Anti-diabetic Agents and the Potentials for Reducing Cardiovascular Risks in Type-2 Diabetes Mellitus

  • IU Ezeani
  • A Eregie
  • AE Ohwovoriole
Keywords: Anti-diabetic Drugs, Cardiovascular Risks, GLP1 Agonist, Outcome Trials, SGLT2 Inhibitors


Recent reports from Cardiovascular Outcome Trials (CVOTs) revealed that some newer anti-diabetic drugs impact Major Adverse Cardiovascular Events (MACE). These medications include the Sodium-Glucose Co-Transporter (SGLT2) inhibitors and the Glucagon-like Peptide-1 (GLP-1) receptor agonists. There is a need for a review of the mechanisms of action of these drugs, in addition to their glucose-lowering effects and CV benefits. This review paper aims to explore the cardio-protective effects and CV risks of anti-diabetic medications, their mechanisms of action and the CV benefits evidenced by CVOTs. Using internet search, with search items such as Type 2 Diabetes mellitus, cardiovascular risk factors, cardiovascular outcome trials, major adverse cardiovascular events, sodium-glucose transporter-2 inhibitors, glucagon-like peptide-1 receptor agonist, the Google Scholar, EMBASE, PubMed, Medline, Web MD, and Scopus were checked for various relevant published articles. Analyses of the results of multiple CVOTs from various parts of the world were considered. These CVOTs were reviewed to assess the role of anti-diabetic agents in reducing cardiovascular risk in patients with T2DM. The SGLT2 inhibitors and GLP1 agonists were found to be beneficial in lowering MACE when compared with placebo. This is in addition to their anti-hyperglycaemic benefits.

In conclusion, SGLT2 inhibitors and GLP-1 agonists confer dramatic beneficial CV risk reduction on patients with T2DM, as shown by the various CVOTs. This is in addition to their anti-hyperglycaemic effects. This remarkable benefit justifies the need by various guidelines to adopt them as second line agents to metformin in managing patients with T2DM.


Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N; IDF Diabetes Atlas Committee. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract 2019; 157: 107843.

Diabetes. World Health Organization: 2020 Diabetes. Available at: Accessed on 08 April 2021.

Colberg SR, Sigal RJ, Fernhall B, Regensteiner JG, Blissmer BJ, Rubin RR, et al.; American College of Sports Medicine; American Diabetes Association. Exercise and Type 2 Diabetes: The American College of Sports Medicine and the American Diabetes Association: Joint Position Statement. Diabetes Care 2010; 33: e147-167.

Ajala O, English P, Pinkney J. Systematic review and meta-analysis of different dietary approaches to the management of Type 2 Diabetes. Am J Clin Nutr 2013; 97: 505-516.

Madden KM. Evidence for the benefit of exercise therapy in patients with type 2 diabetes. Diabetes Metab Syndr Obes 2013; 6: 233-239.

Kalofoutis C, Piperi C, Kalofoutis A, Harris F, Phoenix D, Singh J. Type II diabetes mellitus and cardiovascular risk factors: Current therapeutic approaches. Exp Clin Cardiol 2007; 12: 17-28.

Kannel W, McGee D. Diabetes and glucose tolerance as risk factors for cardiovascular disease: The Framingham study. Diabetes Care 1979; 2: 120–126.

Rosengren A, Hagman M, Wedel H, Wilhelmsen L. Serum cholesterol and long-term prognosis in middle-aged men with myocardial infarction and angina pectoris. A 16-year follow-up of the Primary Prevention Study in Göteborg, Sweden. Eur Heart J 1997; 18: 754-761.

Haffner SM, Lehto S, Rönnemaa T, Pyörälä 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.

Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia 2001; 44 Suppl 2: S14-S21.

Joshi SS, Singh T, Newby DE, Singh J. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure. Heart 2021.

Abdul-Ghani M, DeFronzo RA, Del Prato S, Chilton R, Singh R, Ryder REJ. Cardiovascular Disease and Type 2 Diabetes: Has the Dawn of a New Era Arrived? Diabetes Care 2017; 40: 813-820.

Leon, B. Diabetes and cardiovascular disease: Epidemiology, biological mechanisms, treatment recommendations and future research. World J Diabetes 2015; 6: 1246.

Subramanian S, Hirsch I. Personalised diabetes management: Moving from algorithmic to individualised therapy. Diabetes Spectrum 2014; 27: 87–91.

Kulzer B, Daenschel W, Daenschel I, Schramm W, Messinger D, Weissmann J, et al. Integrated personalised diabetes management improves glycemic control in patients with insulin-treated type 2 diabetes: Results of the PDM-ProValue study program. Diabetes Res Clin Pract 2018; 144: 200-212.

U.S Food and Drug Administration. Endocrinologic and Metabolic Drugs Advisory Committee Meeting 2018. Available at: Accessed 31 March 2021.

Abdul-Ghani M, Jayyous A, Asaad N, Helmy S, Al-Suwaidi J. Pioglitazone and cardiovascular risk in T2DM patients: is it good for all? Ann Transl Med 2018; 6: 192.

Liao HW, Saver JL, Wu YL, Chen TH, Lee M, Ovbiagele B. Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis. BMJ Open 2017; 7: e013927.

Filion KB, Douros A, Azoulay L, Yin H, Yu OH, Suissa S. Sulfonylureas as initial treatment for type 2 diabetes and the risk of adverse cardiovascular events: A population-based cohort study. Br J Clin Pharmacol 2019; 85: 2378-2389.

Phung OJ, Schwartzman E, Allen RW, Engel SS, Rajpathak SN. Sulphonylureas and risk of cardiovascular disease: systematic review and meta-analysis. Diabet Med 2013; 30: 1160-1171. 0.1111/dme.12232

Schernthaner G, Karasik A, Abraitienė A, Ametov AS, Gaàl Z, Gumprecht J, et al. Evidence from routine clinical practice: EMPRISE provides a new perspective on CVOTs. Cardiovasc Diabetol 2019; 18: 115.

Food and Drug Administration. ‘SGLT-2 inhibitors’ 2018. Available at Accessed 31 March 2021.

Bond A. Exenatide (Byetta) as a novel treatment option for type 2 diabetes mellitus. Proc (Bayl Univ Med Cent) 2006; 19: 281-294. https://doi:10.1080/08998280.2006.11928181

Collins L, Costello R. Glucagon-like Peptide-1 Receptor Agonists 2020. Available at: Accessed 08 April 2021.

Kanai Y, Lee WS, You G, Brown D, Hediger MA. The human kidney low-affinity Na+/glucose co-transporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest 1994; 93: 397-404.

Nomura S. Renal Threshold Case Histories in Recent Drug Discovery 2017. Available at: Accessed 10 April 2021.

Hsia DS, Grove O, Cefalu WT. An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol Diabetes Obes 2017; 24: 73-79.

Cornell, S. Mode of action of SGLT2 inhibitors in the kidney. 2015. Available at: Accessed 22 July 2021.

Verma S, McMurray J. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia 2018; 61: 2108–2117.

Lopaschuk G, Verma S. Mechanisms of Cardiovascular Benefits of Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors. JACC Basic Transl Sci 2020; 5: 632-644.

Santos-Gallego CG, Requena-Ibanez JA, San Antonio R. Empagliflozin ameliorates adverse left ventricular remodelling in non-diabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol 2019; 73: 1931–1944.

Iborra-Egea O, Santiago-Vacas E, Yurista SR. Unraveling the molecular mechanism of action of empagliflozin in heart failure with reduced ejection fraction with or without diabetes. J Am Coll Cardiol Basic Trans Science 2019; 4: 831–840.

Chino Y, Samukawa Y, Sakai S. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm Drug Dispos 2014; 35: 391–404.

Nussenzweig SC, Verma S, Finkel T. The role of autophagy in vascular biology. Circ Res 2015; 116: 480–488.

Juni RP, Kuster DWD, Goebel M, Helmes M, musters R, van der Velden J, et al. Cardiac microvascular endothelial enhancement of cardiomyocyte function is impaired by inflammation and restored by empagliflozin. J Am Coll Cardiol Basic Trans Science 2019; 4: 575–591.

Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019; 393: 31-39. Erratum in: Lancet 2019; 393(10166): 30.

Rabizadeh S, Nakhjavani M, Esteghamati A. Cardiovascular and Renal Benefits of SGLT2 Inhibitors: A Narrative Review. Int J Endocrinol Metab 2019; 17: e84353.

Giorgino F, Vora J, Fenici P, Solini A. Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk. Cardiovasc Diabetol 2020; 19: 196.

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015; 373: 2117-2128.

Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu ?? et al.; CANVAS Program Collaborative Group. Canagliflozin, Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377: 644-657.

Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al; DECLARE–TIMI 58 Investigators. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2019; 380: 347-357.

El Mouhayyar C, Riachy R, Khalil AB, Eid A, Azar S. SGLT2 Inhibitors, GLP-1 Agonists, and DPP-4 Inhibitors in Diabetes and Microvascular Complications: A Review. Int J Endocrinol 2020; 2020:1762164.

Batuman V. What is the role of SGLT2 inhibitors in the treatment of diabetic nephropathy? 2019. Available at: Accessed 08 April 2021.

Jardine MJ, Mahaffey KW, Neal B, Agarwal R, Bakris GL, Brenner J, et al. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics. Am J Nephrol 2017; 46: 462-472.

McMurray JJV, DeMets DL, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. A trial to evaluate the effect of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF). Eur J Heart Fail 2019; 21: 665-675.

MacDonald PE, El-Kholy W, Riedel MJ, Salapatek AM, Light PE, Wheeler MB. The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes 2002;51 Suppl 3: S434-S442.

Bonora E, DeFronzo A. Diabetes, Epidemiology, Genetics, Pathogenesis, Diagnosis, Prevention, and Treatment.’ London: Springer Reference 2018.

Iorga RA, Bacalbasa N, Carsote M, Bratu OG, Stanescu AMA, Bungau S, et al. Metabolic and cardiovascular benefits of GLP-1 agonists, besides the hypoglycemic effect (Review). Exp Ther Med 2020;20 : 2396-2400.

Saraiva F, Sposito A. Cardiovascular Effects of Glucagon-like peptide 1 (GLP1) Receptor Agonists. Cardiovasc Diabetol 2014; 13. Available at: Accessed 08 April 2021.

Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab 2018; 27: 740-756.

Wang B, Zhong J, Lin H, Zhao Z, Yan Z, He H, Ni Y, et al. Blood pressure-lowering effects of GLP-1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials. Diabetes Obes Metab 2013; 15: 737-749.

Patel VJ, Joharapurkar AA, Shah GB, Jain MR. Effect of GLP-1 based therapies on diabetic dyslipidemia. Curr Diabetes Rev 2014; 10: 238-250.

Li J, Zheng J, Wang S, Lau HK, Fathi A, Wang Q. Cardiovascular Benefits of Native GLP-1 and its Metabolites: An Indicator for GLP-1-Therapy Strategies. Front Physiol 2017; 8: 15.

Sheahan KH, Wahlberg EA, Gilbert MP. An overview of GLP-1 agonists and recent cardiovascular outcomes trials. Postgrad Med J 2020; 96: 156-161.

Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, et al.; ELIXA Investigators. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med 2015; 373: 2247-2257.

Marso S, Gilbert HD, Brown-Frandsen K, Kristensen P, Johannes FE, Nauck MA, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016; 375: 311-322.

Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, et al.; SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016; 375: 1834-1844.

Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, et al.; EXSCEL Study Group. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2017; 377: 1228-1239.

Hernandez AF, Green JB, Janmohamed S, D'Agostino RB Sr, Granger CB, Jones NP, et al.; Harmony Outcomes committees and investigators. 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: 1519-1529.

Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al.; REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019; 394(10193): 121-130.

Husain M. Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes’, N Engl J Med 2019; 381: 841–851.

Brown-Frandsen K, Emerson SS, McGuire DK, Pieber DR, Poulter NR, Pratley RE, et al. Lower rates of cardiovascular events and mortality associated with liraglutide use in patients treated with basal insulin: A DEVOTE sub-analysis. Diabetes Obes Metab 2019; 21: 1437-1444.