Cardiovascular impact of new drugs (GLP-1 and gliflozins): the ABCD position statement

Ansu Basu, Dipesh Patel, Peter Winocour, Bob Ryder


The glucose intolerance of diabetes aggravates atherosclerosis indirectly through its effect on lipids and endothelial function. The cardiovascular (CV) impact of this metabolic disturbance is seen in the worsening of atherosclerotic vascular disease predominantly manifest as progression of coronary and cerebrovascular disease. The microvascular changes induced by prolonged glucose intolerance lead to ultrastructural changes in the glomerular basement membrane and renal mesangium which alters intrarenal haemodynamics, which may become evident initially as proteinuria and later lead to a decline in glomerular filtration rate. As the kidney plays a central role in blood pressure control, these changes have far-reaching CV consequences in patients with diabetes.

Despite this, glucose lowering has been shown to have only a modest impact on CV outcomes in diabetes. The new antidiabetic medications have been studied in clinical trials designed to assure safety as grounded in the FDA guidance of 2008. Whilst a direct comparison of results from these trials is not possible in view of heterogeneity in trial design, the individual CV outcome measures have broadly re-defined their role in terms of equivalence (non-inferiority) and/or benefit (superiority). The composite endpoint of CV death, non-fatal myocardial infarction and non-fatal stroke (major adverse cardiovascular events, MACE) may be perceived as surrogate markers for atherosclerotic cardiovascular disease (ASCVD). This has been universally accepted as the primary endpoint in these cardiovascular outcome trials (CVOTs) and has been helpful in understanding the possible CV impact these drugs may have on patients with diabetes.

The dipeptidyl peptidase 4 (DPP-IV) inhibitors (sitagliptin, alogliptin, saxagliptin, linagliptin), two sodium-glucose co-transporter 2 (SGLT2) inhibitors (dapagliflozin and ertugliflozin) and two glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1 RA) drugs (lixisenatide and extended-release exenatide) have demonstrated non-inferiority on MACE outcomes with comparators – that is, they have assured CV safety when used in conjunction with other glucose-lowering treatment to improve glycaemic control. Four GLP-1 agonists (liraglutide, albiglutide, semaglutide and dula- glutide) and two SGLT2 inhibitors (empagliflozin and canagliflozin) have demonstrated CV benefit on MACE outcomes; such demonstration of superiority may be seen as evidence for benefit. The SGLT2 inhibitors canagliflozin, empagliflozin, dapagliflozin and ertugliflozin have all demonstrated a significant benefit in reducing the risk of hospitalisation due to heart failure (HHF) as a secondary/ exploratory outcome measure in their CVOTs. Further confirmation of benefit in heart failure independent of the presence of glucose intolerance has been demonstrated with dapagliflozin and empagliflozin in heart failure patients with or without diabetes. However, a comparable benefit in heart failure has not so far been seen in studies with the DPP-IV inhibitors or GLP-1 receptor agonists. Albiglutide is not available in the UK and may have little relevance to the practising clinician other than through the information it contributes about the possible mechanisms of action of GLP-1 RA medications.


CVOT, cardiovascular outcome trials, cardiovascular disease, type 2 diabetes, position statement

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Selvin E, Coresh J, Golden SH, Boland LL, Brancati FL, Steffes MW. Glycemic control, atherosclerosis, and risk factors for cardiovascular disease in individuals with diabetes. The Atherosclerosis Risk in Communities study. Diabetes Care 2005;28(8):1965–73.

Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375(9733):2215–22.

Kennel W, McGee D. Diabetes and cardiovascular risk factors: the Framingham Study. Circulation 1979;59(1):8–13.

Norhammar A, Tenerz A, Nilsson G, et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 2002;359(9324):2140–4.

Nathan D, Cleary P, Backlund J, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;22:2643–53.

Ray KK, Seshasai SRK, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009; 373(9677):1765–72.

Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004;141(6):421–31.

von Heerebeek L, Hamdani N, Handoko ML, et al. Diastolic stiffness of the failing diabetic heart. Circulation 2008;117(1):43–51.

Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972;30(6):595–602.

Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation 2007;115(25):3213–23.

Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: Executive Summary. Circulation 2013;128(16):1810–52.

Nichols GA, Gullion CM, Koro CE, Ephross SA, Brown JB. The incidence of congestive heart failure in type 2 diabetes. An update. Diabetes Care 2004;27(8):1879–84.

van Melle JP, Bot M, de Jonge P, de Boer RA, van Veldhuisen DJ, Whooley MA. Diabetes, glycemic control, and new-onset heart failure in patients with stable coronary artery disease. Data from the Heart and Soul Study. Diabetes Care 2010;33(9):2084–9.

McMurray JJV, Gerstein HC, Holman RR, Pfeffer MA. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol 2014;2(10):843–51.

Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C-Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351(13):1296–305. NEJMoa041031

Kottgen A, Russell SD, Loehr LR, et al. Reduced kidney function as a risk factor for incident heart failure: the Atherosclerosis Risk in Communities (ARIC) Study. J Am Soc Nephrol 2007;18(4):1307–15.

Manjunath G, Tighiouart H, Ibrahim H, et al. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 2003;41(1):47–55.

Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010;375(9731):2073–81.

Orchard TJ, Dorman JS, Maser RE, et al. Prevalence of complications in IDDM by sex and duration: Pittsburgh Epidemiology of Diabetes Complications Study II. Diabetes 1990;39(9):1116–24.

Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 1999;341(15):1127–33.

Adler AI, Stevens RJ, Manley SE, et al. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003;63(1):225–32.

US Food and Drug Administration (FDA). Guidance for industry: diabetes mellitus evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008.

Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356(24):2457–71.

European Medicines Agency (EMA). Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. 2012.

Lesaffre E. Superiority, equivalence, and non-inferiority trials. Bull NYU Hosp Jt Dis 2008;66(2):150–4.

Hirshberg B. Cardiovascular outcome studies with novel antidiabetes agents: scientific and operational considerations. Diabetes Care 2013; 36(Suppl 2):S253–8.

UK Prospective Diabetes Study. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–65.

Holman R, Paul S, Bethel M, Matthews D, Neil H. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577–89.

Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018;41(12):2669–701.

Meinert C, Knatterud G, Prout T, Klimt C. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes 1970;19(Suppl):789–830.

Simpson SH, Lee J, Choi S, Vandermeer B, Abdelmoneim AS, Featherstone TR. Mortality risk among sulfonylureas: a systematic review and network meta-analysis. Lancet Diabetes Endocrinol 2015;3(1):43–51.

ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358(24):2560–72.

Rosenstock J, Kahn SE, Johansen OE, et al. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial. JAMA 2019;322(12):1155–66.

Chiasson J, Josse RG, Gomis R, et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: The STOP-NIDDM trial. JAMA 2003;290(4):486–94.

Holman RR, Coleman RL, Chan JCN, et al. Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2017;5(11):877–86.

Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 2009; 373(9681):2125–35.

Stone JC, Furuya-Kanamori L, Barendregt JJ, Doi SA. Was there really any evidence that rosiglitazone increased the risk of myocardial infarction or death from cardiovascular causes? Pharmacoepidemiol Drug Saf 2015; 24(3):223–7.

Florez H, Reaven PD, Bahn G, et al. Rosiglitazone treatment and cardiovascular disease in the Veterans Affairs Diabetes Trial. Diabetes Obes Metab 2015;17(10):949–55.

Goldberg RB, Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005;28(7):1547–54.

Dormandy JA, Charbonnel B, Eckland DJA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366(9493):1279–89.

Mazzone T, Meyer PM, Feinstein SB, et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes. A randomized trial. JAMA 2006;296(21):2572–81.

Nissen SE, Nicholls SJ, Wolski K, et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 2008; 299(13):1561–73.

Ryder REJ. Pioglitazone has a dubious bladder cancer risk but an undoubted cardiovascular benefit. Diabet Med 2015;32(3):305–13.

Ryder REJ, DeFronzo R. Rehabilitation of pioglitazone. Br J Diabetes Vasc Dis 2015;15:46–9.

Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK, Skene AM. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study. J Am Coll Cardiol 2007;49(17):1772–80.

Wilcox R, Bousser M-G, Betteridge DJ, et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke 2007;38(3):865–73.

Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus. A meta-analysis of randomized trials. JAMA 2007;298(10):1180–8.

Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374(14):1321–31.

Vaccaro O, Masulli M, Nicolucci A, et al. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial. Lancet Diabetes Endocrinol 2017;5(11):887–97.

Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380(4):347–57.

Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375(4):311–22.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486–97.

Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373(3):232–42.

Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373(23):2247–57.

White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369(14):1327–35.

McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019; 381(21):1995–2008.

Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383(15):1413–24.

Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380(24):2295–306.

Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383(15):1436–46.

Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab 2011;13(1):7–18.

Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368(9548):1696–705.

Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369(14):1317–26.

Gantz I, Chen M, Suryawanshi S, et al. A randomized, placebo-controlled study of the cardiovascular safety of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus. Cardiovasc Diabetol 2017;16:112–24.

Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA 2019;321(1):69–79.

McMurray JJV, Ponikowski P, Bolli GB, et al. Effects of vildagliptin on ventricular function in patients with type 2 diabetes mellitus and heart failure: a randomized placebo-controlled trial. JACC Heart Fail 2018;6(1):8–17.

Zannad F, Cannon CP, Cushman WC, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet 2015; 385(9982):2067–76.

Rosenstock J, Marx N, Neubacher D, et al. Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events. Cardiovasc Diabetol 2015;14:1–15.

Li L, Li S, Deng K, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ 2016;352:i610.

Liu J, Li L, Deng K, et al. Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis. BMJ 2017; 357:j2499.

Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375(19):1834–44.

Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017; 377(13):1228–39.

Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 2018;392(10157):1519–29.

Margulies KB, Hernandez AF, Redfield MM, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA 2016;316(5):500–08.

Vilsbøll T, Bain SC, Leiter LA, et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. Diabetes Obes Metab 2018;20(4):889–97.

Davies M, Pieber TR, Hartoft-Nielsen M-L, Hansen OKH, Jabbour S, Rosenstock J. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA 2017;318(15):1460–70.

Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019; 381(9):841–51.

Gerstein HC, Colhoun HM, Dagenais GR, et al. 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 2018;20(1):42–9.

Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394(10193):121–30.

Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet 2019;394(10193):131–8.

Song X, Jia H, Jiang Y, et al. Anti-atherosclerotic effects of the glucagon-like peptide-1 (GLP-1) based therapies in patients with type 2 diabetes mellitus: a meta-analysis. Scientific Reports 2015;5:10202.

Ryder REJ, DeFronzo R. Diabetes medications with cardiovascular protection after HARMONY Outcomes and DECLARE-TIMI 58: could metformin, pioglitazone, SGLT2 inhibitors and long-acting GLP-1 receptor agonists complement each other to save lives by different mechanisms? Br J Diabetes 2019;19:1–5.

Jabbour SA, Goldstein BJ. Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes. Int J Clin Pract 2008;62(8):1279–84.

Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373(22):2117–28.

Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377(7):644–57.

Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020;383(15):1425–35.

Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375(4):323–34.

Cannon CP, McGuire DK, Pratley R, et al. Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV). Am Heart J 2018;206:11–23.

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(2):129–39.

Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358(24):2545–59.

Nathan DM, Cleary PA, Backlund J-YC, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353(25):2643–53.

Kosiborod M, Cavender MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium- Glucose Cotransporter-2 Inhibitors). Circulation 2017;136(3):249–59.

National Cardiac Audit Programme. National Heart Failure Audit 2016/17 Summary. 2018.



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