Cardiovascular protection significantly depends on HbA1c improvement with  GLP-1RAs but not with SGLT2 is in type 2 diabetes: A narrative review.

Scheen, André

doi:10.1016/j.diabet.2023.101508

Article (Scientific journals)

Cardiovascular protection significantly depends on HbA1c improvement with GLP-1RAs but not with SGLT2 is in type 2 diabetes: A narrative review.

Scheen, André

2023 • In Diabetes and Metabolism, 50 (2), p. 101508

Peer Reviewed verified by ORBi

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https://hdl.handle.net/2268/312544

DOI
10.1016/j.diabet.2023.101508

PubMed
38158077

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Keywords :

Cardiovascular outcome; GLP-1 receptor agonist; HbA1c; Mediation; Meta-regression; SGLT2 inhibitor

Abstract :

[en] BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is), while developed as antihyperglycaemic medications for the treatment of type 2 diabetes, have proven to reduce major cardiovascular adverse events (MACEs) and hospitalization for heart failure (especially for SGLT2is) in dedicated cardiovascular outcome trials. The contribution of the glucose-lowering effect in the cardiovascular protection is uncertain and may differ between the two drug classes. METHODS: This narrative review compares the relative effects of glycated hemoglobin (HbA1c) reduction on the cardiovascular protection provided by GLP-1RAs and SGLT2is in placebo-controlled cardiovascular outcome trials by using the results of either post-hoc mediation analyses or meta-regression studies. RESULTS: Both mediation and meta-regression analyses suggest that the lower cardiovascular risk with GLP-1RAs partially but substantially tracks with their glucose-lowering effect, especially when considering the reduction in nonfatal strokes. In contrast, similar analyses fail to demonstrate any significant contribution of the glucose-lowering effect with SGLT2is, not only on MACEs but also on heart failure issues. CONCLUSION: The contribution of improved glucose control in cardiovascular protection is limited, but is much greater for GLP-1RAs than for SGLT2is. Of note, such mediation or meta-regression analyses are exploratory and can only be viewed as hypothesis generating.

Disciplines :

Endocrinology, metabolism & nutrition
Pharmacy, pharmacology & toxicology

Author, co-author :

Scheen, André ; Centre Hospitalier Universitaire de Liège - CHU > > Service de diabétologie, nutrition, maladies métaboliques

Language :

English

Title :

Cardiovascular protection significantly depends on HbA1c improvement with GLP-1RAs but not with SGLT2 is in type 2 diabetes: A narrative review.

Publication date :

28 December 2023

Journal title :

Diabetes and Metabolism

ISSN :

1262-3636

eISSN :

1878-1780

Publisher :

Elsevier Masson, Paris, Fr

Volume :

Issue :

Pages :

101508

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 01 February 2024

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Bibliography

Sarwar, N., Gao, P., Seshasai, S.R., Gobin, R., Kaptoge, S., Di Angelantonio, E., et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 375 (2010), 2215–2222.
Turnbull, F.M., Abraira, C., Anderson, R.J., Byington, R.P., Chalmers, J.P., Duckworth, W.C., et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 52 (2009), 2288–2298.
Yudkin, J.S., Richter, B., Gale, E.A., Intensified glucose lowering in type 2 diabetes: time for a reappraisal. Diabetologia 53 (2010), 2079–2085.
Sattar, N., Revisiting the links between glycaemia, diabetes and cardiovascular disease. Diabetologia 56 (2013), 686–695.
Scheen, A.J., Charbonnel, B., Effects of glucose-lowering agents on vascular outcomes in type 2 diabetes: a critical reappraisal. Diabetes Metab 40 (2014), 176–185.
Eckel, R.H., Bornfeldt, K.E., Goldberg, I.J., Cardiovascular disease in diabetes, beyond glucose. Cell Metab 33 (2021), 1519–1545.
Aroda, V.R., Eckel, R.H., Reconsidering the role of glycaemic control in cardiovascular disease risk in type 2 diabetes: a 21st century assessment. Diabetes Obesity Metab 24 (2022), 2297–2308.
Muller-Wieland, D., Brandts, J., Verket, M., Marx, N., Schutt, K., Glycaemic control in diabetes. Handb Exp Pharmacol 270 (2022), 47–71.
Kristensen, S.L., Rorth, R., Jhund, P.S., Docherty, K.F., Sattar, N., Preiss, D., et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 7 (2019), 776–785.
Sattar, N., Lee, M.M.Y., Kristensen, S.L., Branch, K.R.H., Del Prato, S., Khurmi, N.S., et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol 9 (2021), 653–662.
Scheen, A.J., Sodium-glucose co-transporter type 2 inhibitors for the treatment of type 2 diabetes mellitus. Nature Rev Endocrinol 16 (2020), 556–577.
Vallon, V., Verma, S., Effects of SGLT2 inhibitors on kidney and cardiovascular function. Annu Rev Physiol 83 (2021), 503–528.
Nauck, M.A., Quast, D.R., Wefers, J., Meier, J.J., GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab, 46, 2021, 101102.
Helmstadter, J., Keppeler, K., Kuster, L., Munzel, T., Daiber, A., Steven, S., Glucagon-like peptide-1 (GLP-1) receptor agonists and their cardiovascular benefits-The role of the GLP-1 receptor. Br J Pharmacol 179 (2022), 659–676.
Scheen, A.J., Cardiovascular outcome studies in type 2 diabetes: comparison between SGLT2 inhibitors and GLP-1 receptor agonists. Diabetes Res Clin Pract 143 (2018), 88–100.
Giugliano, D., Scappaticcio, L., Longo, M., Bellastella, G., Esposito, K., GLP-1 receptor agonists vs. SGLT-2 inhibitors: the gap seems to be leveling off. Cardiovasc Diabetol, 20, 2021, 205.
Sabouret, P., Bocchino, P.P., Angelini, F., D'Ascenzo, F., Galati, G., Fysekidis, M., et al. Comparing benefits from sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in randomized clinical trials: a network meta-analysis. Minerva Cardiol Angiol 71 (2023), 199–207.
Scheen, A.J., Do SGLT2 inhibitors and GLP-1 receptor agonists modulate differently the risk of stroke ? Discordance between randomised controlled trials and observational studies. Diabetes Metab, 49, 2023, 101474.
Ambrosi, P., Daumas, A., Villani, P., Giorgi, R, Glycosylated hemoglobin as a surrogate for the prevention of cardiovascular events in cardiovascular outcome trials comparing new antidiabetic drugs to placebo. Cardiology 145 (2020), 370–374.
Yanai, H., Adachi, H., Hakoshima, M., Katsuyama, H., Glucagon-like peptide 1 receptor agonists versus sodium-glucose cotransporter 2 inhibitors for atherosclerotic cardiovascular disease in patients with type 2 diabetes. Cardiol Res 14 (2023), 12–21.
Buse, J.B., Bain, S.C., Mann, J.F.E., Nauck, M.A., Nissen, S.E., Pocock, S., et al. Cardiovascular risk reduction with liraglutide: an exploratory mediation analysis of the LEADER trial. Diabetes Care 43 (2020), 1546–1552.
Mann, J.F.E., Buse, J.B., Idorn, T., Leiter, L.A., Pratley, R.E., Rasmussen, S., et al. Potential kidney protection with liraglutide and semaglutide: exploratory mediation analysis. Diabetes Obesity Metab 23 (2021), 2058–2066.
Mosenzon, O., Capehorn, M.S., De Remigis, A., Rasmussen, S., Weimers, P., Rosenstock, J., Impact of semaglutide on high-sensitivity C-reactive protein: exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials. Cardiovasc Diabetol, 21, 2022, 172.
Konig, M., Riddle, M.C., Colhoun, H.M., Branch, K.R., Atisso, C.M., Lakshmanan, M.C., et al. Exploring potential mediators of the cardiovascular benefit of dulaglutide in type 2 diabetes patients in REWIND. Cardiovasc Diabetol, 20, 2021, 194.
Gerstein, H.C., Hart, R., Colhoun, H.M., Diaz, R., Lakshmanan, M., Botros, F.T., et al. The effect of dulaglutide on stroke: an exploratory analysis of the REWIND trial. Lancet Diabetes Endocrinol 8 (2020), 106–114.
Franek, E., Gerstein, H.C., Riddle, M.C., Nicolay, C., Hickey, A., Botros, F.T., et al. Efficacy and safety outcomes of dulaglutide by baseline HbA1c: a post hoc analysis of the REWIND trial. Diabetes Obes Metab 24 (2022), 1753–1761.
Fralick, M., Colacci, M., Odutayo, A., Siemieniuk, R., Glynn, R.J., Lowering of hemoglobin A1C and risk of cardiovascular outcomes and all-cause mortality, a meta-regression analysis. J Diabetes Complications, 34, 2020, 107704.
Huang, C.J., Wang, W.T., Sung, S.H., Chen, C.H., Lip, G.Y.H., Cheng, H.M., et al. Revisiting 'intensive' blood glucose control: a causal directed acyclic graph-guided systematic review of randomized controlled trials. Diabetes Obes Metab 24 (2022), 2341–2352.
Yoshiji, S., Minamino, H., Tanaka, D., Yamane, S., Harada, N., Inagaki, N., Effects of glucagon-like peptide-1 receptor agonists on cardiovascular and renal outcomes: a meta-analysis and meta-regression analysis. Diabetes Obes Metab 24 (2022), 1029–1037.
Ghosal, S., Sinha, B., The cardiovascular benefits of GLP1-RAs are related to their positive effect on glycemic control: a meta-regression analysis. Diabetes Res Clin Pract, 186, 2022, 109824.
Maiorino, M.I., Longo, M., Scappaticcio, L., Bellastella, G., Chiodini, P., Esposito, K., et al. Improvement of glycemic control and reduction of major cardiovascular events in 18 cardiovascular outcome trials: an updated meta-regression. Cardiovasc Diabetol, 20, 2021, 210.
Giugliano, D., Bellastella, G., Longo, M., Scappaticcio, L., Maiorino, M.I., Chiodini, P., et al. Relationship between improvement of glycaemic control and reduction of major cardiovascular events in 15 cardiovascular outcome trials: a meta-analysis with meta-regression. Diabetes Obes Metab 22 (2020), 1397–1405.
Marx, N., Husain, M., Lehrke, M., Verma, S., Sattar, N., GLP-1 receptor agonists for the reduction of atherosclerotic cardiovascular risk in patients with type 2 diabetes. Circulation 146 (2022), 1882–1894.
Inzucchi, S.E., Zinman, B., Fitchett, D., Wanner, C., Ferrannini, E., Schumacher, M., et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 41 (2018), 356–363.
Inzucchi, S.E., Kosiborod, M., Fitchett, D., Wanner, C., Hehnke, U., Kaspers, S., et al. Improvement in cardiovascular outcomes with empagliflozin is independent of glycemic control. Circulation 138 (2018), 1904–1907.
McKnight, J.A., Fitchett, D., Woerle, H.J., Lee, J., George, J., Mattheus, M., et al. Empagliflozin (EMPA) reduces heart failure outcomes irrespective of blood pressure (BP), low density lipoprotein cholesterol (LDL-C) and HbA1c control. Diabetologia, 2017 Abstract N° 899.
Ceriello, A., Ofstad, A.P., Zwiener, I., Kaspers, S., George, J., Nicolucci, A., Empagliflozin reduced long-term HbA1c variability and cardiovascular death: insights from the EMPA-REG OUTCOME trial. Cardiovasc Diabetol, 19, 2020, 176.
Vaduganathan, M., Claggett, B.L., Solomon, S.D., How do SGLT-2 inhibitors work to prevent heart failure?. JACC Heart Fail 8 (2020), 67–69.
Fitchett, D., Inzucchi, S.E., Zinman, B., Wanner, C., Schumacher, M., Schmoor, C., et al. Mediators of the improvement in heart failure outcomes with empagliflozin in the EMPA-REG OUTCOME trial. ESC Heart Fail 8 (2021), 4517–4527.
Charytan, D.M., Mahaffey, K.W., Jardine, M.J., Cannon, C.P., Neal, B., Lambers Heerspink, H.J., et al. Cardiorenal protective effects of canagliflozin in CREDENCE according to glucose lowering. BMJ Open Diabetes Res Care, 11, 2023, e003270.
Segar, M.W., Kolkailah, A.A., Frederich, R., Pong, A., Cannon, C.P., Cosentino, F., et al. Mediators of ertugliflozin effects on heart failure and kidney outcomes among patients with type 2 diabetes mellitus. Diabetes Obes Metab 24 (2022), 1829–1839.
Li, J., Woodward, M., Perkovic, V., Figtree, G.A., Heerspink, H.J.L., Mahaffey, K.W., et al. Mediators of the effects of canagliflozin on heart failure in patients with type 2 diabetes. JACC Heart Fail 8 (2020), 57–66.
Berg, D., Wiviott, S., Goodrich, E., Murphy, S., Mosenzon, O., Bhatt, D., et al. Mediation analysis for dapagliflozin and the reduction in hospitalisation for heart failure in DECLARE-TIMI 58 (Abstract). J Am Coll Cardiol, 77, 2021, 869.
Hasebe, M., Yoshiji, S., Keidai, Y., Minamino, H., Murakami, T., Tanaka, D., et al. Efficacy of antihyperglycemic therapies on cardiovascular and heart failure outcomes: an updated meta-analysis and meta-regression analysis of 35 randomized cardiovascular outcome trials. Cardiovasc Diabetol, 22, 2023, 62.
Shao, H., Shi, L., Fonseca, V.A., Using the BRAVO risk engine to predict cardiovascular outcomes in clinical trials with sodium-glucose transporter 2 inhibitors. Diabetes Care 43 (2020), 1530–1536.
Gerstein, H.C., Sattar, N., Reduction in heart failure outcomes with SGLT2 inhibitors irrespective of glycaemic status. Lancet Diabetes Endocrinol 10 (2022), 831–832.
Ali, A., Bain, S., Hicks, D., Newland Jones, P., Patel, D.C., Evans, M., et al. SGLT2 inhibitors cardiovascular benefits beyond HbA1c - Translating evidence into practice. Diabetes Ther 10 (2019), 1595–1622.
Stratton, I.M., Adler, A.I., Neil, H.A., Matthews, D.R., Manley, S.E., Cull, C.A., et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321 (2000), 405–412.
Roussel, R., Steg, P.G., Mohammedi, K., Marre, M., Potier, L., Prevention of cardiovascular disease through reduction of glycaemic exposure in type 2 diabetes: a perspective on glucose-lowering interventions. Diabetes Obes Metab 20 (2018), 238–244.
Wu, Y., Tang, L., Zhang, F., Yan, Z., Li, J., Tong, N., Evaluation of the HbA1c reduction cut point for a nonglycemic effect on cardiovascular benefit of hypoglycemic agents in patients with type 2 diabetes based on endpoint events. Int J Endocrinol, 2018, 2018, 8457538.
Sohn, M., Dietrich, J.W., Nauck, M.A., Lim, S., Characteristics predicting the efficacy of SGLT-2 inhibitors versus GLP-1 receptor agonists on major adverse cardiovascular events in type 2 diabetes mellitus: a meta-analysis study. Cardiovasc Diabetol, 22, 2023, 153.
Scheen, A.J., Bonnet, F., Efficacy and safety profile of SGLT2 inhibitors in the elderly: how is the benefit/risk balance?. Diabetes Metab, 49, 2023, 101419.
Cannon, C.P., Perkovic, V., Agarwal, R., Baldassarre, J., Bakris, G., Charytan, D.M., et al. Evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease according to baseline HbA1c, including those with HbA1c < 7%: results from the CREDENCE trial. Circulation 141 (2020), 407–410.
Persson, F., Rossing, P., Vart, P., Chertow, G.M., Hou, F.F., Jongs, N., et al. Efficacy and safety of dapagliflozin by baseline glycemic status: a prespecified analysis from the DAPA-CKD trial. Diabetes Care 44 (2021), 1894–1897.
Cahn, A., Wiviott, S.D., Mosenzon, O., Goodrich, E.L., Murphy, S.A., Yanuv, I., et al. Association of baseline HbA1c with cardiovascular and renal outcomes: analyses from DECLARE-TIMI 58. Diabetes Care 45 (2022), 938–946.
Delgado, E., Jodar, E., Mezquita-Raya, P., Moreno-Perez, O., Benefits of SGLT2i for the treatment of heart failure irrespective of diabetes diagnosis: a state-of-the-art review. Diabetes Ther 13 (2022), 19–34.
Petrie, M.C., Verma, S., Docherty, K.F., Inzucchi, S.E., Anand, I., Belohlavek, J., et al. Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes. JAMA 323 (2020), 1353–1368.
Inzucchi, S.E., Claggett, B.L., Vaduganathan, M., Desai, A.S., Jhund, P.S., de Boer, R.A., et al. Efficacy and safety of dapagliflozin in patients with heart failure with mildly reduced or preserved ejection fraction by baseline glycaemic status (DELIVER): a subgroup analysis from an international, multicentre, double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 10 (2022), 869–881.
Anker, S.D., Butler, J., Filippatos, G., Khan, M.S., Marx, N., Lam, C.S.P., et al. Effect of empagliflozin on cardiovascular and renal outcomes in patients with heart failure by baseline diabetes status - Results from the EMPEROR-Reduced trial. Circulation 143 (2021), 337–349.
Teo, Y.H., Teo, Y.N., Syn, N.L., Kow, C.S., Yoong, C.S.Y., Tan, B.Y.Q., et al. Effects of sodium/glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular and metabolic outcomes in patients without diabetes mellitus: a systematic review and meta-analysis of randomized-controlled trials. J Am Heart Assoc, 10, 2021, e019463.
Giugliano, D., Maiorino, M.I., Bellastella, G., Chiodini, P., Esposito, K., Glycemic control, preexisting cardiovascular disease, and risk of major cardiovascular events in patients with type 2 diabetes mellitus: systematic review with meta-analysis of cardiovascular outcome trials and intensive glucose control trials. J Am Heart Assoc, 8, 2019, e012356.
Pei, J., Wang, X., Pei, Z., Hu, X., Glycemic control, HbA1c variability, and major cardiovascular adverse outcomes in type 2 diabetes patients with elevated cardiovascular risk: insights from the ACCORD study. Cardiovasc Diabetol, 22, 2023, 287.
Martinez, M., Santamarina, J., Pavesi, A., Musso, C., Umpierrez, G.E., Glycemic variability and cardiovascular disease in patients with type 2 diabetes. BMJ Open Diabetes Res Care, 9, 2021, e002032.
Lee, H., Park, S.E., Kim, E.Y., Glycemic variability impacted by SGLT2 inhibitors and GLP 1 agonists in patients with diabetes mellitus: a systematic review and meta-analysis. J Clin Med, 10, 2021, 4078.
Battelino, T., Alexander, C.M., Amiel, S.A., Arreaza-Rubin, G., Beck, R.W., Bergenstal, R.M., et al. Continuous glucose monitoring and metrics for clinical trials: an international consensus statement. Lancet Diabetes Endocrinol 11 (2023), 42–57.
de Carvalho, L.S.F., Nogueira, A.C.C., Bonilha, I., Luchiari, B., Benchimol, A., Couri, C.E.B., et al. Glucose-lowering and the risk of cardiovascular events with antidiabetic therapies: a systematic review and additive-effects network meta-analysis. Front Cardiovasc Med, 9, 2022, 876795.