Considering Cardiovascular Risks of Antidiabetic Drugs

The SGLT₂ inhibitor dapagliflozin has similarly been shown to reduce several of these CV risk factors, while showing no increased risk of adverse CV outcomes, according to a 2014 review from the Ochsner Journal that explored the CV risk associated with various antidiabetic medications.¹ The authors noted that metformin is generally the first-line therapy for type 2 diabetes treatment because, in addition to having an extensive history of use, low cost, and effectiveness in reducing glucose, it is “ weight neutral and may improve blood pressure and lipid parameters.” Additonally, the data “for CV benefits with metformin are encouraging, with studies showing reductions in any diabetes-related end point, diabetes-related death, and all-cause mortality.”¹

Treatment with sulfonylurea has been associated with increased risk of CVD and mortality, especially compared with metformin, though such risk appears to be lower with the second-generation sulfonylurea gliclazide vs the first-generation tolbutamide. “Proposed mechanisms for adverse cardiac effects include the effect of sulfonylureas on ATP-dependent potassium channels on cardiac cells, resulting in hyperpolarization and inadequate coronary vasodilation and in a larger area of myocardial damage at the time of acute MI,” the review authors wrote, concluding that “sulfonylurea monotherapy may not be appropriate for patients with diabetes who are at risk for CVD.”¹

CV risk associated with meglitinides and thiazolidinediones is unclear, based on currently available data, though the latter is not recommended for older patients with a high risk of congestive heart conditions.¹ Incretins, such as the glucagon-like peptide 1 (GLP-1) agonist liraglutide^1,4, and dipeptidyl peptidase 4 (DPP-4) inhibitors^1,5 have been associated with promising results pertaining to CV risk.

While further research is needed to clarify their long-term effects, “second-line therapy consisting of AGIs [alpha-glucosidase inhibitors] or other agents in combination with either metformin or insulin may provide beneficial CV effects,” according to the Oschner Journal review.

Treatment of type 2 diabetes should “be adjusted on an individual basis based on age, duration of diabetes, risk for CVD, and presence of microvascular and macrovascular complications,” according to the review authors.¹

Considering the high prevalence of CV problems in patients with diabetes, treatment should be aimed at reducing these risks in addition to reducing HgA1c and glucose levels.¹

References

1. Azimova K, San Juan Z, Mukherjee D. Cardiovascular safety profile of currently available diabetic drugs. Ochsner J. 2014;14(4): 616–632.
2. Guidance for industry: Diabetes mellitus—Evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring, MD: US Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research; December 2008. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf. Accessed December 23, 2015.
3. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J  Med. 2015. doi: 10.1056/NEJMoa1504720.
4. Gejl M, Starup-Linde J, Scheel-Thomsen J, Gregersen S, Vestergaard P. Risk of cardiovascular disease: the effects of diabetes and anti-diabetic drugs – a nested case-control study. Int J Cardiol. 2015;178:292-296. 
5. Fisman EZ, Tenenbaum A. Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes. Cardiovasc Diabetol. 2015;14:129.