Skip to main content
Erschienen in: Acta Diabetologica 9/2019

16.04.2019 | Original Article

Effects of exenatide long-acting release on cardiovascular events and mortality in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials

verfasst von: B. M. Bonora, A. Avogaro, G. P. Fadini

Erschienen in: Acta Diabetologica | Ausgabe 9/2019

Einloggen, um Zugang zu erhalten

Abstract

Aims

Patients with type 2 diabetes (T2D) have an increased risk of cardiovascular disease. Recent cardiovascular outcome trials (CVOTs) with liraglutide, semaglutide, and albiglutide have shown significant reduction in major adverse cardiovascular events. Conversely, the CVOT with exenatide long-acting release (ELAR) confirmed cardiovascular safety of the drug, but did not reached superiority versus placebo. Herein, we systematically evaluated the effect of ELAR versus placebo or active comparators on cardiovascular events and mortality in patients with T2D.

Methods

We screened the literature for randomized controlled trials reporting cardiovascular events and deaths in patients receiving ELAR versus those receiving placebo or any other glucose-lowering medications. Event rates were pooled and compared using the random-effects model.

Result

We retrieved 16 trials comparing the occurrence of cardiovascular events and mortality in patients treated with ELAR versus placebo or active comparators. The pooled rate ratio for cardiovascular events was similar in the two groups (0.99; 95% CI 0.92–1.06). The rate ratio for all-cause mortality was significantly lower in exenatide group than in comparators (0.87; 95% CI 0.77–0.97). When results of the EXSCEL trial were omitted, the pooled rate ratio for cardiovascular events and mortality was 0.80 (95% CI 0.40–1.63) and 0.75 (95% CI 0.30–1.84), respectively.

Conclusions

Treatment with ELAR does not increase the risk of cardiovascular events and may reduce all-cause mortality.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Sarwar N, Gao P, Kondapally Seshasai SR et al (2010) Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 375(9733):2215–2222CrossRef Sarwar N, Gao P, Kondapally Seshasai SR et al (2010) Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 375(9733):2215–2222CrossRef
2.
Zurück zum Zitat Kondapally Seshasai SR, Kaptoge S, Thompson A et al (2011) Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 364(9):829–841CrossRef Kondapally Seshasai SR, Kaptoge S, Thompson A et al (2011) Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 364(9):829–841CrossRef
3.
Zurück zum Zitat Zoungas S, Arima H, Gerstein HC et al (2017) Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol 5(6):431–437CrossRef Zoungas S, Arima H, Gerstein HC et al (2017) Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol 5(6):431–437CrossRef
4.
Zurück zum Zitat Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359(15):1577–1589CrossRef Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359(15):1577–1589CrossRef
5.
Zurück zum Zitat Uni- M, Sciences HH, Miller ME et al (2011) Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 364(9):818–828CrossRef Uni- M, Sciences HH, Miller ME et al (2011) Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 364(9):818–828CrossRef
6.
Zurück zum Zitat Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356(24):2457–2471CrossRef Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356(24):2457–2471CrossRef
7.
Zurück zum Zitat Petrie JR (2013) The cardiovascular safety of incretin-based therapies: a review of the evidence. Cardiovasc Diabetol 12(1):130CrossRef Petrie JR (2013) The cardiovascular safety of incretin-based therapies: a review of the evidence. Cardiovasc Diabetol 12(1):130CrossRef
8.
Zurück zum Zitat 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(23):2247–2257CrossRef 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(23):2247–2257CrossRef
9.
Zurück zum Zitat Jones B (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes. Ann Clin Biochem 53(6):712CrossRef Jones B (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes. Ann Clin Biochem 53(6):712CrossRef
10.
Zurück zum Zitat Marso SP, Bain SC, Consoli A et al (2016) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 375(19):1834–1844CrossRef Marso SP, Bain SC, Consoli A et al (2016) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 375(19):1834–1844CrossRef
11.
Zurück zum Zitat Hernandez AF, Green JB, Janmohamed S 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(10157):1519–1529CrossRef Hernandez AF, Green JB, Janmohamed S 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(10157):1519–1529CrossRef
12.
Zurück zum Zitat Holman RR, Bethel MA, Mentz RJ et al (2017) Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 377(13):1228–1239CrossRef Holman RR, Bethel MA, Mentz RJ et al (2017) Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 377(13):1228–1239CrossRef
13.
Zurück zum Zitat 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(4):264–269CrossRef 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(4):264–269CrossRef
14.
Zurück zum Zitat Higgins JPT, Altman DG, Gøtzsche PC et al (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 18(343):d5928CrossRef Higgins JPT, Altman DG, Gøtzsche PC et al (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 18(343):d5928CrossRef
15.
Zurück zum Zitat Kunz LM, Normand S-LT, Sedrakyan A (2015) Meta-analysis of rate ratios with differential follow-up by treatment arm: inferring comparative effectiveness of medical devices. Stat Med 34(21):2913–2925CrossRef Kunz LM, Normand S-LT, Sedrakyan A (2015) Meta-analysis of rate ratios with differential follow-up by treatment arm: inferring comparative effectiveness of medical devices. Stat Med 34(21):2913–2925CrossRef
16.
Zurück zum Zitat Newman JD, Vani AK, Aleman JO, Weintraub HS, Berger JS, Schwartzbard AZ (2018) The changing landscape of diabetes therapy for cardiovascular risk reduction: JACC state-of-the-art review. J Am Coll Cardiol 72(15):1856–1869CrossRef Newman JD, Vani AK, Aleman JO, Weintraub HS, Berger JS, Schwartzbard AZ (2018) The changing landscape of diabetes therapy for cardiovascular risk reduction: JACC state-of-the-art review. J Am Coll Cardiol 72(15):1856–1869CrossRef
17.
Zurück zum Zitat Hernandez AF, Green JB, Janmohamed S 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(10157):1519–1529CrossRef Hernandez AF, Green JB, Janmohamed S 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(10157):1519–1529CrossRef
18.
Zurück zum Zitat Walter SD (1991) Statistical significance and fragility criteria for assessing a difference of two proportions. J Clin Epidemiol. 44(12):1373–1378CrossRef Walter SD (1991) Statistical significance and fragility criteria for assessing a difference of two proportions. J Clin Epidemiol. 44(12):1373–1378CrossRef
19.
Zurück zum Zitat Meier JJ (2012) GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 8:728CrossRef Meier JJ (2012) GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 8:728CrossRef
20.
Zurück zum Zitat Lund A, Knop FK, Vilsbøll T (2014) Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes: differences and similarities. Eur J Intern Med 25(5):407–414CrossRef Lund A, Knop FK, Vilsbøll T (2014) Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes: differences and similarities. Eur J Intern Med 25(5):407–414CrossRef
21.
Zurück zum Zitat Gerstein HC, Colhoun HM, Dagenais GR et al (2018) Design and baseline characteristics of participants in the Researching cardiovascular events with a weekly incretin in diabetes (REWIND) trial on the cardiovascular effects of dulaglutide. Diabetes Obes Metab 20(1):42–49CrossRef Gerstein HC, Colhoun HM, Dagenais GR et al (2018) Design and baseline characteristics of participants in the Researching cardiovascular events with a weekly incretin in diabetes (REWIND) trial on the cardiovascular effects of dulaglutide. Diabetes Obes Metab 20(1):42–49CrossRef
22.
Zurück zum Zitat Bain SC, Mosenzon O, Arechavaleta R et al (2018) Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: rationale, design and patient baseline characteristics for the PIONEER 6 trial. Diabetes Obes Metab 21(3):499–508CrossRef Bain SC, Mosenzon O, Arechavaleta R et al (2018) Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: rationale, design and patient baseline characteristics for the PIONEER 6 trial. Diabetes Obes Metab 21(3):499–508CrossRef
25.
26.
Zurück zum Zitat Buse JB, Nauck M, Forst T et al (2013) Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet 381(9861):117–124CrossRef Buse JB, Nauck M, Forst T et al (2013) Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet 381(9861):117–124CrossRef
27.
Zurück zum Zitat Jabbour SA, Frías JP, Hardy E et al (2018) Safety and efficacy of exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy: 52-week results of the DURATION-8 randomized controlled. Diabetes Care 41(10):2136–2146CrossRef Jabbour SA, Frías JP, Hardy E et al (2018) Safety and efficacy of exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy: 52-week results of the DURATION-8 randomized controlled. Diabetes Care 41(10):2136–2146CrossRef
28.
Zurück zum Zitat Ahmann AJ, Capehorn M, Charpentier G et al (2018) Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial. Diabetes Care 41(2):258–266CrossRef Ahmann AJ, Capehorn M, Charpentier G et al (2018) Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial. Diabetes Care 41(2):258–266CrossRef
29.
Zurück zum Zitat Drucker DJ, Buse JB, Taylor K et al (2008) Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 372(9645):1240–1250CrossRef Drucker DJ, Buse JB, Taylor K et al (2008) Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 372(9645):1240–1250CrossRef
30.
Zurück zum Zitat Bergenstal RM, Wysham C, MacConell L et al (2010) Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet 376(9739):431–439CrossRef Bergenstal RM, Wysham C, MacConell L et al (2010) Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet 376(9739):431–439CrossRef
31.
Zurück zum Zitat Diamant M, Van Gaal L, Stranks S et al (2010) Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet 375(9733):2234–2243CrossRef Diamant M, Van Gaal L, Stranks S et al (2010) Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet 375(9733):2234–2243CrossRef
32.
Zurück zum Zitat Russell-Jones D, Cuddihy RM, Hanefeld M et al (2012) Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4). Diabetes Care 35(2):252–258CrossRef Russell-Jones D, Cuddihy RM, Hanefeld M et al (2012) Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4). Diabetes Care 35(2):252–258CrossRef
33.
Zurück zum Zitat Blevins T, Pullman J, Malloy J et al (2011) DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab 96(5):1301–1310CrossRef Blevins T, Pullman J, Malloy J et al (2011) DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab 96(5):1301–1310CrossRef
34.
Zurück zum Zitat Guja C, Frías JP, Somogyi A et al (2018) Effect of exenatide QW or placebo, both added to titrated insulin glargine, in uncontrolled type 2 diabetes: the DURATION-7 randomized study. Diabetes Obes Metab 20:1602–1614CrossRef Guja C, Frías JP, Somogyi A et al (2018) Effect of exenatide QW or placebo, both added to titrated insulin glargine, in uncontrolled type 2 diabetes: the DURATION-7 randomized study. Diabetes Obes Metab 20:1602–1614CrossRef
35.
Zurück zum Zitat Wysham CH, Rosenstock J, Vetter ML (2018) Efficacy and tolerability of the new autoinjected suspension of exenatide once weekly versus exenatide twice daily in patients with type 2 diabetes. Diabetes Obes Metab 20(1):165–172CrossRef Wysham CH, Rosenstock J, Vetter ML (2018) Efficacy and tolerability of the new autoinjected suspension of exenatide once weekly versus exenatide twice daily in patients with type 2 diabetes. Diabetes Obes Metab 20(1):165–172CrossRef
36.
Zurück zum Zitat Gadde KM, Vetter ML, Iqbal N, Hardy E, Öhman P (2017) Efficacy and safety of autoinjected exenatide once-weekly suspension versus sitagliptin or placebo with metformin in patients with type 2 diabetes: the DURATION-NEO-2 randomized clinical study. Diabetes Obes Metab 19(7):979–988CrossRef Gadde KM, Vetter ML, Iqbal N, Hardy E, Öhman P (2017) Efficacy and safety of autoinjected exenatide once-weekly suspension versus sitagliptin or placebo with metformin in patients with type 2 diabetes: the DURATION-NEO-2 randomized clinical study. Diabetes Obes Metab 19(7):979–988CrossRef
37.
Zurück zum Zitat Davies M, Heller S, Sreenan S et al (2013) Once-weekly exenatide versus once- or twice-daily insulin detemir, (5 CC-Metabolic and Endocrine Disorders). Diabetes Care. 36:1368–1376CrossRef Davies M, Heller S, Sreenan S et al (2013) Once-weekly exenatide versus once- or twice-daily insulin detemir, (5 CC-Metabolic and Endocrine Disorders). Diabetes Care. 36:1368–1376CrossRef
38.
Zurück zum Zitat Inagaki N, Atsumi Y, Oura T, Saito H, Imaoka T (2012) Efficacy and safety profile of exenatide once weekly compared with insulin once daily in japanese patients with type 2 diabetes treated with oral antidiabetes drug(s): results from a 26-week, randomized, open-label, parallel-group, multicenter. Noninferio Clin Ther. 34(9):1892–1908.e1CrossRef Inagaki N, Atsumi Y, Oura T, Saito H, Imaoka T (2012) Efficacy and safety profile of exenatide once weekly compared with insulin once daily in japanese patients with type 2 diabetes treated with oral antidiabetes drug(s): results from a 26-week, randomized, open-label, parallel-group, multicenter. Noninferio Clin Ther. 34(9):1892–1908.e1CrossRef
39.
Zurück zum Zitat Ji L, Onishi Y, Ahn CW et al (2013) Efficacy and safety of exenatide once-weekly vs exenatide twice-daily in Asian patients with type 2 diabetes mellitus. J Diabetes Investig 4(1):53–61CrossRef Ji L, Onishi Y, Ahn CW et al (2013) Efficacy and safety of exenatide once-weekly vs exenatide twice-daily in Asian patients with type 2 diabetes mellitus. J Diabetes Investig 4(1):53–61CrossRef
40.
Zurück zum Zitat Abdul-Ghani M, Migahid O, Megahed A, Adams J, Triplitt C, DeFronzo RA et al (2017) Combination therapy with exenatide plus pioglitazone versus basal/bolus insulin in patients with poorly controlled type 2 diabetes on sulfonylurea plus metformin: the qatar study. Diabetes Care 40(3):325–331CrossRef Abdul-Ghani M, Migahid O, Megahed A, Adams J, Triplitt C, DeFronzo RA et al (2017) Combination therapy with exenatide plus pioglitazone versus basal/bolus insulin in patients with poorly controlled type 2 diabetes on sulfonylurea plus metformin: the qatar study. Diabetes Care 40(3):325–331CrossRef
Metadaten
Titel
Effects of exenatide long-acting release on cardiovascular events and mortality in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials
verfasst von
B. M. Bonora
A. Avogaro
G. P. Fadini
Publikationsdatum
16.04.2019
Verlag
Springer Milan
Erschienen in
Acta Diabetologica / Ausgabe 9/2019
Print ISSN: 0940-5429
Elektronische ISSN: 1432-5233
DOI
https://doi.org/10.1007/s00592-019-01347-0

Weitere Artikel der Ausgabe 9/2019

Acta Diabetologica 9/2019 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.