Therapeutic Agents to Manage Diabetes and their Effect on CVD Outcomes
A research summary of the 3 classes of non-insulin, antidiabetic medications for their efficacy in cardiovascular disease in individuals with type 2 diabetes.
October 2016
Volume 7, Issue 3


The advent of a new class of antihyperglycemic agents offers promising new therapies for the treatment of type 2 diabetes (DM2), with particular attention to cardiovascular (CV) outcomes. This review of current literature will provide a valuable assessment for selection of medications to improve overall management of patients with DM2 who are at heightened risk for CV.

Patients with DM2 are at high risk for microvascular complications as well as macrovascular events. In the past, antidiabetic agents were not required to show CV safety. However, in 2007, a meta-analyses of thiazelinediones showed that rosiglitazone was associated with increased cardiovascular mortality.1 In 2008, the US Food and Drug Administration issued a report requiring that new antidiabetic drugs show CV safety with confirmation that no adverse CV events occur as compared to placebo.2

In this EndoScan, we will discuss the results of published CV trials with dipeptidyl-peptidase IV (DPPIV) inhibitors, glucagon-like receptor agonists (GLP-1RA), and sodium-glucose transporter-2 (SGLT2) inhibitors. 

According to the FDA Guidance for diabetes management, CV safety can be demonstrated in different ways.2 One approved method is a metaanalysis, which requires that the upper limit of a two-sided 95% confidence interval of risk ratio with the drug be less than 1.8. Another method is a premarketing application that presents with no increased risk ratio for the drug as compared to placebo. If the upper bound of the 95% confidence interval of the risk ratio is between 1.3 and 1.8, the drug would be approved but would require a post marketing CV safety trial. However, if the upper bound of the 95% confidence interval is less than 1.3, an additional post marketing CV safety trial would not be necessary.

In order to conform to these requirements, several large CV trials have been conducted for the newer antidiabetic medications, which will be discussed in the accompanying research overviews.

The main design of these CV trials has been randomized, double-blinded and powered for non-inferiority of the antidiabetic medications in comparison to placebo for the incidence of CV events. Cardiovascular events have been defined by looking at either 3 or 4 major adverse cardiovascular events (MACE), including mortality, myocardial infarction, stroke with acute coronary syndrome, need for revascularization procedures, and endpoints, such as hospitalization for heart failure. 

In summary, the DPPIV inhibitors did not raise the risk of MACE with the exception of saxagliptin, which revealed an increased risk of hospitalizations for heart failure. The published trials with GLP-1RAs, except lixisenatide, and the only published trial with an SGLT2 inhibitor (EMPA-REG), showed decreased risk for MACE.  


1. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. New Engl J Med. 2007;356(24):2457-2471.

2. Federal Register. Food and Drug Administration Notice on 12/19/2008.  Guidance for Industry on Diabetes Mellitus-Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes; Availability at Accessed September 14, 2016.

First Article:
Cardiovascular Outcomes of GLP-1 Receptor Agonist Therapies
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