Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Current Atherosclerosis Reports
Published in: Current Atherosclerosis Reports 12/2016

01-12-2016 | Clinical Trials and Their Interpretations (J. Kizer, Section Editor)

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

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

Published in: Current Atherosclerosis Reports | Issue 12/2016

Login to get access

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.
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.
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.
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.
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.
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
57.
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
Metadata
Title
Novel Anti-glycemic Drugs and Reduction of Cardiovascular Risk in Diabetes: Expectations Realized, Promises Unmet
Authors
James H. Flory
Jenny K. Ukena
James S. Floyd
Publication date
01-12-2016
Publisher
Springer US
Published in
Current Atherosclerosis Reports / Issue 12/2016
Print ISSN: 1523-3804
Electronic ISSN: 1534-6242
DOI
https://doi.org/10.1007/s11883-016-0633-y

Other articles of this Issue 12/2016

Current Atherosclerosis Reports 12/2016 Go to the issue

Women and Ischemic Heart Disease (E. Jackson, Section Editor)

Aspirin Use in Women: Current Perspectives and Future Directions

Nutrition (A. Garg, Section Editor)

Lipid Lowering with Soluble Dietary Fiber

Genetics (A. Marian, Section Editor)

Transcriptomic Signature of Atherosclerosis in the Peripheral Blood: Fact or Fiction?

Cardiovascular Disease and Stroke (S. Prabhakaran, Section Editor)

Threshold and Target for Blood Pressure Lowering in the Elderly

Clinical Trials and Their Interpretations (J. Kizer, Section Editor)

Emerging Therapeutic Options for Lowering of Lipoprotein(a): Implications for Prevention of Cardiovascular Disease

Clinical Trials and Their Interpretations (J. Kizer, Section Editor)

Surgical Versus Endovascular Aortic Aneurysm Repair: Evidence to Guide the Optimal Approach for the Individual Patient
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits