Applied Evidence

How to use type 2 diabetes meds to lower CV disease risk

Department of Family Medicine, University of Toledo College of Medicine, Ohio
[email protected]

The authors reported no potential conflict of interest relevant to this article.

The author has lectured on behalf of Pfizer and Kos/Abbott. He has participated in clinical trials for Bristol-Myers Squibb, Novo Nordisk, AstraZeneca, KOS/Abbott, Novartis, and Janssen. He has wholly declined compensation from pharmaceutical and medical device manufacturers.

The challenge: Translate evidence from cardiovascular outcomes trials of newer antidiabetic agents into a targeted management strategy.


› Consider American Diabetes Association (ADA) guidance and prescribe a sodium–glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide- 1 (GLP-1) receptor agonist that has demonstrated cardiovascular (CV) disease benefit for your patients who have type 2 diabetes (T2D) and established atherosclerotic CV disease. A

› Consider ADA’s recommendation for preferred therapy and prescribe an SGLT-2 inhibitor for your patients with T2D who have atherosclerotic CV disease and are at high risk of heart failure or in whom heart failure coexists. C

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series



The association between type 2 diabetes (T2D) and cardiovascular (CV) disease is well-established:

  • Type 2 diabetes approximately doubles the risk of coronary artery disease, stroke, and peripheral arterial disease, independent of conventional risk factors1
  • CV disease is the leading cause of morbidity and mortality in patients with T2D
  • CV disease is the largest contributor to direct and indirect costs of the health care of patients who have T2D.2

In recent years, new classes of agents for treating T2D have been introduced (TABLE 1). Prior to 2008, the US Food and Drug Administration (FDA) approved drugs in those new classes based simply on their effectiveness in reducing the blood glucose level. Concerns about the CV safety of specific drugs (eg, rosiglitazone, muraglitazar) emerged from a number of trials, suggesting that these agents might increase the risk of CV events.3,4

Newer agents for treating type 2 diabetes

All glucose-lowering medications used to treat type 2 diabetes are not equally effective in reducing CV complications.

Consequently, in 2008, the FDA issued guidance to the pharmaceutical industry: Preapproval and postapproval trials of all new antidiabetic drugs must now assess potential excess CV risk.5 CV outcomes trials (CVOTs), performed in accordance with FDA guidelines, have therefore become the focus of evaluating novel treatment options. In most CVOTs, combined primary CV endpoints have included CV mortality, nonfatal myocardial infarction (MI), and nonfatal stroke—taken together, what is known as the composite of these 3 major adverse CV events, or MACE-3.

To date, 15 CVOTs have been completed, assessing 3 novel classes of antihyperglycemic agents:

  • dipeptidyl peptidase-4 (DPP-4) inhibitors
  • glucagon-like peptide-1 (GLP-1) receptor agonists
  • sodium–glucose cotransporter-2 (SGLT-2) inhibitors.

None of these trials identified any increased incidence of MACE; 7 found CV benefit. This review summarizes what the CVOTs revealed about these antihyperglycemic agents and their ability to yield a reduction in MACE and a decrease in all-cause mortality in patients with T2D and elevated CV disease risk. Armed with this information, you will have the tools you need to offer patients with T2D CV benefit while managing their primary disease.

Cardiovascular outcomes trials: DPP-4 inhibitors

Four trials. Trials of DPP-4 inhibitors that have been completed and reported are of saxagliptin (SAVOR-TIMI 536), alogliptin (EXAMINE7), sitagliptin (TECOS8), and linagliptin (CARMELINA9); others are in progress. In general, researchers enrolled patients at high risk of CV events, although inclusion criteria varied substantially. Consistently, these studies demonstrated that DPP-4 inhibition neither increased nor decreased (ie, were noninferior) the 3-point MACE (SAVOR-TIMI 53 noninferiority, P < .001; EXAMINE, P < .001; TECOS, P < .001).

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