Abstract
Purpose
A recent large cardiovascular outcome trial in patients with type 2 diabetes (T2DM) demonstrated excess heart failure hospitalization with saxagliptin. We sought to evaluate the impact of saxagliptin on cardiac structure and function using cardiac magnetic resonance imaging (CMR) in patients with T2DM without pre-existing heart failure.
Methods
In this prospective study, patients with T2DM without heart failure were prescribed saxagliptin as part of routine guideline-directed management. Clinical assessment, CMR imaging and biomarkers were assessed in a blinded fashion and compared following 6 months of continued treatment. The primary outcome was the change in left ventricular (LV) ejection fraction (LVEF) after 6 months of therapy. Key secondary outcomes included changes in LV and right ventricular (RV) end-diastolic volume, ventricular mass, LV global strain and cardiac biomarkers [N terminal pro B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP)] over 6 months.
Results
The cohort (n = 16) had a mean age of 59.9 years with 69% being male. The mean hemoglobin A1c (HbA1c) was 8.3%. Mean baseline LVEF was 57% ± 3.4, with no significant change over 6 months (− 0.2%, 95% CI − 2.5, 2.1, p = 0.86). Detailed CMR analyses that included LV/RV volumes, LV mass, and feature tracking-derived strain showed no significant change (all p > 0.50). NT-proBNP and hsCRP levels did not significantly change (p > 0.20).
Conclusions
In this cohort of stable ambulatory patients with T2DM without heart failure, saxagliptin treatment was not associated with adverse ventricular remodeling over 6 months as assessed using CMR and biomarkers.
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References
MacDonald MR, Petrie MC, Hawkins NM et al (2008) Diabetes, left ventricular systolic dysfunction, and chronic heart failure. Eur Heart J 29(10):1224–1240
MacDonald MR, Petrie MC, Varyani F et al (2008) Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure—an analysis of the Candesartan in Heart failure: assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J 29(11):1377–1385
Dauriz M, Targher G, Laroche C et al (2017) Association between diabetes and 1-year adverse clinical outcomes in a multinational cohort of ambulatory patients with chronic heart failure: results from the ESC-HFA Heart Failure Long-Term Registry. Diabetes Care 40(5):671–678
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(14):1317–1326
Green JB, Bethel MA, Armstrong PW et al (2015) Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 373(3):232–242
McGuire DK, Alexander JH, Johansen OE et al (2019) Linagliptin effects on heart failure and related outcomes in individuals with type 2 diabetes mellitus at high cardiovascular and renal risk in CARMELINA. Circulation 139(3):351–361
McMurray JJV, Ponikowski P, Bolli GB et al (2018) Effects of vildagliptin on ventricular function in patients with type 2 diabetes mellitus and heart failure: a randomized placebo-controlled trial. JACC Heart Fail 6(1):8–17
Verma S, Goldenberg RM, Bhatt DL et al (2017) Dipeptidyl peptidase-4 inhibitors and the risk of heart failure: a systematic review and meta-analysis. CMAJ Open 5(1):E152–E177
Mannucci E, Mosenzon O, Avogaro A (2016) Analyses of results from cardiovascular safety trials with DPP-4 inhibitors: cardiovascular outcomes, predefined safety outcomes, and pooled analysis and meta-analysis. Diabetes Care 39(S2):S196–S204
Fu AZ, Johnston SS, Ghannam A et al (2016) Association between hospitalization for heart failure and dipeptidyl peptidase 4 inhibitors in patients with type 2 diabetes: an observational study. Diabetes Care 39(5):726–734
Scirica BM, Braunwald E, Raz I et al (2014) Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation 130(18):1579–1588
Frederich R, Alexander JH, Fiedorek FT et al (2010) A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med 122(3):16–27
Iqbal N, Parker A, Frederich R et al (2014) Assessment of the cardiovascular safety of saxagliptin in patients with type 2 diabetes mellitus: pooled analysis of 20 clinical trials. Cardiovasc Diabetol 13:33
Toh S, Hampp C, Reichman ME et al (2016) Risk for hospitalized heart failure among new users of saxagliptin, sitagliptin, and other antihyperglycemic drugs: a retrospective cohort study. Ann Int Med 164(11):705–714
Constantine G, Shan K, Flamm SD, Sivananthan MU (2004) Role of MRI in clinical cardiology. Lancet 363(9427):2162–2171
Bellenger NG, Davies LC, Francis JM, Coats AJ, Pennell DJ (2000) Reduction in sample size for studies of remodeling in heart failure by the use of cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2(4):271–278
Chung AK, Das SR, Leonard D et al (2006) Women have higher left ventricular ejection fractions than men independent of differences in left ventricular volume: the Dallas Heart Study. Circulation 113(12):1597–1604
Grothues F, Smith GC, Moon JCC et al (2002) Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. Am J Cardiol 90(1):29–34
Götte MJW, Germans T, Rüssel IK et al (2006) Myocardial strain and torsion quantified by cardiovascular magnetic resonance tissue tagging: studies in normal and impaired left ventricular function. J Am Coll Cardiol 48(10):2002–2011
Ong G, Brezden-Masley C, Dhir V et al (2018) Myocardial strain imaging by cardiac magnetic resonance for detection of subclinical myocardial dysfunction in breast cancer patients receiving trastuzumab and chemotherapy. Int J Cardiol 261:228–233
Verma S, Mazer D, Yan AT, Mason T, Garg V, Teoh H et al (2019) Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease. Circulation 140(21):1693–1702
Opie LH, Commerford PJ, Gersh BJ, Pfeffer MA (2006) Controversies in ventricular remodelling. Lancet 367(9507):356–367
Borlaug BA, Redfield MM (2011) Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum. Circulation 123(18):2006–2013
Juillière Y, Barbier G, Feldmann L et al (1997) Additional predictive value of both left and right ventricular ejection fractions on long-term survival in idiopathic dilated cardiomyopathy. Eur Heart J 18(2):276–280
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(14):1327–1335
McGuire DK, Van De Werf F et al (2016) Association between sitagliptin use and heart failure hospitalization and related outcomes in type 2 diabetes mellitus: secondary analysis of a randomized clinical trial. JAMA Cardiol 1(2):126–135
Fadini GP, Bonora BM, Albiero M et al (2017) DPP-4 inhibition has no acute effect on BNP and its N-terminal pro-hormone measured by commercial immune-assays. A randomized cross-over trial in patients with type 2 diabetes. Cardiovasc Diabetol 16(1):22
Pellicori P, Zhang J, Cuthbert J, Urbinati A et al (2020) High-sensitivity C-reactive protein in chronic heart failure: patient characteristics, phenotypes, and mode of death. Cardiovasc Res 116(1):91–100
Jurcut R, Wildiers H, Ganame J et al (2008) Strain rate imaging detects early cardiac effects of pegylated liposomal Doxorubicin as adjuvant therapy in elderly patients with breast cancer. J Am Soc Echocardiogr 21(12):1283–1289
Scheen AJ (2020) Reduction in HbA1c with SGLT2 inhibitors vs. DPP-4 inhibitors as add-ons to metformin monotherapy according to baseline HbA1c: a systematic review of randomized controlled trials. Diabetes Metab 46(3):186–196
Funding
The proposal was funded by an unrestricted educational Grant from Astra Zeneca, who manufacture saxagliptin.
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Dr Connelly is listed as an inventor on a patent application by Boehringer Ingelheim on the use of dipeptidyl peptidase-4 inhibitors in heart failure; and reports receiving research grants to his institution from AstraZeneca, Servier, and Boehringer Ingelheim; support for travel to scientific meetings from Boehringer Ingelheim and honoraria for speaking engagements and ad hoc participation in advisory boards from Servier, Merck, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Ferring, Novo Nordisk, Novartis, and Janssen.
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The study was approved by St. Michael’s Hospital Research Ethics Board.
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All participants were consented to participate. Study team ensured that participants were made aware that participation or lack thereof will have no impact on clinical care provided.
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Sandhu, P., Ong, J.P., Garg, V. et al. The effects of saxagliptin on cardiac structure and function using cardiac MRI (SCARF). Acta Diabetol 58, 633–641 (2021). https://doi.org/10.1007/s00592-020-01661-y
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DOI: https://doi.org/10.1007/s00592-020-01661-y