Abstract
Aims
EMPAREG OUTCOME study showed a reduction in cardiovascular events in patients treated with the sodium-glucose transporter 2 inhibitor (SGLT2i) empagliflozin, as compared to placebo. Other drugs of the same class are currently been investigated for cardiovascular outcomes. In the meanwhile, a re-analysis of data collected in available studies can add relevant insight.
Methods
A MEDLINE search for SGLT-2 inhibitors (dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, ertugliflozin, luseogliflozin) was performed, collecting all randomized trials up to November 16, 2015. All trials with a duration of treatment ≥12 weeks, enrolling patients with type 2 diabetes, comparing a SGLT2i with placebo or other comparators were included. The principal outcome was the effect of SGLT2i on all-cause and cardiovascular mortality. Secondary endpoints were myocardial infarction and stroke. Mantel–Haenszel odds ratio with 95 % confidence interval (MH-OR) was calculated.
Results
A total of 71 trials were included (31,199 and 16,088 patients in SGLT2i and comparator groups). Treatment with SGLT2i was associated with a significant reduction in all-cause mortality (MH-OR 0.70 [0.59–0.83], p < 0.001), cardiovascular mortality (MH-OR 0.43 [0.36–0.53], p < 0.001), and myocardial infarction (MH-OR 0.77 [0.63–0.94], p < 0.01), but not stroke (MH-OR 1.09 [0.86–1.38], p = 0.50), with no apparent difference across molecules (after excluding cardiovascular outcome trials).
Conclusions
Available data suggest that the beneficial action observed with empagliflozin on all-cause and cardiovascular mortality in EMPAREG OUTCOME study is a class effect. The present meta-analysis showed a significantly reduction in myocardial infarction, with no increased risk of stroke.
Similar content being viewed by others
References
Zinman B, Wanner C, Lachin JM et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373:2117–2128
Scirica BM, Bhatt DL, Braunwald E 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 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 et al (2015) Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 373:232–242
Pfeffer MA, Claggett B, Diaz R et al (2015) Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 373:2247–2257
Ceriello A, Genovese S, Mannucci E, Gronda E (2015) Understanding EMPA-REG OUTCOME. Lancet Diabetes Endocrinol 3:929–930
Gilbert RE, Connelly KA (2015) Understanding EMPA-REG OUTCOME. Lancet Diabetes Endocrinol 3:930–931
Muskiet MH, van Raalte DH, van Bommel E, Smits MM, Tonneijck L (2015) Understanding EMPA-REG OUTCOME. Lancet Diabetes Endocrinol 3:928–929
CANVAS—CANagliflozin cardioVascular Assessment Study. https://www.clinicaltrial.gov/ct2/show/NCT01032629?term=canvas&rank=1. Last accessed 25 Jan 2016
Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58). https://www.clinicaltrial.gov/ct2/show/NCT01730534?term=declare+dapagliflozin&rank=1. Last accessed 25 Jan 2016
Cardiovascular outcomes following treatment with ertugliflozin in participants with type 2 diabetes mellitus and established vascular disease (MK-8835-004). https://www.clinicaltrial.gov/ct2/show/NCT01986881?term=ertugliflozin+cardiovascular&rank=1. Last accessed 25 Jan 2016
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000MedR.pdf. Last accessed 25 Jan 2016
Wu JH, Foote C, Blomster J et al (2016) Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 4:411–419
http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015029573. Last accessed 25 Jan 2016
www.fda.gov. Last accessed on 25 Jan 2016
www.ema.europa.eu. Last accessed on 25 Jan 2016
Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101
Egger M, Davey SG, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634
Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264–269
Solini A (2016) Role of SGLT-2 inhibitors in the treatment of type 2 diabetes mellitus. Acta Diabetol. (Epub ahead of print)
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002649/WC500156457.pdf. Last accessed on 25 Jan 2016
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002677/WC500168592.pdf. Last accessed 25 Jan 2016
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204629Orig1s000MedR.pdf. Last accessed 25 Jan 2016
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002322/WC500136026.pdf. Last accessed 25 Jan 2016
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/202293Orig1s000MedR.pdf. Last accessed 25 Jan 2016
Savarese G, D’Amore C, Federici M et al (2016) Effects of dipeptidyl peptidase 4 inhibitors and sodium-glucose linked cotransporter-2 inhibitors on cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis. Int J Cardiol 220:595–601
Monami M, Genovese S, Mannucci E (2013) Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 15:938–953
Monami M, Ragghianti B, Zannoni S, Vitale V, Nreu B, Mannucci E (2016) Identification of predictors of response to basal insulin and DPP4 inhibitors in patients with type 2 diabetes failing to other therapies. Acta Diabetol 53:35–40
Kim SC, Glynn RJ, Liu J, Everett BM, Goldfine AB (2014) Dipeptidyl peptidase-4 inhibitors do not increase the risk of cardiovascular events in type 2 diabetes: a cohort study. Acta Diabetol 51:1015–1023
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM339293.pdf. Last accessed 25 Jan 2016
Mahaffey KW, Roe MT, Dyke CK et al (2002) Misreporting of myocardial infarction end points: results of adjudication by a central clinical events committee in the PARAGON-B trial. Second Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network Trial. Am Heart J 143:242–248
Rosenstock J, Aggarwal N, Polidori D et al (2012) Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care 35:1232–1238
Inagaki N, Kondo K, Yoshinari T, Maruyama N, Susuta Y, Kuki H (2013) Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study. Diabetes Obes Metab 15:1136–1145
Sha S, Polidori D, Heise T et al (2014) Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metab 16:1087–1095
Fulcher G, Matthews DR, Perkovic V et al (2015) Efficacy and safety of canagliflozin used in conjunction with sulfonylurea in patients with type 2 diabetes mellitus: a randomized, controlled trial. Diabetes Ther 6:289–302
Ji L, Han P, Liu Y et al (2015) Canagliflozin in Asian patients with type 2 diabetes on metformin alone or metformin in combination with sulphonylurea. Diabetes Obes Metab 17:23–31
Neal B, Perkovic V, de Zeeuw D et al (2015) Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care 38:403–411
Inagaki N, Kondo K, Yoshinari T, Takahashi N, Susuta Y, Kuki H (2014) Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24-week, randomized, double-blind, placebo-controlled, Phase III study. Expert Opin Pharmacother 15:1501–1515
Forst T, Guthrie R, Goldenberg R et al (2014) Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab 16:467–477
Stenlöf K, Cefalu WT, Kim KA et al (2014) Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study. Curr Med Res Opin 30:163–175
Wilding JP, Charpentier G, Hollander P et al (2013) Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract 67:1267–1282
Weir MR, Kline I, Xie J, Edwards R, Usiskin K (2014) Effect of canagliflozin on serum electrolytes in patients with type 2 diabetes in relation to estimated glomerular filtration rate (eGFR). Curr Med Res Opin 30:1759–1768
Lavalle-González FJ, Januszewicz A, Davidson J et al (2013) Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia 56:2582–2592
Bode B, Stenlöf K, Sullivan D, Fung A, Usiskin K (1995) Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract 2013(41):72–84
Schernthaner G, Gross JL, Rosenstock J et al (2013) Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care 36:2508–2515
Cefalu WT, Leiter LA, Yoon KH et al (2013) Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 382:941–950
.https://clinicaltrials.gov/ct2/show/NCT01340664?term=NCT01340664&rank=1
Kaku K, Inoue S, Matsuoka O et al (2013) Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab 15:432–440
List JF, Woo V, Morales E, Tang W, Fiedorek FT (2009) Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 32:650–657
Wilding JP, Woo V, Soler NG et al (2012) Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med 156:405–415
Lambers HHJ, de Zeeuw D, Wie L, Leslie B, List J (2013) Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab 15:853–862
Weber MA, Mansfield TA, Cain VA, Iqbal N, Parikh S, Ptaszynska A (2015) Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. (Epub ahead of print)
Mudaliar S, Henry RR, Boden G et al (2014) List J.AChanges in insulin sensitivity and insulin secretion with the sodium glucose cotransporter 2 inhibitor dapagliflozin. Diabetes Technol Ther 16:137–144
https://clinicaltrials.gov/ct2/show/NCT01137474?term=NCT01137474&rank=1
Schumm-Draeger PM, Burgess L, Korányi L, Hruba V, Hamer-Maansson JE, de Bruin TW (2015) Twice-daily dapagliflozin co-administered with metformin in type 2 diabetes: a 16-week randomized, placebo-controlled clinical trial. Diabetes Obes Metab 17:42–51
Henry RR, Murray AV, Marmolejo MH, Hennicken D, Ptaszynska A, List JF (2012) Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Pract 66:446–456
Rosenstock J, Hansen L, Zee P et al (2015) Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: a randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care 38:376–383
Bailey CJ, Iqbal N, T’joen C, List JF (2012) Dapagliflozin monotherapy in drug-naïve patients with diabetes: a randomized-controlled trial of low-dose range. Diabetes Obes Metab 14:951–959
Jabbour SA, Hardy E, Sugg J, Parikh S, Study 10 Group (2014) Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Diabetes Care 37:740–750
Mathieu C, Ranetti AE, Li D et al (2015) Randomized, double-blind, Phase 3 Trial of Triple Therapy with Dapagliflozin Add-on to Saxagliptin Plus Metformin in Type 2 Diabetes. Diabetes Care 38:2009–2017
Kaku K, Kiyosue A, Inoue S et al (2014) Efficacy and safety of dapagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise. Diabetes Obes Metab 16:1102–1110
Strojek K, Yoon KH, Hruba V, Elze M, Langkilde AM, Parikh S (2011) Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab 13:928–938
Cefalu WT, Leiter LA, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ (2015) Dapagliflozin’s effects on glycemia and cardiovascular risk factors in high-risk patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. Diabetes Care 38:1218–1227
Ji L, Ma J, Li H, Mansfield TA et al (2014) Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus: a randomized, blinded, prospective phase III study. Clin Ther 36:84–100
Yang W, Han P, Min KW et al (2015) Efficacy and safety of dapagliflozin in Asian patients with type 2 diabetes after metformin failure: a randomized controlled trial. J Diabetes. (Epub ahead of print)
Rosenstock J, Vico M, Wei L, Salsali A, List JF (2012) Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care 35:1473–1478
Matthaei S, Bowering K, Rohwedder K, Grohl A, Parikh S, Study 05 Group (2015) Dapagliflozin improves glycemic control and reduces body weight as add-on therapy to metformin plus sulfonylurea: a 24-week randomized, double-blind clinical trial. Diabetes Care 38:365–372
Leiter LA, Cefalu WT, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ (2014) Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc 62:1252–1262
Bolinder J, Ljunggren Ö, Johansson L et al (2014) Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab 16:159–169
Bailey CJ, Morales Villegas EC, Woo V, Tang W, Ptaszynska A, List JF (2015) Efficacy and safety of dapagliflozin monotherapy in people with Type 2 diabetes: a randomized double-blind placebo-controlled 102-week trial. Diabet Med 32:531–541
Bailey CJ, Gross JL, Pieters A, Bastien A, List JF (2010) Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 375:2223–2233
Kohan DE, Fioretto P, Tang W, List JF (2014) Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 85:962–971
Wilding JP, Woo V, Rohwedder K, Sugg J, Parikh S, Dapagliflozin 006 Study Group (2014) Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab 16:124–136
Nauck MA, Del Prato S, Durán-García S et al (2014) Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin. Diabetes Obes Metab 16:1111–1120
Ferrannini E, Berk A, Hantel S et al (2013) Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: an active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes Care 36:4015–4021
Rosenstock J, Seman LJ, Jelaska A et al (2013) Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab 15:1154–1160
Kadowaki T, Haneda M, Inagaki N et al (2015) Efficacy and safety of empagliflozin monotherapy for 52 weeks in Japanese patients with type 2 diabetes: a randomized, double-blind, parallel-group study. Adv Ther 32:306–318
Tikkanen I, Narko K, Zeller C et al (2015) Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care 38:420–428
https://clinicaltrials.gov/ct2/show/NCT01649297?term=NCT01649297&rank=1
Häring HU, Merker L, Seewaldt-Becker E et al (2013) Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 36:3396–3404
Roden M, Weng J, Eilbracht J et al (2013) Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol 1:208–219
Barnett AH, Mithal A, Manassie J et al (2014) Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2:369–384
Rosenstock J, Jelaska A, Frappin G et al (2014) Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care 37:1815–1823
DeFronzo RA, Lewin A, Patel S et al (2015) Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care 38:384–393
Lewin A, DeFronzo RA, Patel S et al (2015) Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes. Diabetes Care 3:394–402
Kovacs CS, Seshiah V, Swallow R et al (2014) Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab 16:147–158
Merker L, Häring HU, Christiansen AV et al (2015) Empagliflozin as add-on to metformin in people with Type 2 diabetes. Diabet Med 32:1555–1567
Rosenstock J, Jelaska A, Zeller C et al (2015) Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: a 78-week randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab 17:936–948
Araki E, Tanizawa Y, Tanaka Y et al (2015) Long-term treatment with empagliflozin as add-on to oral antidiabetes therapy in Japanese patients with type 2 diabetes mellitus. Diabetes Obes Metab 17:665–674
Ridderstråle M, Andersen KR et al (2014) Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol 2:691–700
Amin NB, Wang X, Mitchell JR, Lee DS, Nucci G, Rusnak JM (2015) Blood pressure-lowering effect of the sodium glucose co-transporter-2 inhibitor ertugliflozin, assessed via ambulatory blood pressure monitoring in patients with type 2 diabetes and hypertension. Diabetes Obes Metab 17:805–808
Wilding JP, Ferrannini E, Fonseca VA, Wilpshaar W, Dhanjal P, Houzer A (2013) Efficacy and safety of ipragliflozin in patients with type 2 diabetes inadequately controlled on metformin: a dose-finding study. Diabetes Obes Metab 15:403–409
Fonseca VA, Ferrannini E, Wilding JP et al (2013) Active- and placebo-controlled dose-finding study to assess the efficacy, safety, and tolerability of multiple doses of ipragliflozin in patients with type 2 diabetes mellitus. J Diabetes Complic 27:268–273
Kashiwagi A, Kazuta K, Goto K, Yoshida S, Ueyama E, Utsuno A (2015) Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 17:304–308
Kashiwagi A, Takahashi H, Ishikawa H et al (2015) A randomized, double-blind, placebo-controlled study on long-term efficacy and safety of ipragliflozin treatment in patients with type 2 diabetes mellitus and renal impairment: results of the long-term ASP1941 safety evaluation in patients with type 2 diabetes with renal impairment (LANTERN) study. Diabetes Obes Metab 17:152–160
Kashiwagi A, Kazuta K, Yoshida S, Nagase I (2014) Randomized, placebo-controlled, double-blind glycemic control trial of novel sodium-dependent glucose cotransporter 2 inhibitor ipragliflozin in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig 5:382–391
Acknowledgments
This research was performed independently of any funding, as part of the institutional activity of the investigators.
Authors contribution
Matteo Monami designed the study, collected the data, performed the analysis, and wrote the manuscript. Ilaria Dicembrini collected the data and revised the manuscript. Edoardo Mannucci designed the study, collected the data, performed the analysis, and wrote the manuscript. All the authors approved the final version of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Matteo Monami has received speaking fees from Bristol Myers Squibb, Eli-Lilly, Merck, Novonordisk, Merck, and Takeda; and research grants from Bristol Myers Squibb. Ilaria Dicembrini has no conflicts of interest. Edoardo Mannucci has received consultancy fees from Merck and Novartis; speaking fees from Astra Zeneca, Bristol Myers Squibb, Merck, and Novartis; and research grants from Merck, Novartis, and Takeda.
Ethical standard
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Human and animal rights
This article does not contain any studies with animals performed by any of the authors.
Informed consent
For this type of study formal consent is not required.
Additional information
Managed by Massimo Federici.
An erratum to this article is available at http://dx.doi.org/10.1007/s00592-016-0922-5.
Rights and permissions
About this article
Cite this article
Monami, M., Dicembrini, I. & Mannucci, E. Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials. Acta Diabetol 54, 19–36 (2017). https://doi.org/10.1007/s00592-016-0892-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00592-016-0892-7