Skip to main content
Top
Published in: Cardiovascular Diabetology 1/2016

Open Access 01-12-2016 | Review

The EMPA-REG outcome study: critical appraisal and potential clinical implications

Authors: Gianluca Perseghin, Anna Solini

Published in: Cardiovascular Diabetology | Issue 1/2016

Login to get access

Abstract

Diabetes health care professionals have to face a study with results of incomparable success in secondary and tertiary cardiovascular disease prevention. In the past, no studies in patients with type 2 diabetes resulted to be successful in inducing an improvement of cardiovascular prognosis, no matter whether they were focused on a target, on life-style or on pharmacological intervention. On a clinical perspective, should the diabetologist’s way to think about the anti-diabetic therapy of patients on secondary cardiovascular prevention change based on the results of Empa-Reg outcome? Due to the complexity of the clinical picture of patients with type 2 diabetes, a tailored therapy based on targets, complications, co-morbidity, familial and social environment, personal and cultural features must be conceived and applied in starting pharmacological therapy; however, the question whether should we consider empagliflozin as first choice therapy in individuals with type 2 diabetes exposed to high cardiovascular risk, the Empa-Reg outcome-like patient, awaits now for an answer. Waiting for data confirming the results of the Empa-Reg outcome study, this report goes through the good reasons in support of this way of thinking, but at the same time explores the many unanswered questions raising potential concerns about this clinical choice.
Literature
1.
go back to reference Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. EMPA-REG outcome investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.CrossRefPubMed Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. EMPA-REG outcome investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.CrossRefPubMed
2.
go back to reference Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone clinical trial in macrovascular events): a randomised controlled trial. Lancet. 2005;366:1279–89.CrossRefPubMed Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone clinical trial in macrovascular events): a randomised controlled trial. Lancet. 2005;366:1279–89.CrossRefPubMed
3.
go back to reference ORIGIN trial investigators, Gerstein HC, Bosch J, Dagenais GR, Díaz R, Jung H, Maggioni AP, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319–28.CrossRef ORIGIN trial investigators, Gerstein HC, Bosch J, Dagenais GR, Díaz R, Jung H, Maggioni AP, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319–28.CrossRef
4.
go back to reference Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. SAVOR-TIMI 53 Steering committee and investigators. saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26.CrossRefPubMed Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. SAVOR-TIMI 53 Steering committee and investigators. saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26.CrossRefPubMed
5.
go back to reference White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, EXAMINE investigators, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35.CrossRefPubMed White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, EXAMINE investigators, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35.CrossRefPubMed
6.
go back to reference Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, TECOS study group, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42.CrossRefPubMed Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, TECOS study group, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42.CrossRefPubMed
7.
go back to reference Gilbert RE, Krum H. Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy. Lancet. 2015;385:2107–17.CrossRefPubMed Gilbert RE, Krum H. Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy. Lancet. 2015;385:2107–17.CrossRefPubMed
8.
go back to reference Fadini GP, Avogaro A, Degli Esposti L, Russo P, Saragoni S, Buda S, OsMed Health-DB Network. Risk of hospitalization for heart failure in patients with type 2 diabetes newly treated with DPP-4 inhibitors or other oral glucose-lowering medications: a retrospective registry study on 127,555 patients from the nationwide osmed health-db database. Eur Heart J. 2015;36(36):2454–62.CrossRefPubMed Fadini GP, Avogaro A, Degli Esposti L, Russo P, Saragoni S, Buda S, OsMed Health-DB Network. Risk of hospitalization for heart failure in patients with type 2 diabetes newly treated with DPP-4 inhibitors or other oral glucose-lowering medications: a retrospective registry study on 127,555 patients from the nationwide osmed health-db database. Eur Heart J. 2015;36(36):2454–62.CrossRefPubMed
9.
go back to reference Filion KB, Azoulay L, Platt RW, Dahl M, Dormuth CR, Clemens KK, CNODES investigators, et al. A multicenter observational study of incretin-based drugs and heart failure. N Engl J Med. 2016;374:1145–54.CrossRefPubMed Filion KB, Azoulay L, Platt RW, Dahl M, Dormuth CR, Clemens KK, CNODES investigators, et al. A multicenter observational study of incretin-based drugs and heart failure. N Engl J Med. 2016;374:1145–54.CrossRefPubMed
10.
go back to reference Li L, Li S, Deng K, Liu J, Vandvik PO, Zhao P, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ. 2016;352:i610.CrossRefPubMedPubMedCentral Li L, Li S, Deng K, Liu J, Vandvik PO, Zhao P, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ. 2016;352:i610.CrossRefPubMedPubMedCentral
11.
go back to reference Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, ELIXA investigators, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247–57.CrossRefPubMed Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, ELIXA investigators, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247–57.CrossRefPubMed
12.
go back to reference UK prospective diabetes study (UKPDS) group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33. Lancet. 1998;352:837–53.CrossRef UK prospective diabetes study (UKPDS) group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33. Lancet. 1998;352:837–53.CrossRef
13.
go back to reference Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC, Bigger JT, Buse JB, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.CrossRef Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC, Bigger JT, Buse JB, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.CrossRef
14.
go back to reference ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.CrossRef ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.CrossRef
15.
go back to reference Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, VADT investigators, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39.CrossRefPubMed Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, VADT investigators, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39.CrossRefPubMed
16.
go back to reference Gerstein HC, Miller ME, Ismail-Beigi F, Largay J, McDonald C, Lochnan HA, ACCORD Study Group, et al. Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial. Lancet. 2014;384:1936–41.CrossRefPubMedPubMedCentral Gerstein HC, Miller ME, Ismail-Beigi F, Largay J, McDonald C, Lochnan HA, ACCORD Study Group, et al. Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial. Lancet. 2014;384:1936–41.CrossRefPubMedPubMedCentral
17.
go back to reference Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, et al. VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;372:2197–206.CrossRefPubMed Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, et al. VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;372:2197–206.CrossRefPubMed
18.
go back to reference Holman RR, Paul SK, Bethel MA, Neil HA, Matthews DR. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.CrossRefPubMed Holman RR, Paul SK, Bethel MA, Neil HA, Matthews DR. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.CrossRefPubMed
19.
go back to reference Look AHEAD research group, Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369:145–54.CrossRef Look AHEAD research group, Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369:145–54.CrossRef
20.
go back to reference Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, PREDIMED Study Investigators, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368:1279–90.CrossRefPubMed Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, PREDIMED Study Investigators, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368:1279–90.CrossRefPubMed
21.
go back to reference Nishimura R, Tanaka Y, Koiwai K, Inoue K, Hach T, Salsali A, Lund SS, Broedl UC, et al. Effect of empagliflozin monotherapy on postprandial glucose and 24-hour glucose variability in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, 4-week study. Cardiovasc Diabetol. 2015;14:11.CrossRefPubMedPubMedCentral Nishimura R, Tanaka Y, Koiwai K, Inoue K, Hach T, Salsali A, Lund SS, Broedl UC, et al. Effect of empagliflozin monotherapy on postprandial glucose and 24-hour glucose variability in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, 4-week study. Cardiovasc Diabetol. 2015;14:11.CrossRefPubMedPubMedCentral
22.
go back to reference Neeland IJ, McGuire DK, Chilton R, Crowe S, Lund SS, Woerle HJ, et al. Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2016;13:119–26.CrossRefPubMedPubMedCentral Neeland IJ, McGuire DK, Chilton R, Crowe S, Lund SS, Woerle HJ, et al. Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2016;13:119–26.CrossRefPubMedPubMedCentral
23.
go back to reference Roden M, Merker L, Christiansen AV, Roux F, Salsali A, Kim G, EMPA-REG EXTEND™ MONO investigators, et al. Safety, tolerability and effects on cardiometabolic risk factors of empagliflozin monotherapy in drug-naïve patients with type 2 diabetes: a double-blind extension of a Phase III randomized controlled trial. Cardiovasc Diabetol. 2015;14:154.CrossRefPubMedPubMedCentral Roden M, Merker L, Christiansen AV, Roux F, Salsali A, Kim G, EMPA-REG EXTEND™ MONO investigators, et al. Safety, tolerability and effects on cardiometabolic risk factors of empagliflozin monotherapy in drug-naïve patients with type 2 diabetes: a double-blind extension of a Phase III randomized controlled trial. Cardiovasc Diabetol. 2015;14:154.CrossRefPubMedPubMedCentral
24.
go back to reference Soltani Z, Rasheed K, Kapusta DR, Reisin E. Potential role of uric acid in metabolic syndrome, hypertension, kidney injury, and cardiovascular diseases: is it time for reappraisal? Curr Hypertens Rep. 2013;15:175–81.CrossRefPubMedPubMedCentral Soltani Z, Rasheed K, Kapusta DR, Reisin E. Potential role of uric acid in metabolic syndrome, hypertension, kidney injury, and cardiovascular diseases: is it time for reappraisal? Curr Hypertens Rep. 2013;15:175–81.CrossRefPubMedPubMedCentral
25.
go back to reference vonLueder TG, Girerd N, Atar D, Agewall S, Lamiral Z, Kanbay M, et al. High-risk myocardial infarction database initiative investigators serum uric acid is associated with mortality and heart failure hospitalizations in patients with complicated myocardial infarction: findings from the high-risk myocardial infarction database initiative. Eur J Heart Fail. 2015;17:1144–51.CrossRef vonLueder TG, Girerd N, Atar D, Agewall S, Lamiral Z, Kanbay M, et al. High-risk myocardial infarction database initiative investigators serum uric acid is associated with mortality and heart failure hospitalizations in patients with complicated myocardial infarction: findings from the high-risk myocardial infarction database initiative. Eur J Heart Fail. 2015;17:1144–51.CrossRef
26.
go back to reference MacIsaac RL, Salatzki J, Higgins P, Walters MR, Padmanabhan S, Dominiczak AF, et al. Allopurinol and cardiovascular outcomes in adults with hypertension. Hypertension. 2016;67:535–40.PubMed MacIsaac RL, Salatzki J, Higgins P, Walters MR, Padmanabhan S, Dominiczak AF, et al. Allopurinol and cardiovascular outcomes in adults with hypertension. Hypertension. 2016;67:535–40.PubMed
27.
go back to reference Larsen KS, Pottegård A, Lindegaard HM, Hallas J. Effect of allopurinol on cardiovascular outcomes in hyperuricemic patients: a cohort study. Am J Med. 2016;129:299–306.CrossRefPubMed Larsen KS, Pottegård A, Lindegaard HM, Hallas J. Effect of allopurinol on cardiovascular outcomes in hyperuricemic patients: a cohort study. Am J Med. 2016;129:299–306.CrossRefPubMed
28.
go back to reference SøltoftLarsen K, Pottegård A, Lindegaard HM, Hallas J. Impact of urate level on cardiovascular risk in allopurinol treated patients a nested case-control study. PLoS ONE. 2016;11(1):e0146172.CrossRef SøltoftLarsen K, Pottegård A, Lindegaard HM, Hallas J. Impact of urate level on cardiovascular risk in allopurinol treated patients a nested case-control study. PLoS ONE. 2016;11(1):e0146172.CrossRef
29.
go back to reference Terami N, Ogawa D, Tachibana H, Hatanaka T, Wada J, Nakatsuka A, et al. Long-term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. PLoS ONE. 2014;9:e100777.CrossRefPubMedPubMedCentral Terami N, Ogawa D, Tachibana H, Hatanaka T, Wada J, Nakatsuka A, et al. Long-term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. PLoS ONE. 2014;9:e100777.CrossRefPubMedPubMedCentral
30.
go back to reference Cheng ST, Chen L, Li SY, Mayoux E, Leung PS. The effects of empagliflozin, an SGLT2 inhibitor, on pancreatic β-cell mass and glucose homeostasis in type 1 diabetes. PLoS ONE. 2016;11:e0147391.CrossRefPubMedPubMedCentral Cheng ST, Chen L, Li SY, Mayoux E, Leung PS. The effects of empagliflozin, an SGLT2 inhibitor, on pancreatic β-cell mass and glucose homeostasis in type 1 diabetes. PLoS ONE. 2016;11:e0147391.CrossRefPubMedPubMedCentral
31.
go back to reference Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, EMPA-REG OUTCOME® trial investigators et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J. 2016;37:1526–34. Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, EMPA-REG OUTCOME® trial investigators et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J. 2016;37:1526–34.
33.
go back to reference Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499–508.CrossRefPubMedPubMedCentral Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499–508.CrossRefPubMedPubMedCentral
34.
go back to reference Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, et al. Shift to fatty substrates utilization in response to sodium-glucose co-transporter-2 inhibition in nondiabetic subjects and type 2 diabetic patients. Diabetes. 2016;65:1190–5.CrossRefPubMed Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, et al. Shift to fatty substrates utilization in response to sodium-glucose co-transporter-2 inhibition in nondiabetic subjects and type 2 diabetic patients. Diabetes. 2016;65:1190–5.CrossRefPubMed
35.
go back to reference Škrtić M, Cherney DZ. Sodium-glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy. Curr Opin Nephrol Hypertens. 2015;24:96–103.CrossRefPubMed Škrtić M, Cherney DZ. Sodium-glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy. Curr Opin Nephrol Hypertens. 2015;24:96–103.CrossRefPubMed
36.
go back to reference Cherney DZ, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13:28.CrossRefPubMedPubMedCentral Cherney DZ, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13:28.CrossRefPubMedPubMedCentral
37.
go back to reference Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587–97.CrossRefPubMed Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587–97.CrossRefPubMed
Metadata
Title
The EMPA-REG outcome study: critical appraisal and potential clinical implications
Authors
Gianluca Perseghin
Anna Solini
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2016
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-016-0403-8

Other articles of this Issue 1/2016

Cardiovascular Diabetology 1/2016 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.