Skip to main content
Top

11-15-2016 | Heart failure | Review | Article

Novel Anti-glycemic Drugs and Reduction of Cardiovascular Risk in Diabetes: Expectations Realized, Promises Unmet

Journal: Current Atherosclerosis Reports

Authors: James H. Flory, Jenny K. Ukena, James S. Floyd

Publisher: Springer US

Abstract

Purpose of Review

The purpose is to review evidence on cardiovascular risks and benefits of new treatments for type 2 diabetes mellitus.

Recent Findings

In response to guidance issued by the Food and Drug Administration, thousands of patients have been enrolled in large randomized trials evaluating the cardiovascular effects of the three newest diabetes drug classes: glucagon-like peptide-1 (GLP-1) receptor agonists, sodium glucose cotransporter 2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors. Two studies of GLP-1 receptor agonists—one of liraglutide and one of semaglutide—have shown cardiovascular benefit relative to placebo, and one study of the SGLT-2 inhibitor empagliflozin has shown benefit. The other published cardiovascular outcome studies of the newest drug classes have generally supported safety, apart from an as-yet unresolved safety concern about increased rates of heart failure with DPP-4 inhibitors. Recent research suggests the thiazolidinedione pioglitazone may have beneficial effects on some cardiovascular outcomes as well, but these are counterbalanced by a known increase of the risk of heart failure with this drug. In general, more prospective randomized trial data is now available regarding the cardiovascular effects of the newer diabetes drugs than on the older drug classes.

Summary

New evidence suggests that the newest diabetes drugs are safe from a cardiovascular perspective. Evidence on benefit from at least some members of the GLP-1 receptor agonist and SGLT-2 inhibitor classes is encouraging but not yet decisive.
Literature
1.
Go A, Mozaffarian D, Roger V, et al. Executive summary: heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127(1):143–52.CrossRefPubMed
2.
Standards of Medical Care in Diabetes—2016. Diabetes Care S52–S59.
3.
Hiatt W, Kaul S, Smith R. The cardiovascular safety of diabetes drugs—insights from the rosiglitazone experience. N Engl J Med. 2013;369(14):1285–7.CrossRefPubMed
4.
Smith R, Goldfine A, Hiatt W. Evaluating the cardiovascular safety of new medications for type 2 diabetes: time to reassess? Diabetes Care. 2016;39(5):738–42.CrossRefPubMed
5.
Ingelfinger J, Rosen C. Cardiac and renovascular complications in type 2 diabetes—is there hope? N Engl J Med. 2016;375(4):380–2.CrossRefPubMed
6.
Lipska K, Krumholz H. Comparing diabetes medications: where do we set the bar? JAMA Intern Med. 2014;174(3):317–8.CrossRefPubMed
7.
Association AD. Approaches to glycemic treatment. Sec. 7. In: Standards of medical care in diabetes—2016. Diabetes Care 2016;39 Suppl. 1: S52–S59.
8.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):837–53
9.
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(15):1577–89.CrossRefPubMed
10.
Hong J, Zhang Y, Lai S, et al. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care. 2013;36(5):1304–11.CrossRefPubMedPubMedCentral
11.
Hampp C, Borders-Hemphill V, Moeny D, Wysowski D. Use of antidiabetic drugs in the U.S., 2003–2012. Diabetes Care. 2014;37(5):1367–74.CrossRefPubMed
12.
Nathan D. Diabetes: advances in diagnosis and treatment. JAMA. 2015;314(10):1052–62.CrossRefPubMed
13.
Goldner M, Knatterud G, Prout T. Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. JAMA. 1971;218(9):1400–10.CrossRefPubMed
14.
Hong J, Zhang Y, Lai S, et al. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care. 2013;36(5):1304–11.CrossRefPubMedPubMedCentral
15.
Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013;15(10):938–53.CrossRefPubMed
16.
Phung O, Schwartzman E, Allen R, Engel S, Rajpathak S. Sulfonylureas and risk of cardiovascular disease: systematic review and meta-analysis. Diabet Med. 2013;30(10):1160–71.CrossRefPubMed
17.
Ou S, Shih C, Chao P, et al. Effects on clinical outcomes of adding dipeptidyl peptidase-4 inhibitors versus sulfonylureas to metformin therapy in patients with type 2 diabetes mellitus. Ann Intern Med. 2015;163(9):663–72.CrossRefPubMed
18.
Morgan C, Mukherjee J, Jenkins-Jones S, Holden S, Currie C. Combination therapy with metformin plus sulfonylureas versus metformin plus DPP-4 inhibitors: association with major adverse cardiovascular events and all-cause mortality. Diabetes Obes Metab. 2014;16(10):977–83.CrossRefPubMed
19.
Cryer P. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2013;369(4):362–72.CrossRefPubMed
20.
Wright R, Frier B. Vascular disease and diabetes: is hypoglycemia an aggravating factor? Diabetes Metab Res Rev. 2008;24(5):353–63.CrossRefPubMed
21.
Desouza C, Bolli G, Fonesca V. Hypoglycemia, diabetes, and cardiovascular events. Diabetes Care. 2010;33(6):1389–94.CrossRefPubMedPubMedCentral
22.
Ashcroft F, Gribble F. Tissue-specific effects of sulfonylureas: lessons from studies of cloned K(ATP) channels. J Diabetes Complicat. 2000;14(4):192–6.CrossRefPubMed
23.
Zunkler B. Human ether-a-go-go-related (HERG) gene and ATP-sensitive potassium channels as targets for adverse drug effects. Pharmacol Ther. 2006;112(1):12–37.CrossRefPubMed
24.
Hattersley A, Thorens B. Type 2 diabetes, SGLT2 inhibitors, and glucose secretion. N Engl J Med. 2015;373:974–97.CrossRefPubMed
25.
Brunton S. The potential role of sodium glucose co-transporter 2 inhibitors in the early treatment of type 2 diabetes mellitus. Int J Clin Pract. 2015;69(10):1071–87.CrossRefPubMedPubMedCentral
26.
Inzucchi S, Zinman B, Wanner C, et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12(2):90–100.CrossRefPubMedPubMedCentral
27.
Ceriello A, Genovese S, Mannucci E, Gronda E. Understanding EMPA-REG OUTCOME. Lancet Diabetes Endocrinol. 2015;3(12):929–30.CrossRefPubMed
28.
Mudaliar S, Alloju S, Henry R. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care. 2016;39(7):1115–22.CrossRefPubMed
29.
Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159(4):262–74.CrossRefPubMed
30.
•• Zinman B, Wanner C, Lachin J, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28. Recent cardiovascular outcome study showing evidence of cardiovascular benefit from a new antidiabetic drug.CrossRefPubMed
31.
Perseghin G, Solini A. The EMPA-REG outcome study: critical appraisal and potential clinical implications. Cardiovascular Diabetol 2016;15(85).
32.
Neumiller J. Incretin-based therapies. Med Clin N Am. 2015;99(1):107–29.CrossRefPubMed
33.
Vergès B, Bonnard C, Renard E. Beyond glucose lowering: glucagon-like peptide-1 receptor agonists, body weight and the cardiovascular system. Diabetes Metab. 2011;37(6):477–88.CrossRefPubMed
34.
Poornima I, Brown S, Bhashyam S, Parikh P, Bolukoglu H, Shannon R. Chronic glucagon-like peptide-1 infusion sustains left ventricular systolic function and prolongs survival in the spontaneously hypertensive, heart failure-prone rat. Circ Heart Fail. 2008;1(3):153–60.CrossRefPubMedPubMedCentral
35.
Treiman M, Elvekjaer M, Engstrøm T, Jensen J. Glucagon-like peptide 1—a cardiologic dimension. Trends Cardiovasc Med. 2010;20(1):8–12.CrossRefPubMed
36.
Sokos G, Nikolaidis L, Mankad S, Elahi D, Shannon R. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006;12(9):694–9.CrossRefPubMed
37.
•• Marso S, Daniels G, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22. Recent cardiovascular outcome study showing evidence of cardiovascular benefit from a new antidiabetic drug.CrossRefPubMed
38.
•• Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016. Recent cardiovascular outcome study showing evidence of cardiovascular benefit from a new antidiabetic drug.
39.
Pfeffer M, 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.CrossRefPubMed
40.
Ban K, Noyan-Ashraf M, Hoefer J, Bolz S, Drucker D, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 2008;117(18):2340–50.CrossRefPubMed
41.
White W, Cannon C, Heller S, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327–35.CrossRefPubMed
42.
Green J, Bethel M, Armstrong P, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232–42.CrossRefPubMed
43.
Scirica B, Bhatt D, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26.CrossRefPubMed
44.
Maruther N, Tseng E, Hutfless S, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2016;164(11):740–51.CrossRef
45.
Gilbert R, Krum H. Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy. Lancet. 2015;385(9982):2107–17.CrossRefPubMed
46.
Filion K, Azoulay L, Platt R, et al. A multicenter observational study of incretin-based drugs and heart failure. N Engl J Med. 2016;374(12):1145–54.CrossRefPubMed
47.
Morgan C, Mukherjee J, Jenkins-Jones S, Holden S, Currie C. Combination therapy with metformin plus sulphonylureas versus metformin plus DPP-4 inhibitors: association with major adverse cardiovascular events and all-cause mortality. Diabetes Obes Metab. 2014;16(10):977–83.CrossRefPubMed
48.
Kahn C, Chen L, Cohen S. Unraveling the mechanism of action thiazolidinediones. J Clin Invest. 2000;106(11):1305–7.CrossRefPubMedPubMedCentral
49.
Nissen S, 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.CrossRefPubMed
50.
Home P, Pocock S, 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.CrossRefPubMed
51.
Psaty B, Furberg C. The record on rosiglitazone and the risk of myocardial infarction. N Engl J Med. 2007;357(1):67–9.CrossRefPubMed
52.
Psaty B, Prentice R. Variation in event rates in trials of patients with type 2 diabetes. JAMA. 2009;302(15):1698–700.CrossRefPubMed
53.
Dormandy J, Charbonnel B, Eckland D, 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 randomized controlled trial. Lancet. 2005;366(9493):1279–89.CrossRefPubMed
54.
Erdmann E, Charbonnel B, Wilcox R, et al. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08). Diabetes Care. 2007;30(11):2773–8.CrossRefPubMed
55.
Kernan W, Viscoli C, Furie K, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374(14):1321–31.CrossRefPubMedPubMedCentral
56.
Tahrani A, Barnett A, Bailey C. Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat Rev Endocrinol. 2016;12(10):566–92.CrossRefPubMed
58.
Floyd J, Wiggins K, Sitlani C, et al. Case–control study of second-line therapies for type 2 diabetes in combination with metformin and the comparative risks of myocardial infarction and stroke. Diabetes Obes Metab. 2015;17(12):1194–7.CrossRefPubMed

Be confident that your patient care is up to date

Medicine Matters is being incorporated into Springer Medicine, our new medical education platform. 

Alongside the news coverage and expert commentary you have come to expect from Medicine Matters diabetes, Springer Medicine's complimentary membership also provides access to articles from renowned journals and a broad range of Continuing Medical Education programs. Create your free account »