Eli Lilly, Janssen, Mendor, Merck Sharp & Dohme, Mitsubishi, Novartis, Novo Nordisk, OM Pharma, Roche Diagnostics, Sanofi, Servier, Takeda, and Unilever. SG has received speaking fees, consulting fees, or research grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, and Takeda. EM has received speaking fees, consulting fees, or research grants from AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme, and Novartis. EG declares no competing interests. We thank Kimberly Katte from CIBERDEM for her editorial assistance with the Correspondence. An increased incidence of heart failure has been reported in patients treated with saxagliptin in the SAVOR-TIMI study, and the authors of a recent meta-analysis warned about the possibility that dipeptidyl peptidase-4 (DPP4) inhibitors, as a class, could precipitate heart failure in type 2 diabetes, although this point is controversial considering that in the TECOS Trial1Green JB Bethel MA Armstrong PW et al.TECOS Study GroupEffect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes.N Engl J Med. 2015; 373: 232-242Crossref PubMed Scopus (1907) Google Scholar with sitaglipton this was not observed.2Savarese G Perrone-Filardi P D'Amore C et al.Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in diabetic patients: a meta-analysis.Int J Cardiol. 2015; 181: 239-244Summary Full Text Full Text PDF PubMed Scopus (76) Google Scholar Conversely, a cardiovascular safety trial with the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin unexpectedly showed a reduction in major adverse cardiovascular events and even greater reductions in cardiovascular death and heart failure, which cannot be entirely accounted for by improvements in classic risk factors.3Zinman B Wanner C Lachin JM et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; (published online Sept 17.)https://doi.org/10.1056/NEJMoa1504720Crossref PubMed Scopus (6811) Google Scholar, 4The Lancet Diabetes & EndocrinologyGetting to the heart of the matter in type 2 diabetes.Lancet Diabetes Endocrinol. 2015; 3: 827Summary Full Text Full Text PDF Scopus (6) Google Scholar Both the detrimental effect of saxagliptin and the beneficial action of empagliflozin on heart failure were not expected. Many different mechanisms could be postulated to explain the apparently opposite effects of saxagliptin and empagliflozin on heart failure. One possible unifying hypothesis is the modification of glucagon concentrations, which are reduced by DPP4 inhibitors5Janardhan S Sastry GN Dipeptidyl peptidase IV inhibitors: a new paradigm in type 2 diabetes treatment.Curr Drug Targets. 2014; 15: 600-621Crossref PubMed Scopus (24) Google Scholar and increased by SGLT2 inhibitors.6Ferrannini E Muscelli E Frascerra S et al.Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients.J Clin Invest. 2014; 124: 499-508Crossref PubMed Scopus (759) Google Scholar Glucagon has a key role in the regulation of myocardial glucose uptake and modulates cardiac function.7Jones BJ Tan T Bloom SR Minireview: glucagon in stress and energy homeostasis.Endocrinology. 2012; 153: 1049-1054Crossref PubMed Scopus (85) Google Scholar Glucagon also has a direct inotropic action, mediated by an increase in cyclic adenosine monophosphate and activation of myocardial calcium ion currents.6Ferrannini E Muscelli E Frascerra S et al.Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients.J Clin Invest. 2014; 124: 499-508Crossref PubMed Scopus (759) Google Scholar Additionally, glucagon exerts an antiarrhythmic action.7Jones BJ Tan T Bloom SR Minireview: glucagon in stress and energy homeostasis.Endocrinology. 2012; 153: 1049-1054Crossref PubMed Scopus (85) Google Scholar For all these reasons, glucagon has been proposed, in the past, as a possible treatment for heart failure.7Jones BJ Tan T Bloom SR Minireview: glucagon in stress and energy homeostasis.Endocrinology. 2012; 153: 1049-1054Crossref PubMed Scopus (85) Google ScholarThe reduced risk of admission to hospital for heart failure with empagliflozin3Zinman B Wanner C Lachin JM et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; (published online Sept 17.)https://doi.org/10.1056/NEJMoa1504720Crossref PubMed Scopus (6811) Google Scholar could be partly explained by a direct enhancement of myocardial function, determined by increased concentrations of glucagon. Additionally, the beneficial effect of glucagon on disturbances of cardiac rhythm could partly cause the reduction of cardiovascular mortality with empagliflozin. Conversely, the reduction of glucagon concentrations during treatment with DPP4 inhibitors could precipitate heart failure in individuals with unstable haemodynamic compensation. Our hypothesis provides a reasonable explanation for the results of both saxagliptin and empagliflozin cardiovascular trials, and suggests a new possible target, glucagon, for the prevention of heart failure and cardiovascular death in patients with diabetes. Future studies are needed to confirm this mechanistic hypothesis. However, if the glucagon hypothesis is confirmed, it would be quite paradoxical for a hormone that has always been considered detrimental in diabetes to play a part in the prevention of cardiovascular complications of the disease. AC has received speaking fees, consulting fees, or research grants from AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Danone, DOC Generici, Eli Lilly, Janssen, Mendor, Merck Sharp & Dohme, Mitsubishi, Novartis, Novo Nordisk, OM Pharma, Roche Diagnostics, Sanofi, Servier, Takeda, and Unilever. SG has received speaking fees, consulting fees, or research grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, and Takeda. EM has received speaking fees, consulting fees, or research grants from AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme, and Novartis. EG declares no competing interests. We thank Kimberly Katte from CIBERDEM for her editorial assistance with the Correspondence. Getting to the heart of the matter in type 2 diabetesCardiovascular health and disease are of central importance in patients with diabetes. Despite early studies failing to show an effect of strict glycaemic control on cardiovascular outcomes, the benefits of glucose lowering on microvascular complications, and an apparent absence of cardiovascular harm, have led to measures of glycaemia becoming the accepted proxy for treatment benefit. However, after concerns were raised about the cardiovascular safety of rosiglitazone, the US Food and Drug Administration (FDA) in 2008 mandated that all new drugs for diabetes undergo specific cardiovascular safety assessment, a policy that has since been implemented by other regulatory agencies internationally. Full-Text PDF
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