Effect of Dapagliflozin on Myocardial Insulin Sensitivity and Perfusion: Rationale and Design of The DAPAHEART Trial

Gian Pio Sorice, Francesca Cinti, Lucia Leccisotti, Domenico D'Amario, Margherita Lorusso, Maria Angela Guzzardi, Teresa Mezza, Camilla Cocchi, Umberto Capece, Pietro Manuel Ferraro, Filippo Crea, Alessandro Giordano, Patricia Iozzo, Andrea Giaccari, Gian Pio Sorice, Francesca Cinti, Lucia Leccisotti, Domenico D'Amario, Margherita Lorusso, Maria Angela Guzzardi, Teresa Mezza, Camilla Cocchi, Umberto Capece, Pietro Manuel Ferraro, Filippo Crea, Alessandro Giordano, Patricia Iozzo, Andrea Giaccari

Abstract

Introduction: Sodium-glucose co-transporter-2 (SGLT-2) inhibitors have been shown to have beneficial effects on various cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) in primary prevention and in those with a high CV risk profile. However, the mechanism(s) responsible for these CV benefits remain elusive and unexplained. The aim of the DAPAHEART study will be to demonstrate that treatment with SGLT-2 inhibitors is associated with greater myocardial insulin sensitivity in patients with T2D, and to determine whether this improvement can be attributed to a decrease in whole-body (and tissue-specific) insulin resistance and to increased myocardial perfusion and/or glucose uptake. We will also determine whether there is an appreciable degree of improvement in myocardial-wall conditions subtended by affected and non-affected coronary vessels, and if this relates to changes in left ventricular function.

Methods: The DAPAHEART trial will be a phase III, single-center, randomized, two-arm, parallel-group, double-blind, placebo-controlled study. A cohort of 52 T2D patients with stable coronary artery disease (without any previous history of myocardial infarction, with or without previous percutaneous coronary intervention), with suboptimal glycemic control (glycated hemoglobin [HbA1c] 7-8.5%) on their current standard of care anti-hyperglycemic regimen, will be randomized in a 1:1 ratio to dapagliflozin or placebo. The primary outcome is to detect changes in myocardial glucose uptake from baseline to 4 weeks after treatment initiation. The main secondary outcome will be changes in myocardial blood flow, as measured by 13N-ammonia positron emission tomography/computed tomography (PET/CT). Other outcomes include cardiac function, glucose uptake in skeletal muscle, adipose tissue, liver, brain and kidney, as assessed by fluorodeoxyglucose (FDG) PET-CT imaging during hyperinsulinemic-euglycemic clamp; pericardial, subcutaneous and visceral fat, and browning as observed on CT images during FDG PET-CT studies; systemic insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp, glycemic control, urinary glucose output; and microbiota modification.

Discussion: SGLT-2 inhibitors, in addition to their insulin-independent plasma glucose-lowering effect, are able to directly (substrate availability, fuel utilization, insulin sensitivity) as well as indirectly (cardiac after-load reduction, decreased risk factors for heart failure) affect myocardial functions. Our study will provide novel insights into how these drugs exert CV protection in a diabetic population.

Trial registration: EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.

Keywords: Coronary flow reserve; Dapagliflozin; Myocardial blood flow; Myocardial dysfunction; Myocardial glucose uptake; Myocardial insulin sensitivity; PET; Precision medicine; SGLT-2.

Figures

Fig. 1
Fig. 1
Study design flowchart. FDG fluorodeoxyglucose, CT computed tomography, PET positron emission tomography

References

    1. Kasznicki J, Drzewoski J. Heart failure in the diabetic population—pathophysiology, diagnosis and management. Arch Med Sci. 2014;10:546–556.
    1. Masi S, Lautamaki R, Guiducci L, et al. Similar patterns of myocardial metabolism and perfusion in patients with type 2 diabetes and heart disease of ischaemic and non-ischaemic origin. Diabetologia. 2012;55:2494–2500.
    1. Iozzo P, Chareonthaitawee P, Dutka D, Betteridge DJ, Ferrannini E, Camici PG. Independent association of type 2 diabetes and coronary artery disease with myocardial insulin resistance. Diabetes. 2002;51:3020–3024.
    1. Marinho NV, Keogh BE, Costa DC, Lammerstma AA, Ell PJ, Camici PG. Pathophysiology of chronic left ventricular dysfunction. New insights from the measurement of absolute myocardial blood flow and glucose utilization. Circulation. 1996;93:737–744.
    1. Semeniuk LM, Kryski AJ, Severson DL. Echocardiographic assessment of cardiac function in diabetic db/db and transgenic db/db-hGLUT4 mice. Am J Physiol Heart Circ Physiol. 2002;283:H976–982.
    1. Lehto HR, Parkka J, Borra R, et al. Effects of acute and one-week fatty acid lowering on cardiac function and insulin sensitivity in relation with myocardial and muscle fat and adiponectin levels. J Clin Endocrinol Metab. 2012;97:3277–3284.
    1. Salerno A, Fragasso G, Esposito A, et al. Effects of short-term manipulation of serum FFA concentrations on left ventricular energy metabolism and function in patients with heart failure: no association with circulating bio-markers of inflammation. Acta Diabetol. 2015;52:753–761.
    1. Tuunanen H, Engblom E, Naum A, et al. Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation. 2006;114:2130–2137.
    1. Nielsen R, Norrelund H, Kampmann U, Botker HE, Moller N, Wiggers H. Effect of acute hyperglycemia on left ventricular contractile function in diabetic patients with and without heart failure: two randomized cross-over studies. PLoS ONE. 2013;8:e53247.
    1. Guzzardi MA, Hodson L, Guiducci L, et al. Independent effects of circulating glucose, insulin and NEFA on cardiac triacylglycerol accumulation and myocardial insulin resistance in a swine model. Diabetologia. 2014;57:1937–1946.
    1. Zinman B, Wanner C, Lachin JM, et al. Investigators E-RO: empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128.
    1. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–357.
    1. Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:2099.
    1. Sattar N, McLaren J, Kristensen SL, Preiss D, McMurray JJ. SGLT2 Inhibition and cardiovascular events: why did EMPA-REG Outcomes surprise and what were the likely mechanisms? Diabetologia. 2016;59:1333–1339.
    1. Tikkanen I, Narko K, Zeller C, et al. Investigators E-RB: empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38:420–428.
    1. Sha S, Polidori D, Heise T, et al. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2014;16:1087–1095.
    1. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981–97.
    1. Zannad F, McMurray JJ, Krum H, et al. Group E-HS: Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21.
    1. Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: a "Thrifty Substrate" Hypothesis. Diabetes Care. 2016;39:1108–1114.
    1. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A Unifying Hypothesis. Diabetes Care. 2016;39:1115–1122.
    1. Lopaschuk GD, Verma S. Empagliflozin's fuel hypothesis: not so soon. Cell Metab. 2016;24:200–202.
    1. Aubert G, Martin OJ, Horton JL, et al. The failing heart relies on ketone bodies as a fuel. Circulation. 2016;133:698–705.
    1. Horton JL, Martin OJ, Lai L, et al. Mitochondrial protein hyperacetylation in the failing heart. JCI Insight 2016;2(1):e84897.
    1. Russell RR, 3rd, Taegtmeyer H. Changes in citric acid cycle flux and anaplerosis antedate the functional decline in isolated rat hearts utilizing acetoacetate. J Clin Invest. 1991;87:384–390.
    1. DeFronzo RA. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerosis. Neth J Med. 1997;50:191–197.
    1. Playford D, Watts GF. Endothelial dysfunction, insulin resistance and diabetes: exploring the web of causality. Aust N Z J Med. 1999;29:523–534.
    1. Iozzo P, Chareonthaitawee P, Di Terlizzi M, Betteridge DJ, Ferrannini E, Camici PG. Regional myocardial blood flow and glucose utilization during fasting and physiological hyperinsulinemia in humans. Am J Physiol Endocrinol Metab. 2002;282:E1163–1171.
    1. Jagasia D, Whiting JM, Concato J, Pfau S, McNulty PH. Effect of non-insulin-dependent diabetes mellitus on myocardial insulin responsiveness in patients with ischemic heart disease. Circulation. 2001;103:1734–1739.
    1. Vettor R, Inzucchi SE, Fioretto P. The cardiovascular benefits of empagliflozin: SGLT2-dependent and -independent effects. Diabetologia. 2017;60:395–398.
    1. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. Group ESCSD: 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J. 2019;40:87–165.
    1. Lautamaki R, Airaksinen KE, Seppanen M, et al. Rosiglitazone improves myocardial glucose uptake in patients with type 2 diabetes and coronary artery disease: a 16-week randomized, double-blind, placebo-controlled study. Diabetes. 2005;54:2787–2794.
    1. Emerging Risk Factors Collaboration; Sarwar N, Gao P, et al.. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215–22.
    1. IDF Diabetes Atlas Group. Update of mortality attributable to diabetes for the IDF Diabetes atlas: estimates for the year 2011. Diabetes Res Clin Pract 2013;100:277–9.
    1. Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J. 2015;36:2288–2296.
    1. McMurray JJV, Solomon SD, Inzucchi SE, et al. Committees D-HT, Investigators: dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995–2008.
    1. Packer M, Anker SD, Butler J, et al. Investigators EM-RT: cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–1424.
    1. Bhatt DL, Szarek M, Steg PG, et al. Investigators S-WT: sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384:117–128.
    1. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383:1425–1435.
    1. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010;90:207–258.
    1. Zhang L, Jaswal JS, Ussher JR, et al. Cardiac insulin-resistance and decreased mitochondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy. Circ Heart Fail. 2013;6:1039–1048.
    1. Merovci A, Mari A, Solis-Herrera C, et al. Dapagliflozin lowers plasma glucose concentration and improves beta-cell function. J Clin Endocrinol Metab. 2015;100:1927–1932.
    1. Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care. 1990;13:610–630.
    1. Latva-Rasku A, Honka MJ, Kullberg J, et al. The SGLT2 inhibitor dapagliflozin reduces liver fat but does not affect tissue insulin sensitivity: a randomized, double-blind, placebo-controlled study with 8-week treatment in type 2 diabetes patients. Diabetes Care. 2019;42:931–937.
    1. Lauritsen KM, Nielsen BRR, Tolbod LP, et al. SGLT2 inhibition does not affect myocardial fatty acid oxidation or uptake, but reduces myocardial glucose uptake and blood flow in individuals with type 2 diabetes: a randomized double-blind placebo-controlled crossover trial. Diabetes. 2021;70:800–808.
    1. Oldgren J, Laurila S, Akerblom A, et al. Effects of 6 weeks of treatment with dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on myocardial function and metabolism in patients with type 2 diabetes: a randomized, placebo-controlled, exploratory study. Diabetes Obes Metab. 2021. 10.1111/dom.14363.
    1. Giaccari A. Sodium-glucose co-transporter inhibitors: medications that mimic fasting for cardiovascular prevention. Diabetes Obes Metab. 2019;21:2211–2218.
    1. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229–234.
    1. Iribarren C, Karter AJ, Go AS. Glycemic control and heart failure among adult patients with diabetes. Circulation. 2001;103:2668–2673.
    1. Turner RC, Millns H, Neil HA. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23) BMJ. 1998;316:823–828.
    1. ACCORD Study Group; Cushman WC, Evans GW, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575–85.
    1. ADVANCE Collaborative Group; Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.
    1. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–139.
    1. Riehle C, Abel ED. Insulin signaling and heart failure. Circ Res. 2016;118:1151–1169.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi